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Bibliography on: The Denisovans, Another Human Ancestor

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The Denisovans, Another Human Ancestor

Wikipedia: The Denisovans are an extinct species or subspecies of human in the genus Homo. In March 2010, scientists announced the discovery of a finger bone fragment of a juvenile female who lived about 41,000 years ago, found in the remote Denisova Cave in the Altai Mountains in Siberia, a cave that has also been inhabited by Neanderthals and modern humans. Two teeth belonging to different members of the same population have since been reported. In November 2015, a tooth fossil containing DNA was reported to have been found and studied. A bone needle dated to 50,000 years ago was discovered at the archaeological site in 2016 and is described as the most ancient needle known. Analysis of the mitochondrial DNA (mtDNA) of the finger bone showed it to be genetically distinct from the mtDNAs of Neanderthals and modern humans. Subsequent study of the nuclear genome from this specimen suggests that Denisovans shared a common origin with Neanderthals, that they ranged from Siberia to Southeast Asia, and that they lived among and interbred with the ancestors of some modern humans. A comparison with the genome of a Neanderthal from the same cave revealed significant local interbreeding with local Neanderthal DNA representing 17% of the Denisovan genome, while evidence was also detected of interbreeding with an as yet unidentified ancient human lineage.

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Citations The Papers (from PubMed®)

RevDate: 2018-08-04

Helsen CW, Hammill JA, Lau VWC, et al (2018)

The chimeric TAC receptor co-opts the T cell receptor yielding robust anti-tumor activity without toxicity.

Nature communications, 9(1):3049 pii:10.1038/s41467-018-05395-y.

Engineering T cells with chimeric antigen receptors (CARs) is an effective method for directing T cells to attack tumors, but may cause adverse side effects such as the potentially lethal cytokine release syndrome. Here the authors show that the T cell antigen coupler (TAC), a chimeric receptor that co-opts the endogenous TCR, induces more efficient anti-tumor responses and reduced toxicity when compared with past-generation CARs. TAC-engineered T cells induce robust and antigen-specific cytokine production and cytotoxicity in vitro, and strong anti-tumor activity in a variety of xenograft models including solid and liquid tumors. In a solid tumor model, TAC-T cells outperform CD28-based CAR-T cells with increased anti-tumor efficacy, reduced toxicity, and faster tumor infiltration. Intratumoral TAC-T cells are enriched for Ki-67+ CD8+ T cells, demonstrating local expansion. These results indicate that TAC-T cells may have a superior therapeutic index relative to CAR-T cells.

RevDate: 2018-08-01

Morgunov LY, Denisova IA, Rozhkova TI, et al (2018)

Hypogonadism and its treatment following ischaemic stroke in men with type 2 diabetes mellitus.

The aging male : the official journal of the International Society for the Study of the Aging Male [Epub ahead of print].

Premature mortality in Russia is a major socio-economic problem, especially from acute cerebrovascular diseases which constitute 21.4% of the total mortality and is a considerable contributor to chronic disability. Risk of vascular catastrophe is higher in males than females, thought, in part, due to anti-atherosclerotic effects of oestrogens in females whilst an associated age-related deficiency of testosterone is observed in men. Clinical symptoms such as high blood pressure, changes in lipid profile, insulin resistance, obesity, and blood coagulation factors often accompany declining testosterone in males and reduced total testosterone is considered a cardiovascular risk factor. In the present study, the prevalence of hypogonadism in men who had suffered ischaemic stroke was evaluated along with the efficacy of testosterone undecanoate injections (TU) in patients with testosterone deficiency and type-2 diabetes (T2DM) in the acute phase of hemispheric ischaemic stroke. Hypogonadism was present in 66.3% of patients with ischaemic stroke, 50% with T2DM, and 26.3% without T2DM, respectively. TU treatment, at both the 2 and 5-year observation points, demonstrated significant improvements in biochemical, physical, and mental parameters. This supports that testosterone deficiency is a contributing factor in ischaemic events and that long-term testosterone therapy could play an important role in patient recovery.

RevDate: 2018-07-19

Dolgova O, O Lao (2018)

Evolutionary and Medical Consequences of Archaic Introgression into Modern Human Genomes.

Genes, 9(7): pii:genes9070358.

The demographic history of anatomically modern humans (AMH) involves multiple migration events, population extinctions and genetic adaptations. As genome-wide data from complete genome sequencing becomes increasingly abundant and available even from extinct hominins, new insights of the evolutionary history of our species are discovered. It is currently known that AMH interbred with archaic hominins once they left the African continent. Current non-African human genomes carry fragments of archaic origin. This review focuses on the fitness consequences of archaic interbreeding in current human populations. We discuss new insights and challenges that researchers face when interpreting the potential impact of introgression on fitness and testing hypotheses about the role of selection within the context of health and disease.

RevDate: 2018-07-16

Denisova K (2018)

Neurobiology, not artifacts: Challenges and guidelines for imaging the high risk infant.

NeuroImage pii:S1053-8119(18)30638-4 [Epub ahead of print].

The search for the brain-basis of atypical development in human infants is challenging because the process of imaging and the generation of the MR signal itself relies on assumptions that reflect biophysical properties of the brain tissue. These assumptions are not inviolate, have been questioned by recent empirical evidence from high risk infant-sibling studies, and to date remain largely under-examined at the between-group level. In particular, I consider recent work showing that infants at High vs. Low familial risk (HR vs. LR, respectively) for developing Autism Spectrum Disorders (ASD) have atypical patterns of head movements during an MR scan that are functionally important-they are linked to future learning trajectories in toddlerhood. Addressing head movement issues in neuroimaging analyses in infant research as well as understanding the causes of these movements from a developmental perspective requires acknowledging the complexity of this endeavor. For example, head movement signatures in infants can interact with experimental task conditions (such as listening to language compared to sleeping), autism risk, and age. How can new knowledge about newborns' individual, subject-specific behavioral differences which may impact MR signal acquisition and statistical inference ignite critical thinking for the field of infant brain imaging across the spectrum of typical and atypical development? Early behavioral differences between HR and LR infant cohorts that are often examples of "artifactual" confounds in MR work provide insight into nascent neurobiological differences, including biophysical tissue properties and hemodynamic response variability, in these and related populations at risk for atypical development. Are these neurobiological drivers of atypical development? This work identifies important knowledge gaps and suggests guidelines at the leading edge of baby imaging science to transform our understanding of atypical brain development in humans. The precise study of the neurobiological underpinnings of atypical development in humans calls for approaches including quantitative MRI (qMRI) pulse sequences, multi-modal imaging (including DTI, MRS, as well as MEG), and infant-specific HRF shapes when modeling BOLD signal.

RevDate: 2018-07-13

Raevis JJ, Denisova K, Mechel E, et al (2018)


Retinal cases & brief reports [Epub ahead of print].

BACKGROUND/PURPOSE: Report a case of markedly asymmetric retinal tessellations and propose mosaicism as a mechanism.

METHODS AND RESULTS: A 59-year-old pseudophakic woman presented with uncorrected 20/20 vision and was found to have markedly different retinal tessellation appearances in both eyes. The axial lengths were 25.66 mm and 25.88 mm in the right and left eyes, respectively, and no significant asymmetrical choroidal thinning was seen on optical coherence tomography or optical coherence tomography angiography. Fluorescein angiogram showed significant hyperfluorescence, representing the underlying choroid, which correlated with the tessellation patterns in the left eye. She had no other ocular or systemic findings such as stripes or whorled skin.

CONCLUSION: This is the first reported case of markedly asymmetric retinal tessellation patterns that are not due to asymmetric axial myopia or choroidal thinning. We propose that mosaicism is a possible mechanism causing this finding.

RevDate: 2018-07-20

Zhao G, Walsh K, Long J, et al (2018)

Reduced structural complexity of the right cerebellar cortex in male children with autism spectrum disorder.

PloS one, 13(7):e0196964 pii:PONE-D-17-23324.

The cerebellum contains 80% of all neurons in the human brain and contributes prominently to implicit learning and predictive processing across motor, sensory, and cognitive domains. As morphological features of the cerebellum in atypically developing individuals remain unexplored in-vivo, this is the first study to use high-resolution 3D fractal analysis to estimate fractal dimension (FD), a measure of structural complexity of an object, of the left and right cerebellar cortex (automatically segmented from Magnetic Resonance Images using FreeSurfer), in male children with Autism Spectrum Disorders (ASD) (N = 20; mean age: 8.8 years old, range: 7.13-10.27) and sex, age, verbal-IQ, and cerebellar volume-matched typically developing (TD) boys (N = 18; mean age: 8.9 years old, range: 6.47-10.52). We focus on an age range within the 'middle and late childhood' period of brain development, between 6 and 12 years. A Mann-Whitney U test revealed a significant reduction in the FD of the right cerebellar cortex in ASD relative to TD boys (P = 0.0063, Bonferroni-corrected), indicating flatter and less regular surface protrusions in ASD relative to TD males. Consistent with the prediction that the cerebellum participates in implicit learning, those ASD boys with a higher (vs. lower) PIQ>VIQ difference showed higher, more normative complexity values, closer to TD children, providing new insight on our understanding of the neurological basis of differences in verbal and performance cognitive abilities that often characterize individuals with ASD.

RevDate: 2018-06-27

Malyarchuk B, Derenko M, Denisova G, et al (2018)

Whole mitochondrial genome diversity in two Hungarian populations.

Molecular genetics and genomics : MGG pii:10.1007/s00438-018-1458-x [Epub ahead of print].

Complete mitochondrial genomics is an effective tool for studying the demographic history of human populations, but there is still a deficit of mitogenomic data in European populations. In this paper, we present results of study of variability of 80 complete mitochondrial genomes in two Hungarian populations from eastern part of Hungary (Szeged and Debrecen areas). The genetic diversity of Hungarian mitogenomes is remarkably high, reaching 99.9% in a combined sample. According to the analysis of molecular variance (AMOVA), European populations showed a low, but statistically significant level of between-population differentiation (Fst = 0.61%, p = 0), and two Hungarian populations demonstrate lack of between-population differences. Phylogeographic analysis allowed us to identify 71 different mtDNA sub-clades in Hungarians, sixteen of which are novel. Analysis of ancestry-informative mtDNA sub-clades revealed a complex genetic structure associated with the genetic impact of populations from different parts of Eurasia, though the contribution from European populations is the most pronounced. At least 8% of ancestry-informative haplotypes found in Hungarians demonstrate similarity with East and West Slavic populations (sub-clades H1c23a, H2a1c1, J2b1a6, T2b25a1, U4a2e, K1c1j, and I1a1c), while the influence of Siberian populations is not so noticeable (sub-clades A12a, C4a1a, and probably U4b1a4).

RevDate: 2018-06-21

Rzaev DA, Denisova NP, Moisak GI, et al (2018)

[Experience of the use of gasserian ganglion balloon compression in patients with trigeminal neuralgia associated with multiple sclerosis].

Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova, 118(5):30-35.

AIM: To evaluate the efficacy of gasserian ganglion balloon compression in patients with trigeminal neuralgia associated with multiple sclerosis (MS).

MATERIAL AND METHODS: Eight patients (3 men, 5 women), aged from 46 to 66 years (mean age 55 years), with trigeminal neuralgia associated with MS underwent surgery. An average duration of the pain syndrome was 8,4 years. Six patients had previous surgeries due to facial pain. Percutaneous balloon compression of gasserian ganglion was performed to all patients. Follow up period was from 2 to 24 months.

RESULTS: Six patients (75%) reported 100% of pain relief right after the surgery, 2 patients (25%) reported a significant decrease of pain (2-3 points on VAS). Pain recurrence occurred in 3 patients: in 4 months, in 12 months and in 6 months. All of them were operated repeatedly. After the surgery, hypoesthesia on the side of surgery was observed in all patients with a trend towards regression. There was no keratopathy or any complications.

CONCLUSION: Percutaneous balloon compression of gasserian ganglion is an effective and minimally invasive method which can be performed repeatedly in patients with trigeminal neuralgia associated with MS.

RevDate: 2018-06-28

Cserhati MF, Mooter ME, Peterson L, et al (2018)

Motifome comparison between modern human, Neanderthal and Denisovan.

BMC genomics, 19(1):472 pii:10.1186/s12864-018-4710-1.

BACKGROUND: The availability of the genomes of two archaic humans, Neanderthal and Denisovan, and that of modern humans provides researchers an opportunity to investigate genetic differences between these three subspecies on a genome-wide scale. Here we describe an algorithm that predicts statistically significant motifs based on the difference between a given motif's actual and expected distributions. The algorithm was previously applied to plants but was modified for this work.

RESULTS: The result of applying the algorithm to the human, Neanderthal, and Denisovan genomes is a catalog of potential regulatory motifs in these three human subspecies. We examined the distributions of these motifs in genetic elements including human retroviruses, human accelerated regions, and human accelerated conserved noncoding sequences regions. Differences in these distributions could be the origin of differences in phenotype between the three subspecies. Twenty significant motifs common to all three genomes were found; thirty-three were found in endogenous retroviruses in Neanderthal and Denisovan. Ten of these motifs mapped to the 22 bp core of MiR-1304. The core of this genetic element regulates the ENAM and AMTN genes, which take part in odontogenesis and whose 3' UTRs contained significant motifs. The introns of 20 genes were found to contain a large number of significant motifs, which were also overrepresented in 49 human accelerated regions. These genes include NAV2, SorCS2, TRAPPC9, GRID1, PRDM16, CAMTA1, and ASIC which are all involved in neuroregulation. Further analysis of these genes using the GO database indicates that many are associated with neurodevelopment. Also, varying numbers of significant motifs were found to occur in regions of the Neanderthal and Denisovan genomes that are missing from the human genome, suggesting further functional differences between modern and archaic humans.

CONCLUSION: Although Neanderthal and Denisovan are now extinct, detailed examination of elements from their genomes can shed light on possible phenotypic and cognitive differences between these two archaic human subspecies and modern humans. Genetic similarities and differences between these three subspecies and other fossil hominids would also be of interest.

RevDate: 2018-05-15

Banerjee N, Polushina T, Bettella F, et al (2018)

Recently evolved human-specific methylated regions are enriched in schizophrenia signals.

BMC evolutionary biology, 18(1):63 pii:10.1186/s12862-018-1177-2.

BACKGROUND: One explanation for the persistence of schizophrenia despite the reduced fertility of patients is that it is a by-product of recent human evolution. This hypothesis is supported by evidence suggesting that recently-evolved genomic regions in humans are involved in the genetic risk for schizophrenia. Using summary statistics from genome-wide association studies (GWAS) of schizophrenia and 11 other phenotypes, we tested for enrichment of association with GWAS traits in regions that have undergone methylation changes in the human lineage compared to Neanderthals and Denisovans, i.e. human-specific differentially methylated regions (DMRs). We used analytical tools that evaluate polygenic enrichment of a subset of genomic variants against all variants.

RESULTS: Schizophrenia was the only trait in which DMR SNPs showed clear enrichment of association that passed the genome-wide significance threshold. The enrichment was not observed for Neanderthal or Denisovan DMRs. The enrichment seen in human DMRs is comparable to that for genomic regions tagged by Neanderthal Selective Sweep markers, and stronger than that for Human Accelerated Regions. The enrichment survives multiple testing performed through permutation (n = 10,000) and bootstrapping (n = 5000) in INRICH (p < 0.01). Some enrichment of association with height was observed at the gene level.

CONCLUSIONS: Regions where DNA methylation modifications have changed during recent human evolution show enrichment of association with schizophrenia and possibly with height. Our study further supports the hypothesis that genetic variants conferring risk of schizophrenia co-occur in genomic regions that have changed as the human species evolved. Since methylation is an epigenetic mark, potentially mediated by environmental changes, our results also suggest that interaction with the environment might have contributed to that association.

RevDate: 2018-05-09

Akkuratov EE, Gelfand MS, EE Khrameeva (2018)

Neanderthal and Denisovan ancestry in Papuans: A functional study.

Journal of bioinformatics and computational biology, 16(2):1840011.

Sequencing of complete nuclear genomes of Neanderthal and Denisovan stimulated studies about their relationship with modern humans demonstrating, in particular, that DNA alleles from both Neanderthal and Denisovan genomes are present in genomes of modern humans. The Papuan genome is a unique object because it contains both Neanderthal and Denisovan alleles. Here, we have shown that the Papuan genomes contain different gene functional groups inherited from each of the ancient people. The Papuan genomes demonstrate a relative prevalence of Neanderthal alleles in genes responsible for the regulation of transcription and neurogenesis. The enrichment of specific functional groups with Denisovan alleles is less pronounced; these groups are responsible for bone and tissue remodeling. This analysis shows that introgression of alleles from Neanderthals and Denisovans to Papuans occurred independently and retention of these alleles may carry specific adaptive advantages.

RevDate: 2018-06-05
CmpDate: 2018-06-05

Shkliaev AE, Denisova NI, IV Kulikov (2018)

[Splenic artery aneurysm masked by postcholecystectomy syndrome].

Angiologiia i sosudistaia khirurgiia = Angiology and vascular surgery, 24(1):175-178.

Visceral artery aneurysms appear to belong to uncommon and potentially lethal vascular diseases. They are usually revealed accidentally during an ultrasonographic examination, magnetic resonance imaging, or computed tomography. Described in the article is a clinical case report concerning a sacciform aneurysm of the splenic artery, detected in a 53-year-old woman presenting with postcholecystectomy syndrome and followed up for abdominalgia by therapeutists and gastroenterologists. Timely performed radiodiagnosis (including multispiral computed tomography and angiography of the abdominal vessels) made it possible not only to detect the aneurysm, having thus verified the volumetric formation previously found on ultrasonographic examination, but to take adequate measures aimed at preventing rupture of the aneurysm and consisting in endovascular occlusion of the aneurysmatic cavity with metal spirals. Lack of complete clarity in the understanding of the mechanisms of the origin of and no distinctly defined therapeutic-and-diagnostic algorithm for visceral artery aneurysms dictate the necessity to continue collecting and generalizing clinical case reports regarding this rarely encountered vascular pathology.

RevDate: 2018-04-18

Bogomolov DV, Fetisov VA, Denisova OP, et al (2018)

[The principal and auxiliary immunohistochemical markers of intravital mechanical strangulation asphyxia].

Sudebno-meditsinskaia ekspertiza, 61(2):11-13.

The objective of the present study was the evaluation of the auxiliary methods for the diagnostics of the intravital formation of the constriction marks; the secondary objective was to determine the pace at which the death and asphyxia occur.

MATERIAL AND METHODS: The materials on which the study was based included 17 cases of mechanical strangulation asphyxia involving 13 men and 4 women at the age from 8 to 28 years. All cases of hanging were associated with different blood alcohol levels. Their characteristic feature was the formation of the obliquely ascending constriction marks. The group of comparison was comprised of three cases of death by drowning and one case of manual strangulation. The control group consisted of 10 patients who died from the acute form of coronary heart disease and 5 cases of death from traumatic shock. All the corpses were examined with the use of the traditional methods within the first 24 hours after death. The special laboratory studies were performed by means of the standard histological and immunohistochemical methods with the use of the polyclonal antibodies against total cytokeratin, fibrinogen, immunoglobulin-lambda, fibronectin, and CD-117 antigen. The histological preparations were stained by the method of Spielmeyer and with toluidine blue.

RESULTS: The results of the study give evidence of the possibility of diagnostics of mechanical strangulation asphyxia making use of the reaction with anti-fibrinogen antibodies in the stromal tissue of the constriction mark even in the absence of other intravital signs of death. Such diagnostics is also possible with the use of the CD-117 antigen in the pulmonary tissue. The expression of this antigen is characteristic of the cases of alveolar hypoxia. The possibility of application of other markers for the differential diagnostics of mechanical strangulation asphyxia from other causes of death is discussed.

RevDate: 2018-05-04

Khabarova EA, Denisova NP, Dmitriev AB, et al (2018)

Deep Brain Stimulation of the Subthalamic Nucleus in Patients with Parkinson Disease with Prior Pallidotomy or Thalamotomy.

Brain sciences, 8(4): pii:brainsci8040066.

Objective. To evaluate the efficacy of deep brain stimulation of the subthalamic nucleus (STN DBS) in patients with Parkinson disease (PD) who previously underwent lesioning of the basal ganglia. Material and methods. The study included 22 patients who underwent STN DBS. Eleven patients had undergone prior unilateral pallidotomy (n = 6) or VL/VIM thalamotomy (n = 5) while the other 11 patients had not. The primary outcome was the change from baseline in the motor subscore of the Unified Parkinson Disease Rating Scale (UPDRS-III) 12 months after STN DBS. Secondary outcomes included change in motor response complications (UPDRS-IV) and change in levodopa equivalent daily dose (LEDD). Results. In the group with prior lesioning UPDRS-III improved by 45%, from 51.5 &plusmn; 9.0% (range, 35&ndash;65) to 26.5 &plusmn; 8.4 (range, 21&ndash;50) (p < 0.01) and UPDRS-IV by 75%, from 8.0 &plusmn; 2.01 (range, 5&ndash;11) to 2.1 &plusmn; 0.74 (range, 1&ndash;3) (p < 0.01). In the group without prior lesioning UPDRS-III improved by 61%, from 74.2% &plusmn; 7.32 (range, 63&ndash;82) to 29.3 &plusmn; 5.99 (range, 20&ndash;42) (p < 0.01) and UPDRS-IV by 77%, from 9.1 &plusmn; 2.46 (range, 5&ndash;12) to 2.0 &plusmn; 1.1 (range, 1&ndash;4) (p < 0.01). Comparing the two groups (with and without lesioning) no significant differences were found either in UPDRS-III (p > 0.05) or UPDRS-IV scores (p > 0.05) at 12 months post-DBS. The LEDD was reduced by 51.4%, from 1008.2 &plusmn; 346.4 to 490.0 &plusmn; 194.3 in those with prior surgery (p < 0.01) and by 55.0%, from 963.4 &plusmn; 96.2 to 433.3 &plusmn; 160.2 in those without (p < 0.01).UPDRS-III improved by 51.8%, from 53.7 &plusmn; 4.6 (range, 50&ndash;62) to 25.0 &plusmn; 3.8 (range, 21&ndash;31) in those with prior pallidotomy (p < 0.01), and by 37.5%, from 48.8 &plusmn; 12.6 (range, 35&ndash;65) to 29.8 &plusmn; 13.6 (range, 22&ndash;50) in those with prior thalamotomy (p < 0.01). This numerical difference in improvement was not statistically significant (p > 0.05). Conclusion. Our comparative study indicates that bilateral STN DBS is effective and can be used in patients with Parkinson disease with prior unilateral stereotactic destructive operations on subcortical structures. The results in our patient cohort are generally consistent with previously published reports of smaller series from multiple centers worldwide.

RevDate: 2018-04-25

Viscardi LH, Paixão-Côrtes VR, Comas D, et al (2018)

Searching for ancient balanced polymorphisms shared between Neanderthals and Modern Humans.

Genetics and molecular biology, 41(1):67-81.

Hominin evolution is characterized by adaptive solutions often rooted in behavioral and cognitive changes. If balancing selection had an important and long-lasting impact on the evolution of these traits, it can be hypothesized that genes associated with them should carry an excess of shared polymorphisms (trans- SNPs) across recent Homo species. In this study, we investigate the role of balancing selection in human evolution using available exomes from modern (Homo sapiens) and archaic humans (H. neanderthalensis and Denisovan) for an excess of trans-SNP in two gene sets: one associated with the immune system (IMMS) and another one with behavioral system (BEHS). We identified a significant excess of trans-SNPs in IMMS (N=547), of which six of these located within genes previously associated with schizophrenia. No excess of trans-SNPs was found in BEHS, but five genes in this system harbor potential signals for balancing selection and are associated with psychiatric or neurodevelopmental disorders. Our approach evidenced recent Homo trans-SNPs that have been previously implicated in psychiatric diseases such as schizophrenia, suggesting that a genetic repertoire common to the immune and behavioral systems could have been maintained by balancing selection starting before the split between archaic and modern humans.

RevDate: 2018-06-07

Zehra R, AA Abbasi (2018)

Homo sapiens-Specific Binding Site Variants within Brain Exclusive Enhancers Are Subject to Accelerated Divergence across Human Population.

Genome biology and evolution, 10(3):956-966.

Empirical assessments of human accelerated noncoding DNA frgaments have delineated presence of many cis-regulatory elements. Enhancers make up an important category of such accelerated cis-regulatory elements that efficiently control the spatiotemporal expression of many developmental genes. Establishing plausible reasons for accelerated enhancer sequence divergence in Homo sapiens has been termed significant in various previously published studies. This acceleration by including closely related primates and archaic human data has the potential to open up evolutionary avenues for deducing present-day brain structure. This study relied on empirically confirmed brain exclusive enhancers to avoid any misjudgments about their regulatory status and categorized among them a subset of enhancers with an exceptionally accelerated rate of lineage specific divergence in humans. In this assorted set, 13 distinct transcription factor binding sites were located that possessed unique existence in humans. Three of 13 such sites belonging to transcription factors SOX2, RUNX1/3, and FOS/JUND possessed single nucleotide variants that made them unique to H. sapiens upon comparisons with Neandertal and Denisovan orthologous sequences. These variants modifying the binding sites in modern human lineage were further substantiated as single nucleotide polymorphisms via exploiting 1000 Genomes Project Phase3 data. Long range haplotype based tests laid out evidence of positive selection to be governing in African population on two of the modern human motif modifying alleles with strongest results for SOX2 binding site. In sum, our study acknowledges acceleration in noncoding regulatory landscape of the genome and highlights functional parts within it to have undergone accelerated divergence in present-day human population.

RevDate: 2018-03-23

Vernot B, S Pääbo (2018)

The Predecessors Within . . .

Cell, 173(1):6-7.

By examining the genomes of present-day people from Asia, researchers show that modern humans met and interbred with Denisovans, distant relatives to Neanderthals, on at least two occasions. As a result, people today carry DNA from two different Denisovan populations.

RevDate: 2018-03-25

Browning SR, Browning BL, Zhou Y, et al (2018)

Analysis of Human Sequence Data Reveals Two Pulses of Archaic Denisovan Admixture.

Cell, 173(1):53-61.e9.

Anatomically modern humans interbred with Neanderthals and with a related archaic population known as Denisovans. Genomes of several Neanderthals and one Denisovan have been sequenced, and these reference genomes have been used to detect introgressed genetic material in present-day human genomes. Segments of introgression also can be detected without use of reference genomes, and doing so can be advantageous for finding introgressed segments that are less closely related to the sequenced archaic genomes. We apply a new reference-free method for detecting archaic introgression to 5,639 whole-genome sequences from Eurasia and Oceania. We find Denisovan ancestry in populations from East and South Asia and Papuans. Denisovan ancestry comprises two components with differing similarity to the sequenced Altai Denisovan individual. This indicates that at least two distinct instances of Denisovan admixture into modern humans occurred, involving Denisovan populations that had different levels of relatedness to the sequenced Altai Denisovan. VIDEO ABSTRACT.

RevDate: 2018-02-25

Warren KA, Ritzman TB, Humphreys RA, et al (2018)

Craniomandibular form and body size variation of first generation mouse hybrids: A model for hominin hybridization.

Journal of human evolution, 116:57-74.

Hybridization occurs in a number of mammalian lineages, including among primate taxa. Analyses of ancient genomes have shown that hybridization between our lineage and other archaic hominins in Eurasia occurred numerous times in the past. However, we still have limited empirical data on what a hybrid skeleton looks like, or how to spot patterns of hybridization among fossils for which there are no genetic data. Here we use experimental mouse models to supplement previous studies of primates. We characterize size and shape variation in the cranium and mandible of three wild-derived inbred mouse strains and their first generation (F1) hybrids. The three parent taxa in our analysis represent lineages that diverged over approximately the same period as the human/Neanderthal/Denisovan lineages and their hybrids are variably successful in the wild. Comparisons of body size, as quantified by long bone measurements, are also presented to determine whether the identified phenotypic effects of hybridization are localized to the cranium or represent overall body size changes. The results indicate that hybrid cranial and mandibular sizes, as well as limb length, exceed that of the parent taxa in all cases. All three F1 hybrid crosses display similar patterns of size and form variation. These results are generally consistent with earlier studies on primates and other mammals, suggesting that the effects of hybridization may be similar across very different scenarios of hybridization, including different levels of hybrid fitness. This paper serves to supplement previous studies aimed at identifying F1 hybrids in the fossil record and to introduce further research that will explore hybrid morphologies using mice as a proxy for better understanding hybridization in the hominin fossil record.

RevDate: 2018-05-04

Leacock S, Syed P, James VM, et al (2018)

Structure/Function Studies of the α4 Subunit Reveal Evolutionary Loss of a GlyR Subtype Involved in Startle and Escape Responses.

Frontiers in molecular neuroscience, 11:23.

Inhibitory glycine receptors (GlyRs) are pentameric ligand-gated anion channels with major roles in startle disease/hyperekplexia (GlyR α1), cortical neuronal migration/autism spectrum disorder (GlyR α2), and inflammatory pain sensitization/rhythmic breathing (GlyR α3). However, the role of the GlyR α4 subunit has remained enigmatic, because the corresponding human gene (GLRA4) is thought to be a pseudogene due to an in-frame stop codon at position 390 within the fourth membrane-spanning domain (M4). Despite this, a recent genetic study has implicated GLRA4 in intellectual disability, behavioral problems and craniofacial anomalies. Analyzing data from sequenced genomes, we found that GlyR α4 subunit genes are predicted to be intact and functional in the majority of vertebrate species-with the exception of humans. Cloning of human GlyR α4 cDNAs excluded alternative splicing and RNA editing as mechanisms for restoring a full-length GlyR α4 subunit. Moreover, artificial restoration of the missing conserved arginine (R390) in the human cDNA was not sufficient to restore GlyR α4 function. Further bioinformatic and mutagenesis analysis revealed an additional damaging substitution at K59 that ablates human GlyR α4 function, which is not present in other vertebrate GlyR α4 sequences. The substitutions K59 and X390 were also present in the genome of an ancient Denisovan individual, indicating that GLRA4 has been a pseudogene for at least 30,000-50,000 years. In artificial synapses, we found that both mouse and gorilla α4β GlyRs mediate synaptic currents with unusually slow decay kinetics. Lastly, to gain insights into the biological role of GlyR α4 function, we studied the duplicated genes glra4a and glra4b in zebrafish. While glra4b expression is restricted to the retina, using a novel tol2-GAL4FF gene trap line (SAIGFF16B), we found that the zebrafish GlyR α4a subunit gene (glra4a) is strongly expressed in spinal cord and hindbrain commissural neurones. Using gene knockdown and a dominant-negative GlyR α4aR278Q mutant, we found that GlyR α4a contributes to touch-evoked escape behaviors in zebrafish. Thus, although GlyR α4 is unlikely to be involved in human startle responses or disease states, this subtype may contribute to escape behaviors in other organisms.

RevDate: 2018-07-10

Jiang L, Peng J, Huang M, et al (2018)

Differentiation analysis for estimating individual ancestry from the Tibetan Plateau by an archaic altitude adaptation EPAS1 haplotype among East Asian populations.

International journal of legal medicine pii:10.1007/s00414-018-1789-5 [Epub ahead of print].

Tibetans have adapted to the extreme environment of high altitude for hundreds of generations. A highly differentiated 5-SNP (Single Nucleotide Polymorphism) haplotype motif (AGGAA) on a hypoxic pathway gene, EPAS1, is observed in Tibetans and lowlanders. To evaluate the potential usage of the 5-SNP haplotype in ancestry inference for Tibetan or Tibetan-related populations, we analyzed this haplotype in 1053 individuals of 12 Chinese populations residing on the Tibetan Plateau, peripheral regions of Tibet, and plain regions. These data were integrated with the genotypes from the 1000 Genome populations and populations in a previously reported paper for population structure analyses. We found that populations representing highland and lowland groups have different dominant ancestry components. The core Denisovan haplotype (AGGAA) was observed at a frequency of 72.32% in the Tibetan Plateau, with a frequency range from 9.48 to 21.05% in the peripheral regions and < 2.5% in the plains area. From the individual perspective, 87.57% of the individuals from the Tibetan Plateau carried the archaic haplotype, while < 5% of the Chinese Han people carried the haplotype. Our findings indicate that the 5-SNP haplotype has a special distribution pattern in populations of Tibet and peripheral regions and could be integrated into AISNP (Ancestry Informative Single Nucleotide Polymorphism) panels to enhance ancestry resolution.

RevDate: 2018-03-13
CmpDate: 2018-03-13

Rodríguez-Paredes M, Bormann F, Raddatz G, et al (2018)

Methylation profiling identifies two subclasses of squamous cell carcinoma related to distinct cells of origin.

Nature communications, 9(1):577 pii:10.1038/s41467-018-03025-1.

Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer and usually progresses from a UV-induced precancerous lesion termed actinic keratosis (AK). Despite various efforts to characterize these lesions molecularly, the etiology of AK and its progression to cSCC remain partially understood. Here, we use Infinium MethylationEPIC BeadChips to interrogate the DNA methylation status in healthy, AK and cSCC epidermis samples. Importantly, we show that AK methylation patterns already display classical features of cancer methylomes and are highly similar to cSCC profiles. Further analysis identifies typical features of stem cell methylomes, such as reduced DNA methylation age, non-CpG methylation, and stem cell-related keratin and enhancer methylation patterns. Interestingly, this signature is detected only in half of the samples, while the other half shows patterns more closely related to healthy epidermis. These findings suggest the existence of two subclasses of AK and cSCC emerging from distinct keratinocyte differentiation stages.

RevDate: 2018-02-19

Yew CW, Lu D, Deng L, et al (2018)

Genomic structure of the native inhabitants of Peninsular Malaysia and North Borneo suggests complex human population history in Southeast Asia.

Human genetics, 137(2):161-173.

Southeast Asia (SEA) is enriched with a complex history of peopling. Malaysia, which is located at the crossroads of SEA, has been recognized as one of the hubs for early human migration. To unravel the genomic complexity of the native inhabitants of Malaysia, we sequenced 12 samples from 3 indigenous populations from Peninsular Malaysia and 4 native populations from North Borneo to a high coverage of 28-37×. We showed that the Negritos from Peninsular Malaysia shared a common ancestor with the East Asians, but exhibited some level of gene flow from South Asia, while the North Borneo populations exhibited closer genetic affinity towards East Asians than the Malays. The analysis of time of divergence suggested that ancestors of Negrito were the earliest settlers in the Malay Peninsula, whom first separated from the Papuans ~ 50-33 thousand years ago (kya), followed by East Asian (~ 40-15 kya), while the divergence time frame between North Borneo and East Asia populations predates the Austronesian expansion period implies a possible pre-Neolithic colonization. Substantial Neanderthal ancestry was confirmed in our genomes, as was observed in other East Asians. However, no significant difference was observed, in terms of the proportion of Denisovan gene flow into these native inhabitants from Malaysia. Judging from the similar amount of introgression in the Southeast Asians and East Asians, our findings suggest that the Denisovan gene flow may have occurred before the divergence of these populations and that the shared similarities are likely an ancestral component.

RevDate: 2018-06-27
CmpDate: 2018-06-27

Shipilovskikh SA, Vaganov VY, Denisova EI, et al (2018)

Dehydration of Amides to Nitriles under Conditions of a Catalytic Appel Reaction.

Organic letters, 20(3):728-731.

A highly expedient protocol for a catalytic Appel-type dehydration of amides to nitriles has been developed that employs oxalyl chloride and triethylamine along with triphenylphosphine oxide as a catalyst. The reactions are usually complete in less than 10 min with only a 1 mol % catalyst loading. The reaction scope includes aromatic, heteroaromatic, and aliphatic amides, including derivatives of α-hydroxy and α-amino acids.

RevDate: 2018-02-10

Belousov AB, Nishimune H, Denisova JV, et al (2018)

A potential role for neuronal connexin 36 in the pathogenesis of amyotrophic lateral sclerosis.

Neuroscience letters, 666:1-4.

Neuronal gap junctional protein connexin 36 (Cx36) contributes to neuronal death following a range of acute brain insults such as ischemia, traumatic brain injury and epilepsy. Whether Cx36 contributes to neuronal death and pathological outcomes in chronic neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), is not known. We show here that the expression of Cx36 is significantly decreased in lumbar segments of the spinal cord of both human ALS subjects and SOD1G93A mice as compared to healthy human and wild-type mouse controls, respectively. In purified neuronal cultures prepared from the spinal cord of wild-type mice, knockdown of Cx36 reduces neuronal death caused by overexpression of the mutant human SOD1-G93A protein. Taken together, these data suggest a possible contribution of Cx36 to ALS pathogenesis. A perspective for the use of blockers of Cx36 gap junction channels for ALS therapy is discussed.

RevDate: 2018-06-15

Derenko M, Denisova G, Malyarchuk B, et al (2018)

Mitogenomic diversity and differentiation of the Buryats.

Journal of human genetics, 63(1):71-81.

In this paper we present a results of first comprehensive study of the complete mitogenomes in the Buryats with regard to their belonging to the main regional (eastern and western Buryats); tribal (Khori, Ekhirid, Bulagad, and Khongodor), and ethno-territorial (Aginsk, Alar, Balagansk, Barguzin, Ida, Khorinsk, Kuda, Selenga, Verkholensk, Olkhon, Tunka, and Shenehen Buryats) groups. The analysis of molecular variation performed using regional, tribal, and ethno-territorial divisions of the Buryats showed lack of genetic differentiation at all levels. Nonetheless, the complete mitogenome analysis revealed a very high level of genetic diversity in the Buryats which is the highest among Siberian populations and comparable to that in populations of eastern and western Asia. The AMOVA and MDS analyses results imply to a strong genetic similarity between the Buryats and eastern Asian populations of Chinese and Japanese, suggesting their origin on the basis of common maternal ancestry components. Several new Buryat-specific branches of haplogroup G (G2a2a, G2a1i, G2a5a) display signals of dispersals dating to 2.6-6.6 kya with a possible origin in eastern Asia, thus testifying Bronze Age and Neolithic arrival of ancestral eastern Asian component to the South Siberia region.

RevDate: 2017-12-15

Walter Costa MB, Höner Zu Siederdissen C, Tulpan D, et al (2018)

Temporal ordering of substitutions in RNA evolution: Uncovering the structural evolution of the Human Accelerated Region 1.

Journal of theoretical biology, 438:143-150.

The Human Accelerated Region 1 (HAR1) is the most rapidly evolving region in the human genome. It is part of two overlapping long non-coding RNAs, has a length of only 118 nucleotides and features 18 human specific changes compared to an ancestral sequence that is extremely well conserved across non-human primates. The human HAR1 forms a stable secondary structure that is strikingly different from the one in chimpanzee as well as other closely related species, again emphasizing its human-specific evolutionary history. This suggests that positive selection has acted to stabilize human-specific features in the ensemble of HAR1 secondary structures. To investigate the evolutionary history of the human HAR1 structure, we developed a computational model that evaluates the relative likelihood of evolutionary trajectories as a probabilistic version of a Hamiltonian path problem. The model predicts that the most likely last step in turning the ancestral primate HAR1 into the human HAR1 was exactly the substitution that distinguishes the modern human HAR1 sequence from that of Denisovan, an archaic human, providing independent support for our model. The MutationOrder software is available for download and can be applied to other instances of RNA structure evolution.

RevDate: 2018-03-27
CmpDate: 2018-03-27

Kovalkova NA, Ragino YI, Travnikova NY, et al (2017)

[Associations between metabolic syndrome and reduced lung function in young people].

Terapevticheskii arkhiv, 89(10):54-61.

AIM: To reveal possible associations between metabolic syndrome (MS) and reduced lung function.

SUBJECTS AND METHODS: In 2013-016, a cross-sectional survey was conducted in 908 Novosibirsk dwellers, which included spirometry to evaluate external respiratory function (ERF). For the detection of MS, the investigators used the 2009 All-Russian Research Society of Cardiologists criteria: waist circumference (WC) > 80 cm for women and >94 cm for men in combination with two of the following criteria: blood pressure (BP) ≥130/85 mm Hg, triglycerides (TG) ≥1.7 mmol/l, high-density lipoproteins (HDL) cholesterol <1.0 mmol/l for men and <1.2 mmol/l for women, low-density lipoprotein (LDL) cholesterol >3.0 mmol/l, and glucose ≥6.1 mmol/l.

RESULTS: The mean values of WC were significantly greater with a forced expiratory volume in one second (FEV1) <80% than those with a FEV1 of ≥80% in both men (p=0.002) and women (p=0.050); in women, the mean values of WS were higher than those with a FEV1/forced vital capacity (FVC) <70% than those with a FEV1/FVC of ≥70% (p=0.047); the mean systolic and diastolic BP levels were significantly more with reductions in FEV1 and FVC, and the level of HDL cholesterol was significantly lower than that with a FEV1 of < 80% in men only. Significant correlations were found between FEV1 and all components of MS in men, between the majority of components of MS and FVC in men, between WC, BP, and FEV1/FVC in men and women, between plasma glucose levels and FEV1/FVC in women. Linear regression analysis revealed significant inverse correlations of FEV1 with TG, glucose, BP; those of FVC with TG, glucose; at the same time a positive association with HDL cholesterol in men, and only a negative correlation of FEV1/FVC with WC.

CONCLUSION: The revealed associations between MS and reduced lung function can most likely be explained by the greater prevalence of both MS and its components (hypertension, hypertriglyceridemia, hyperglycemia, LDL hypercholesterolemia) among Novosibirsk men. This is consistent with the assertion that the decline in ERF, particularly FEV1, may be a marker of future cardiovascular disease morbidity and mortality.

RevDate: 2018-03-15
CmpDate: 2018-03-15

Soldatsky YL, Denisova OA, SA Bulynko (2017)

[The specific features of the past medical history and etiology of pharyngeal abscess in the children].

Vestnik otorinolaringologii, 82(5):12-14.

The present study was undertaken for the purpose of elucidating the specific features of the past medical history and the etiological factors responsible for the development of tonsillogenic pharyngeal abscesses in the children. We performed the retrospective analysis of the medical histories of 291 children presenting with this condition who had been admitted for the treatment to the ENT Department of the Morozovskzya City Children's Clinical Hospital during the period from January till December 2015. The study has demonstrated the following most common shortcomings of the outpatient treatment of the patients suffering from chronic tonsillitis at the stage preceding formation of paratonsillar abscess: inadequate antibacterial therapy of acute chronic tonsillitis or its exacerbation and limited indications for tonsillectomy at the level of the outpatient treatment. The leading role in the etiology of tonsillogenic pharyngeal abscesses in the children is played by beta-hemolytic Streptococcus of group A. It is concluded that the medical history suggesting past paratonsillar abscess is the absolute indication for the subsequent tonsillectomy in the children of any age.

RevDate: 2018-04-18
CmpDate: 2018-04-18

Yazdanyar A, Rizzuti AE, Mechel E, et al (2018)

Gout Keratitis: A Case of Peripheral Ulcerative Keratitis Secondary to Gout With a Review of the Literature.

Cornea, 37(3):379-381.

PURPOSE: To report a case of peripheral ulcerative keratitis secondary to gout.

METHODS: A 41-year-old man with a history of severe gout disease presented with pain and redness of the right eye. Physical examination revealed 2 areas of peripheral corneal thinning with overlying epithelial defects. Adjacent to these areas, reflective crystals were identified in the corneal stroma. Anterior segment optical coherence tomography demonstrated stromal corneal deposits.

RESULTS: Systemic workup was negative aside from an elevated serum uric acid level. The patient was administered oral prednisone, allopurinol, and colchicine. At his 2-month follow-up visit, the patient was asymptomatic and his corneal thinning had significantly improved.

CONCLUSIONS: Gout is the most common type of inflammatory arthritis in adults with rising incidence and prevalence. Ocular findings in gout are common, but patients are usually asymptomatic. Monosodium urate crystal deposition has been reported to occur in various parts of the eye, with and without ocular inflammation. Crystal deposition in the cornea is extremely rare and may be a cause of peripheral ulcerative keratitis.

RevDate: 2018-03-09

Vashee S, Stockwell TB, Alperovich N, et al (2017)

Cloning, Assembly, and Modification of the Primary Human Cytomegalovirus Isolate Toledo by Yeast-Based Transformation-Associated Recombination.

mSphere, 2(5): pii:mSphere00331-17.

Genetic engineering of cytomegalovirus (CMV) currently relies on generating a bacterial artificial chromosome (BAC) by introducing a bacterial origin of replication into the viral genome using in vivo recombination in virally infected tissue culture cells. However, this process is inefficient, results in adaptive mutations, and involves deletion of viral genes to avoid oversized genomes when inserting the BAC cassette. Moreover, BAC technology does not permit the simultaneous manipulation of multiple genome loci and cannot be used to construct synthetic genomes. To overcome these limitations, we adapted synthetic biology tools to clone CMV genomes in Saccharomyces cerevisiae. Using an early passage of the human CMV isolate Toledo, we first applied transformation-associated recombination (TAR) to clone 16 overlapping fragments covering the entire Toledo genome in Saccharomyces cerevisiae. Then, we assembled these fragments by TAR in a stepwise process until the entire genome was reconstituted in yeast. Since next-generation sequence analysis revealed that the low-passage-number isolate represented a mixture of parental and fibroblast-adapted genomes, we selectively modified individual DNA fragments of fibroblast-adapted Toledo (Toledo-F) and again used TAR assembly to recreate parental Toledo (Toledo-P). Linear, full-length HCMV genomes were transfected into human fibroblasts to recover virus. Unlike Toledo-F, Toledo-P displayed characteristics of primary isolates, including broad cellular tropism in vitro and the ability to establish latency and reactivation in humanized mice. Our novel strategy thus enables de novo cloning of CMV genomes, more-efficient genome-wide engineering, and the generation of viral genomes that are partially or completely derived from synthetic DNA. IMPORTANCE The genomes of large DNA viruses, such as human cytomegalovirus (HCMV), are difficult to manipulate using current genetic tools, and at this time, it is not possible to obtain, molecular clones of CMV without extensive tissue culture. To overcome these limitations, we used synthetic biology tools to capture genomic fragments from viral DNA and assemble full-length genomes in yeast. Using an early passage of the HCMV isolate Toledo containing a mixture of wild-type and tissue culture-adapted virus. we directly cloned the majority sequence and recreated the minority sequence by simultaneous modification of multiple genomic regions. Thus, our novel approach provides a paradigm to not only efficiently engineer HCMV and other large DNA viruses on a genome-wide scale but also facilitates the cloning and genetic manipulation of primary isolates and provides a pathway to generating entirely synthetic genomes.

RevDate: 2018-04-17
CmpDate: 2018-04-17

Saakyan SV, Katargina LA, Krichevskaya GI, et al (2017)

[Specific immunoglobulins G and M in blood serum in retinoblastoma and 'pseudoretinoblastoma'].

Vestnik oftalmologii, 133(4):12-16.

Perinatal inflammatory retinal diseases and intrauterine retinal maldevelopments are mistaken for retinoblastoma as often as in 8-16% of cases.

AIM: To analyze the infectious status in children with retinoblastoma and pseudoretinoblastoma at different ages.

MATERIAL AND METHODS: A total of 47 retinoblastoma suspects aged 4-69 months were enrolled. Pseudoretinoblastoma (inflammatory retinal diseases and intrauterine maldevelopments of the retina) was detected in 14 children (group 1), retinoblastoma - in 33 children (group 2). In each group, two subgroups were identified: 'a' - children under 12 months of age (1a - 5 patients, 2a - 10 patients) and 'b'- children over 12 months of age (1b - 9 patients, 2b - 23 patients). Their blood sera were examined for antibodies to herpes simplex virus types 1 and 2, cytomegalovirus, Epstein-Barr virus, toxoplasma, toxocara, chlamydia, and mycoplasma (enzyme-linked immunosorbent assay).

RESULTS: According to serological screening, all patients from group 1a (children under 12 months of age with pseudoretinoblastoma), in contrast to other groups, were infected perinatally with cytomegalovirus infection. All 47 patients were seronegative to toxoplasma. Toxocara infection was identified in children over 12 months of age: in 3 out of 9 patients with pseudoretinoblastoma and in 2 out of 23 patients with retinoblastoma (p>0.05). Markers of Epstein-Barr viral activity were detected only in 3 retinoblastoma children over 12 months of age.

CONCLUSION: The results suggest that cytomegalovirus infection plays the leading role in the development of perinatal eye pathology, which, in infants, is clinically similar to retinoblastoma. In children over 12 months of age we found no serological signs that could be regarded as specific of either retinoblastoma, or pseudoretinoblastoma. The only thing worth paying attention to is the activation of Epstein-Barr virus infection in children over 12 months of age with retinoblastoma.

RevDate: 2018-01-08
CmpDate: 2018-01-08

Xu D, Jaber Y, Pavlidis P, et al (2017)

VCFtoTree: a user-friendly tool to construct locus-specific alignments and phylogenies from thousands of anthropologically relevant genome sequences.

BMC bioinformatics, 18(1):426 pii:10.1186/s12859-017-1844-0.

BACKGROUND: Constructing alignments and phylogenies for a given locus from large genome sequencing studies with relevant outgroups allow novel evolutionary and anthropological insights. However, no user-friendly tool has been developed to integrate thousands of recently available and anthropologically relevant genome sequences to construct complete sequence alignments and phylogenies.

RESULTS: Here, we provide VCFtoTree, a user friendly tool with a graphical user interface that directly accesses online databases to download, parse and analyze genome variation data for regions of interest. Our pipeline combines popular sequence datasets and tree building algorithms with custom data parsing to generate accurate alignments and phylogenies using all the individuals from the 1000 Genomes Project, Neanderthal and Denisovan genomes, as well as reference genomes of Chimpanzee and Rhesus Macaque. It can also be applied to other phased human genomes, as well as genomes from other species. The output of our pipeline includes an alignment in FASTA format and a tree file in newick format.

CONCLUSION: VCFtoTree fulfills the increasing demand for constructing alignments and phylogenies for a given loci from thousands of available genomes. Our software provides a user friendly interface for a wider audience without prerequisite knowledge in programming. VCFtoTree can be accessed from .

RevDate: 2017-10-31
CmpDate: 2017-10-31

Zanolli C, Hourset M, Esclassan R, et al (2017)

Neanderthal and Denisova tooth protein variants in present-day humans.

PloS one, 12(9):e0183802 pii:PONE-D-17-13273.

Environment parameters, diet and genetic factors interact to shape tooth morphostructure. In the human lineage, archaic and modern hominins show differences in dental traits, including enamel thickness, but variability also exists among living populations. Several polymorphisms, in particular in the non-collagenous extracellular matrix proteins of the tooth hard tissues, like enamelin, are involved in dental structure variation and defects and may be associated with dental disorders or susceptibility to caries. To gain insights into the relationships between tooth protein polymorphisms and dental structural morphology and defects, we searched for non-synonymous polymorphisms in tooth proteins from Neanderthal and Denisova hominins. The objective was to identify archaic-specific missense variants that may explain the dental morphostructural variability between extinct and modern humans, and to explore their putative impact on present-day dental phenotypes. Thirteen non-collagenous extracellular matrix proteins specific to hard dental tissues have been selected, searched in the publicly available sequence databases of Neanderthal and Denisova individuals and compared with modern human genome data. A total of 16 non-synonymous polymorphisms were identified in 6 proteins (ameloblastin, amelotin, cementum protein 1, dentin matrix acidic phosphoprotein 1, enamelin and matrix Gla protein). Most of them are encoded by dentin and enamel genes located on chromosome 4, previously reported to show signs of archaic introgression within Africa. Among the variants shared with modern humans, two are ancestral (common with apes) and one is the derived enamelin major variant, T648I (rs7671281), associated with a thinner enamel and specific to the Homo lineage. All the others are specific to Neanderthals and Denisova, and are found at a very low frequency in modern Africans or East and South Asians, suggesting that they may be related to particular dental traits or disease susceptibility in these populations. This modern regional distribution of archaic dental polymorphisms may reflect persistence of archaic variants in some populations and may contribute in part to the geographic dental variations described in modern humans.

RevDate: 2017-09-17

Denisova K, G Zhao (2017)

Inflexible neurobiological signatures precede atypical development in infants at high risk for autism.

Scientific reports, 7(1):11285 pii:10.1038/s41598-017-09028-0.

Variability in neurobiological signatures is ubiquitous in early life but the link to adverse developmental milestones in humans is unknown. We examined how levels of signal and noise in movement signatures during the 1st year of life constrain early development in 71 healthy typically developing infants, either at High or Low familial Risk (HR or LR, respectively) for developing Autism Spectrum Disorders (ASD). Delays in early learning developmental trajectories in HR infants (validated in an analysis of 1,445 infants from representative infant-sibling studies) were predicted by worse stochastic patterns in their spontaneous head movements as early as 1-2 months after birth, relative to HR infants who showed more rapid developmental progress, as well as relative to all LR infants. While LR 1-2 mo-old infants' movements were significantly different during a language listening task compared to during sleep, HR infants' movements were more similar during both conditions, a striking lack of diversity that reveals context-inflexible experience of ambient information. Contrary to expectation, it is not the level of variability per se that is particularly detrimental in early life. Rather, inflexible sensorimotor systems and/or atypical transition between behavioral states may interfere with the establishment of capacity to extract structure and important cues from sensory input at birth, preceding and contributing to an atypical brain developmental trajectory in toddlerhood.

RevDate: 2018-07-02
CmpDate: 2018-06-12

Gardner EJ, Lam VK, Harris DN, et al (2017)

The Mobile Element Locator Tool (MELT): population-scale mobile element discovery and biology.

Genome research, 27(11):1916-1929.

Mobile element insertions (MEIs) represent ∼25% of all structural variants in human genomes. Moreover, when they disrupt genes, MEIs can influence human traits and diseases. Therefore, MEIs should be fully discovered along with other forms of genetic variation in whole genome sequencing (WGS) projects involving population genetics, human diseases, and clinical genomics. Here, we describe the Mobile Element Locator Tool (MELT), which was developed as part of the 1000 Genomes Project to perform MEI discovery on a population scale. Using both Illumina WGS data and simulations, we demonstrate that MELT outperforms existing MEI discovery tools in terms of speed, scalability, specificity, and sensitivity, while also detecting a broader spectrum of MEI-associated features. Several run modes were developed to perform MEI discovery on local and cloud systems. In addition to using MELT to discover MEIs in modern humans as part of the 1000 Genomes Project, we also used it to discover MEIs in chimpanzees and ancient (Neanderthal and Denisovan) hominids. We detected diverse patterns of MEI stratification across these populations that likely were caused by (1) diverse rates of MEI production from source elements, (2) diverse patterns of MEI inheritance, and (3) the introgression of ancient MEIs into modern human genomes. Overall, our study provides the most comprehensive map of MEIs to date spanning chimpanzees, ancient hominids, and modern humans and reveals new aspects of MEI biology in these lineages. We also demonstrate that MELT is a robust platform for MEI discovery and analysis in a variety of experimental settings.

RevDate: 2018-06-04
CmpDate: 2018-05-15

Jinam TA, Phipps ME, Aghakhanian F, et al (2017)

Discerning the Origins of the Negritos, First Sundaland People: Deep Divergence and Archaic Admixture.

Genome biology and evolution, 9(8):2013-2022.

Human presence in Southeast Asia dates back to at least 40,000 years ago, when the current islands formed a continental shelf called Sundaland. In the Philippine Islands, Peninsular Malaysia, and Andaman Islands, there exist indigenous groups collectively called Negritos whose ancestry can be traced to the "First Sundaland People." To understand the relationship between these Negrito groups and their demographic histories, we generated genome-wide single nucleotide polymorphism data in the Philippine Negritos and compared them with existing data from other populations. Phylogenetic tree analyses show that Negritos are basal to other East and Southeast Asians, and that they diverged from West Eurasians at least 38,000 years ago. We also found relatively high traces of Denisovan admixture in the Philippine Negritos, but not in the Malaysian and Andamanese groups, suggesting independent introgression and/or parallel losses involving Denisovan introgressed regions. Shared genetic loci between all three Negrito groups could be related to skin pigmentation, height, facial morphology and malarial resistance. These results show the unique status of Negrito groups as descended from the First Sundaland People.

RevDate: 2018-06-04
CmpDate: 2018-04-27

Sharbrough J, Havird JC, Noe GR, et al (2017)

The Mitonuclear Dimension of Neanderthal and Denisovan Ancestry in Modern Human Genomes.

Genome biology and evolution, 9(6):1567-1581.

Some human populations interbred with Neanderthals and Denisovans, resulting in substantial contributions to modern-human genomes. Therefore, it is now possible to use genomic data to investigate mechanisms that shaped historical gene flow between humans and our closest hominin relatives. More generally, in eukaryotes, mitonuclear interactions have been argued to play a disproportionate role in generating reproductive isolation. There is no evidence of mtDNA introgression into modern human populations, which means that all introgressed nuclear alleles from archaic hominins must function on a modern-human mitochondrial background. Therefore, mitonuclear interactions are also potentially relevant to hominin evolution. We performed a detailed accounting of mtDNA divergence among hominin lineages and used population-genomic data to test the hypothesis that mitonuclear incompatibilities have preferentially restricted the introgression of nuclear genes with mitochondrial functions. We found a small but significant underrepresentation of introgressed Neanderthal alleles at such nuclear loci. Structural analyses of mitochondrial enzyme complexes revealed that these effects are unlikely to be mediated by physically interacting sites in mitochondrial and nuclear gene products. We did not detect any underrepresentation of introgressed Denisovan alleles at mitochondrial-targeted loci, but this may reflect reduced power because locus-specific estimates of Denisovan introgression are more conservative. Overall, we conclude that genes involved in mitochondrial function may have been subject to distinct selection pressures during the history of introgression from archaic hominins but that mitonuclear incompatibilities have had, at most, a small role in shaping genome-wide introgression patterns, perhaps because of limited functional divergence in mtDNA and interacting nuclear genes.

RevDate: 2018-05-31
CmpDate: 2018-05-31

Rogers AR, Bohlender RJ, CD Huff (2017)

Early history of Neanderthals and Denisovans.

Proceedings of the National Academy of Sciences of the United States of America, 114(37):9859-9863.

Extensive DNA sequence data have made it possible to reconstruct human evolutionary history in unprecedented detail. We introduce a method to study the past several hundred thousand years. Our results show that (i) the Neanderthal-Denisovan lineage declined to a small size just after separating from the modern lineage, (ii) Neanderthals and Denisovans separated soon thereafter, and (iii) the subsequent Neanderthal population was large and deeply subdivided. They also (iv) support previous estimates of gene flow from Neanderthals into modern Eurasians. These results suggest an archaic human diaspora early in the Middle Pleistocene.

RevDate: 2017-07-14

Slon V, Viola B, Renaud G, et al (2017)

A fourth Denisovan individual.

Science advances, 3(7):e1700186 pii:1700186.

The presence of Neandertals in Europe and Western Eurasia before the arrival of anatomically modern humans is well supported by archaeological and paleontological data. In contrast, fossil evidence for Denisovans, a sister group of Neandertals recently identified on the basis of DNA sequences, is limited to three specimens, all of which originate from Denisova Cave in the Altai Mountains (Siberia, Russia). We report the retrieval of DNA from a deciduous lower second molar (Denisova 2), discovered in a deep stratigraphic layer in Denisova Cave, and show that this tooth comes from a female Denisovan individual. On the basis of the number of "missing substitutions" in the mitochondrial DNA determined from the specimen, we find that Denisova 2 is substantially older than two of the other Denisovans, reinforcing the view that Denisovans were likely to have been present in the vicinity of Denisova Cave over an extended time period. We show that the level of nuclear DNA sequence diversity found among Denisovans is within the lower range of that of present-day human populations.

RevDate: 2017-07-11

Margaryan A, Derenko M, Hovhannisyan H, et al (2017)

Eight Millennia of Matrilineal Genetic Continuity in the South Caucasus.

Current biology : CB, 27(13):2023-2028.e7.

The South Caucasus, situated between the Black and Caspian Seas, geographically links Europe with the Near East and has served as a crossroad for human migrations for many millennia [1-7]. Despite a vast archaeological record showing distinct cultural turnovers, the demographic events that shaped the human populations of this region is not known [8, 9]. To shed light on the maternal genetic history of the region, we analyzed the complete mitochondrial genomes of 52 ancient skeletons from present-day Armenia and Artsakh spanning 7,800 years and combined this dataset with 206 mitochondrial genomes of modern Armenians. We also included previously published data of seven neighboring populations (n = 482). Coalescence-based analyses suggest that the population size in this region rapidly increased after the Last Glacial Maximum ca. 18 kya. We find that the lowest genetic distance in this dataset is between modern Armenians and the ancient individuals, as also reflected in both network analyses and discriminant analysis of principal components. We used approximate Bayesian computation to test five different demographic scenarios explaining the formation of the modern Armenian gene pool. Despite well documented cultural shifts in the South Caucasus across this time period, our results strongly favor a genetic continuity model in the maternal gene pool. This has implications for interpreting prehistoric migration dynamics and cultural shifts in this part of the world.

RevDate: 2018-01-22
CmpDate: 2017-09-25

Easton JD, Aunes M, Albers GW, et al (2017)

Risk for Major Bleeding in Patients Receiving Ticagrelor Compared With Aspirin After Transient Ischemic Attack or Acute Ischemic Stroke in the SOCRATES Study (Acute Stroke or Transient Ischemic Attack Treated With Aspirin or Ticagrelor and Patient Outcomes).

Circulation, 136(10):907-916.

BACKGROUND: Patients with minor acute ischemic stroke or transient ischemic attack are at high risk for subsequent stroke, and more potent antiplatelet therapy in the acute setting is needed. However, the potential benefit of more intense antiplatelet therapy must be assessed in relation to the risk for major bleeding. The SOCRATES trial (Acute Stroke or Transient Ischemic Attack Treated With Aspirin or Ticagrelor and Patient Outcomes) was the first trial with ticagrelor in patients with acute ischemic stroke or transient ischemic attack in which the efficacy and safety of ticagrelor were compared with those of aspirin. The main safety objective was assessment of PLATO (Platelet Inhibition and Patient Outcomes)-defined major bleeds on treatment, with special focus on intracranial hemorrhage (ICrH).

METHODS: An independent adjudication committee blinded to study treatment classified bleeds according to the PLATO, TIMI (Thrombolysis in Myocardial Infarction), and GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) definitions. The definitions of ICrH and major bleeding excluded cerebral microbleeds and asymptomatic hemorrhagic transformations of cerebral infarctions so that the definitions better discriminated important events in the acute stroke population.

RESULTS: A total of 13 130 of 13 199 randomized patients received at least 1 dose of study drug and were included in the safety analysis set. PLATO major bleeds occurred in 31 patients (0.5%) on ticagrelor and 38 patients (0.6%) on aspirin (hazard ratio, 0.83; 95% confidence interval, 0.52-1.34). The most common locations of major bleeds were intracranial and gastrointestinal. ICrH was reported in 12 patients (0.2%) on ticagrelor and 18 patients (0.3%) on aspirin. Thirteen of all 30 ICrHs (4 on ticagrelor and 9 on aspirin) were hemorrhagic strokes, and 4 (2 in each group) were symptomatic hemorrhagic transformations of brain infarctions. The ICrHs were spontaneous in 6 and 13, traumatic in 3 and 3, and procedural in 3 and 2 patients on ticagrelor and aspirin, respectively. In total, 9 fatal bleeds occurred on ticagrelor and 4 on aspirin. The composite of ICrH or fatal bleeding included 15 patients on ticagrelor and 18 on aspirin. Independently of bleeding classification, PLATO, TIMI, or GUSTO, the relative difference between treatments for major/severe bleeds was similar. Nonmajor bleeds were more common on ticagrelor.

CONCLUSIONS: Antiplatelet therapy with ticagrelor in patients with acute ischemic stroke or transient ischemic attack showed a bleeding profile similar to that of aspirin for major bleeds. There were few ICrHs.

CLINICAL TRIAL REGISTRATION: URL: Unique identifier: NCT01994720.

RevDate: 2018-04-25
CmpDate: 2018-04-25

Alexeeva EI, Namazova-Baranova LS, Bzarova TM, et al (2017)

Predictors of the response to etanercept in patients with juvenile idiopathic arthritis without systemic manifestations within 12 months: results of an open-label, prospective study conducted at the National Scientific and Practical Center of Children's Health, Russia.

Pediatric rheumatology online journal, 15(1):51 pii:10.1186/s12969-017-0178-9.

BACKGROUND: The aim of this study was to investigate the efficacy of etanercept treatment and to identify predictors of response to therapy within 12 months in patients with juvenile idiopathic arthritis (JIA) without systemic manifestations.

METHODS: A total of 197 juvenile patients were enrolled in this study. Response to therapy was assessed using the ACRPedi 30/50/70/90 criteria, the Wallace criteria, and the Juvenile Arthritis Disease Activity Score 71 (JADAS-71). Univariate and multivariate logistic regression analyses were performed to identify potential baseline factors associated with treatment response in different JIA categories.

RESULTS: One year after treatment initiation, 179 (90.9%) patients achieved ACRPedi30; 177 (89.8%) patients achieved ACRPedi50; 168 (85.3%) patients achieved ACRPedi70; and 135 (68.5%) patients achieved ACRPedi90 response. A total of 132 (67.0%) and 92 (46.7%) patients achieved inactive disease according to the Wallace criteria and the JADAS-71 cut-off point, respectively. Excellent response (achieving ACRPedi90 and clinically inactive disease according both to the Wallace criteria and the JADAS71 cut-off point) was associated with persistent oligoarticular JIA category, shorter disease duration before the start of etanercept, a lower number of DMARDs used before the introduction of etanercept, a lower number of joints with limited motion, and lower C-reactive protein at baseline. Poor response (failure to achieve ACR 70 or active disease according to both the Wallace criteria and JADAS71 even when ACR 70 was achieved) was associated with the polyarticular or enthesitis-related JIA categories, higher disease duration before the start of etanercept, and older age at disease onset.

CONCLUSION: Almost half (45.7%) of the patients who initiated etanercept treatment achieved an excellent response (inactive disease and ACRPedi90) after 1 year. What may be novel is our finding that the response to etanercept therapy was strongly associated with the JIA category. The response to etanercept therapy was also associated with the disease duration before the start of etanercept treatment.

RevDate: 2018-05-15

Guo S, Lai C, Wu C, et al (2017)

Conversion Discriminative Analysis on Mild Cognitive Impairment Using Multiple Cortical Features from MR Images.

Frontiers in aging neuroscience, 9:146.

Neuroimaging measurements derived from magnetic resonance imaging provide important information required for detecting changes related to the progression of mild cognitive impairment (MCI). Cortical features and changes play a crucial role in revealing unique anatomical patterns of brain regions, and further differentiate MCI patients from normal states. Four cortical features, namely, gray matter volume, cortical thickness, surface area, and mean curvature, were explored for discriminative analysis among three groups including the stable MCI (sMCI), the converted MCI (cMCI), and the normal control (NC) groups. In this study, 158 subjects (72 NC, 46 sMCI, and 40 cMCI) were selected from the Alzheimer's Disease Neuroimaging Initiative. A sparse-constrained regression model based on the l2-1-norm was introduced to reduce the feature dimensionality and retrieve essential features for the discrimination of the three groups by using a support vector machine (SVM). An optimized strategy of feature addition based on the weight of each feature was adopted for the SVM classifier in order to achieve the best classification performance. The baseline cortical features combined with the longitudinal measurements for 2 years of follow-up data yielded prominent classification results. In particular, the cortical thickness produced a classification with 98.84% accuracy, 97.5% sensitivity, and 100% specificity for the sMCI-cMCI comparison; 92.37% accuracy, 84.78% sensitivity, and 97.22% specificity for the cMCI-NC comparison; and 93.75% accuracy, 92.5% sensitivity, and 94.44% specificity for the sMCI-NC comparison. The best performances obtained by the SVM classifier using the essential features were 5-40% more than those using all of the retained features. The feasibility of the cortical features for the recognition of anatomical patterns was certified; thus, the proposed method has the potential to improve the clinical diagnosis of sub-types of MCI and predict the risk of its conversion to Alzheimer's disease.

RevDate: 2017-05-17

Denisova OA, Livzan MA, AP Denisov (2017)

[Comparative characteristics of patients with gastroesophageal reflux disease in the age aspect].

Terapevticheskii arkhiv, 89(4):53-56.

AIM: To compare the characteristics of patients with gastroesophageal reflux disease (GERD) by age groups, a wide range of clinical signs, including life-of-quality (QOL) indicators, and instrumental findings.

SUBJECTS AND METHODS: A total of 110 patients aged 18 to 86 years with GERD were examined in accordance with the standard protocol. Two groups with equal numbers of patents were formed. A study group included elderly and senile patients and a control group consisted of young and adult ones.

RESULTS: The elderly patients with GERD were observed to have a number of age-related clinical features and age-unrelated symptoms. The scores in the scales characterizing the physical health component and those in the general health and vital activity scales were markedly decreased in patients older than 60 years of age. No age-related statistically significant differences were found in the esophageal, gastric, and duodenal mucosae. Daily pH-metry in the elderly showed indirect evidence for esophageal hypomotor dyskinesia in the predominance of alkaline refluxes.

CONCLUSION: The cohort of elderly patients with GERD was ascertained to have statistically significant clinical characteristics, and QOL and pH-metry indicators, which will be able to improve methods for diagnosis and early prevention in this age group.

RevDate: 2018-02-14
CmpDate: 2017-08-21

Reales G, Rovaris DL, Jacovas VC, et al (2017)

A tale of agriculturalists and hunter-gatherers: Exploring the thrifty genotype hypothesis in native South Americans.

American journal of physical anthropology, 163(3):591-601.

OBJECTIVES: To determine genetic differences between agriculturalist and hunter-gatherer southern Native American populations for selected metabolism-related markers and to test whether Neel's thrifty genotype hypothesis (TGH) could explain the genetic patterns observed in these populations.

MATERIALS AND METHODS: 375 Native South American individuals from 17 populations were genotyped using six markers (APOE rs429358 and rs7412; APOA2 rs5082; CD36 rs3211883; TCF7L2 rs11196205; and IGF2BP2 rs11705701). Additionally, APOE genotypes from 39 individuals were obtained from the literature. AMOVA, main effects, and gene-gene interaction tests were performed.

RESULTS: We observed differences in allele distribution patterns between agriculturalists and hunter-gatherers for some markers. For instance, between-groups component of genetic variance (FCT) for APOE rs429358 showed strong differences in allelic distributions between hunter-gatherers and agriculturalists (p = 0.00196). Gene-gene interaction analysis indicated that the APOE E4/CD36 TT and APOE E4/IGF2BP2 A carrier combinations occur at a higher frequency in hunter-gatherers, but this combination is not replicated in archaic (Neanderthal and Denisovan) and ancient (Anzick, Saqqaq, Ust-Ishim, Mal'ta) hunter-gatherer individuals.

DISCUSSION: A complex scenario explains the observed frequencies of the tested markers in hunter-gatherers. Different factors, such as pleotropic alleles, rainforest selective pressures, and population dynamics, may be collectively shaping the observed genetic patterns. We conclude that although TGH seems a plausible hypothesis to explain part of the data, other factors may be important in our tested populations.

RevDate: 2018-01-25
CmpDate: 2018-01-25

Slon V, Hopfe C, Weiß CL, et al (2017)

Neandertal and Denisovan DNA from Pleistocene sediments.

Science (New York, N.Y.), 356(6338):605-608.

Although a rich record of Pleistocene human-associated archaeological assemblages exists, the scarcity of hominin fossils often impedes the understanding of which hominins occupied a site. Using targeted enrichment of mitochondrial DNA, we show that cave sediments represent a rich source of ancient mammalian DNA that often includes traces of hominin DNA, even at sites and in layers where no hominin remains have been discovered. By automation-assisted screening of numerous sediment samples, we detected Neandertal DNA in eight archaeological layers from four caves in Eurasia. In Denisova Cave, we retrieved Denisovan DNA in a Middle Pleistocene layer near the bottom of the stratigraphy. Our work opens the possibility of detecting the presence of hominin groups at sites and in areas where no skeletal remains are found.

RevDate: 2017-08-12
CmpDate: 2017-05-30

Hu H, Petousi N, Glusman G, et al (2017)

Evolutionary history of Tibetans inferred from whole-genome sequencing.

PLoS genetics, 13(4):e1006675 pii:PGENETICS-D-16-02023.

The indigenous people of the Tibetan Plateau have been the subject of much recent interest because of their unique genetic adaptations to high altitude. Recent studies have demonstrated that the Tibetan EPAS1 haplotype is involved in high altitude-adaptation and originated in an archaic Denisovan-related population. We sequenced the whole-genomes of 27 Tibetans and conducted analyses to infer a detailed history of demography and natural selection of this population. We detected evidence of population structure between the ancestral Han and Tibetan subpopulations as early as 44 to 58 thousand years ago, but with high rates of gene flow until approximately 9 thousand years ago. The CMS test ranked EPAS1 and EGLN1 as the top two positive selection candidates, and in addition identified PTGIS, VDR, and KCTD12 as new candidate genes. The advantageous Tibetan EPAS1 haplotype shared many variants with the Denisovan genome, with an ancient gene tree divergence between the Tibetan and Denisovan haplotypes of about 1 million years ago. With the exception of EPAS1, we observed no evidence of positive selection on Denisovan-like haplotypes.

RevDate: 2018-05-11
CmpDate: 2018-02-01

Jégou B, Sankararaman S, Rolland AD, et al (2017)

Meiotic Genes Are Enriched in Regions of Reduced Archaic Ancestry.

Molecular biology and evolution, 34(8):1974-1980.

About 1-6% of the genetic ancestry of modern humans today originates from admixture with archaic humans. It has recently been shown that autosomal genomic regions with a reduced proportion of Neanderthal and Denisovan ancestries (NA and DA) are significantly enriched in genes that are more expressed in testis than in other tissues. To determine whether a cellular segregation pattern would exist, we combined maps of archaic introgression with a cross-analysis of three transcriptomic datasets deciphering the transcriptional landscape of human gonadal cell types. We reveal that the regions deficient in both NA and DA contain a significant enrichment of genes transcribed in meiotic germ cells. The interbreeding of anatomically modern humans with archaic humans may have introduced archaic-derived alleles that contributed to genetic incompatibilities affecting meiosis that were subsequently purged by natural selection.

RevDate: 2018-04-04
CmpDate: 2018-04-04

Ao H, Liu CR, Roberts AP, et al (2017)

An updated age for the Xujiayao hominin from the Nihewan Basin, North China: Implications for Middle Pleistocene human evolution in East Asia.

Journal of human evolution, 106:54-65.

The Xujiayao site in the Nihewan Basin (North China) is one of the most important Paleolithic sites in East Asia. Twenty Homo fossils, which were previously assigned to an archaic Homo sapiens group, have been excavated along with more than 30,000 lithic artifacts and ∼5000 mammalian fossil specimens. Dating of the Xujiayao hominin has been pursued since its excavation in the 1970s, but its age has remained controversial because of limitations of the dating techniques that have been applied to available materials. Here, we report new ages for the Xujiayao hominin based on combined electron spin resonance (ESR) dating of quartz in the sediments and high-resolution magnetostratigraphy of the fluvio-lacustrine sequence. The magnetostratigraphy suggests that the upper Matuyama and Brunhes polarity chrons are recorded at Xujiayao. The ESR dating results indicate a pooled average age of 260-370 ka for the Homo-bearing layer, which is consistent with its position within the middle Brunhes normal polarity chron indicated by magnetostratigraphy. This age estimate makes the Xujiayao hominin among the oldest mid-Pleistocene hominins with derived Neanderthal traits in East Asia. This age is consistent with the time when early Denisovans, a sister group of Neanderthals, appeared and colonized eastern Eurasia. Our updated age and the Neanderthal-like traits of the Xujiayao Homo fossils, particularly the Denisovan-like molar teeth, make it possible that the Xujiayao hominin could represent an early Denisovan.

RevDate: 2018-03-26
CmpDate: 2018-03-26

Heidenreich B, Denisova E, Rachakonda S, et al (2017)

Genetic alterations in seborrheic keratoses.

Oncotarget, 8(22):36639-36649.

Seborrheic keratoses are common benign epidermal lesions that are associated with increased age and sun-exposure. Those lesions despite harboring multiple somatic alterations in contrast to malignant tumors appear to be genetically stable. In order to investigate and characterize the presence of recurrent mutations, we performed exome sequencing on DNA from one seborrheic keratosis lesion and corresponding blood cells from the same patients with follow up investigation of alterations identified by exome sequencing in 24 additional lesions from as many patients. In addition we investigated alterations in all lesions at specific genes loci that included FGFR3, PIK3CA, HRAS, BRAF, CDKN2A and TERT and DHPH3 promoters. The exome sequencing data indicated three mutations per Mb of the targeted sequence. The mutational pattern depicted typical UV signature with majority of alterations being C>T and CC>TT base changes at dipyrimidinic sites. The FGFR3 mutations were the most frequent, detected in 12 of 25 (48%) lesions, followed by the PIK3CA (32%), TERT promoter (24%) and DPH3 promoter mutations (24%). TERT promoter mutations associated with increased age and were present mainly in the lesions excised from head and neck. Three lesions also carried alterations in CDKN2A. FGFR3, TERT and DPH3 expression did not correlate with mutations in the respective genes and promoters; however, increased FGFR3 transcript levels were associated with increased FOXN1 levels, a suggested positive feedback loop that stalls malignant progression. Thus, in this study we report overall mutation rate through exome sequencing and show the most frequent mutations seborrheic keratosis.

RevDate: 2017-11-24
CmpDate: 2017-08-21

Kharitonova MI, Denisova AO, Andronova VL, et al (2017)

New modified 2-aminobenzimidazole nucleosides: Synthesis and evaluation of their activity against herpes simplex virus type 1.

Bioorganic & medicinal chemistry letters, 27(11):2484-2487.

Using the enzymatic transglycosylation reaction β-d-ribo- and 2'-deoxyribofuranosides of 2-amino-5,6-difluorobenzimidazole nucleosides have been synthesized. 2-Amino-5,6-difluoro-benzimidazole riboside proved to exhibit a selective antiviral activity (selectivity index >32) against a wild strain of the herpes simplex virus type 1, as well as towards virus strains that are resistant to acyclovir, cidofovir, and foscarnet. We believe that this compound might be used for treatment of herpes infections in those cases, when acyclovir is not efficient.

RevDate: 2018-06-14
CmpDate: 2017-08-14

Hu Y, Malyutina S, Pikhart H, et al (2017)

The Relationship between Body Mass Index and 10-Year Trajectories of Physical Functioning in Middle-Aged and Older Russians: Prospective Results of the Russian HAPIEE Study.

The journal of nutrition, health & aging, 21(4):381-388.

OBJECTIVE: To investigate the associations of overweight and obesity with longitudinal decline in physical functioning (PF) among middle-aged and older Russians.

DESIGN: Prospective cohort study.

SETTING: Four rounds of data collection in the Russian Health, Alcohol and Psychosocial factors In Eastern Europe study with up to 10 years of follow-up.

PARTICIPANTS: 9,222 men and women aged 45-69 years randomly selected from the population of two districts of Novosibirsk, Russia.

MEASUREMENTS: PF score (range 0-100) was measured by the Physical Functioning Subscale (PF-10) of the 36-item Short Form Health Survey (SF-36) at baseline and three subsequent occasions. Body mass index (BMI), derived from objectively measured body height and weight at baseline, was classified into normal weight (BMI 18.5-24.9), overweight (BMI 25.0-29.9), obesity class I (BMI 30.0-34.9), and obesity class II+ (BMI≥35.0).

RESULTS: The mean annual decline in the PF score during the follow-up was -1.92 (95% confidence interval -2.17; -1.68) in men and -1.91 (-2.13; -1.68) in women. At baseline, compared with normal weight, obesity classes I and II+ (but not overweight) were associated with significantly lower PF in both sexes. In prospective analyses, the decline in PF was faster in overweight men (difference from normal weight subjects -0.38 [-0.63; -0.14]), class I obese men and women (-0.49 [-0.82; -0.17] and -0.44 [-0.73; -0.15] respectively) and class II+ obese men and women (-1.13 [-1.73; -0.53] and -0.43 [-0.77; -0.09] respectively). Adjustment for physical activity and other covariates did not materially change the results.

CONCLUSIONS: PF decreased more rapidly in obese men and women than among those with normal weight. The adverse effect of high BMI on PF trajectories appeared to be more pronounced in men than in women, making more extremely obese Russian men an important target population to prevent/slow down the process of decline in PF.

RevDate: 2018-01-18
CmpDate: 2018-01-18

Baklanova YV, Lipina OA, Maksimova LG, et al (2017)

Nd3+, Ho3+-codoped garnet-related Li7La3Hf2O12 phosphor with NIR luminescence.

Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy, 180:105-109.

Simultaneous emission lines around 1.05μm, 1.3μm, 1.8μm, 2.1μm and 2.7μm have been observed in Li7La3-xNdxHf2O12:Ho3+ (x=0.00-0.15) under 808nm laser diode excitation. Near-infrared luminescence due to holmium ions with residual concentration in the Li7La3Hf2O12 host has been studied. The intensity of 2.1 and 2.7μm lines associated with 5I7→5I8 and 5I6→5I7 transitions in Ho3+ depends on the neodymium codopant concentration. This result indicates that Nd3+ ions can be potentially used as sensitizers for Ho3+ ions to stimulate the intense near-infrared emission in this system. Possible energy transfer mechanisms between lanthanide ions have been briefly discussed.

RevDate: 2017-05-09
CmpDate: 2017-05-09

Denisova AV, Tibbelin J, Emanuelsson R, et al (2017)

A Computational Investigation of the Substituent Effects on Geometric, Electronic, and Optical Properties of Siloles and 1,4-Disilacyclohexa-2,5-dienes.

Molecules (Basel, Switzerland), 22(3): pii:molecules22030370.

Thirty two differently substituted siloles 1a-1p and 1,4-disilacyclohexa-2,5-dienes 2a-2p were investigated by quantum chemical calculations using the PBE0 hybrid density functional theory (DFT) method. The substituents included σ-electron donating and withdrawing, as well as π-electron donating and withdrawing groups, and their effects when placed at the Si atom(s) or at the C atoms were examined. Focus was placed on geometries, frontier orbital energies and the energies of the first allowed electronic excitations. We analyzed the variation in energies between the orbitals which correspond to HOMO and LUMO for the two parent species, here represented as ΔεHL, motivated by the fact that the first allowed transitions involve excitation between these orbitals. Even though ΔεHL and the excitation energies are lower for siloles than for 1,4-disilacyclohexa-2,5-dienes the latter display significantly larger variations with substitution. The ΔεHL of the siloles vary within 4.57-5.35 eV (ΔΔεHL = 0.78 eV) while for the 1,4-disilacyclohexa-2,5-dienes the range is 5.49-7.15 eV (ΔΔεHL = 1.66 eV). The excitation energy of the first allowed transitions display a moderate variation for siloles (3.60-4.41 eV) whereas the variation for 1,4-disilacyclohexa-2,5-dienes is nearly doubled (4.69-6.21 eV). Cyclobutadisiloles combine the characteristics of siloles and 1,4-disilacyclohexa-2,5-diene by having even lower excitation energies than siloles yet also extensive variation in excitation energies to substitution of 1,4-disilacyclohexa-2,5-dienes (3.47-4.77 eV, variation of 1.30 eV).

RevDate: 2017-07-06
CmpDate: 2017-07-06

Bogomolov DV, Putintsev VA, Zbrueva YV, et al (2017)

[Certain immunohistochemical markers of the intravitality of strangulation mechanical asphyxia].

Sudebno-meditsinskaia ekspertiza, 60(1):8-10.

Thus article was designed to report the results of the investigations into specific histological features of the skin and soft tissue samples taken from the strangulation areas on the neck and from the lungs of the persons who had committed suicide by hanging. The studies revealed the well apparent expression of fibrinogen in the derma and the subdermal cellolocutaneous layer of the skin subjected to intravital strangulation. Similar changes were absent in lung alveoli.

RevDate: 2017-03-15
CmpDate: 2017-03-15

Bugaeva LI, Denisova TD, Sergeeva SA, et al (2017)

Effects of Afobazole on Postnatal Development of Rat Offspring.

Bulletin of experimental biology and medicine, 162(4):441-444.

Physical development, development of sensory and motor reflexes, behavioral and mnestic patterns were studied infantile and juvenile rat pups born by female rats receiving Afobazole during pregnancy. Physical development and development of sensory and motor reflexes in rats were completed without pathologies by the age of 2 months. During the infantile period, the rat pups demonstrated reduced body weight gain, delayed eye opening and pupillary response formation, decreased muscle force, and suppressed motor behavior. During the juvenile period, body weight gain and development of motor behavior were intensified. Females demonstrated later vagina opening and poorer mnestic responses. In males, the terms of sexual maturation were unchanged and processes of learning and memory retrieval were not impaired.

RevDate: 2017-12-14
CmpDate: 2017-10-30

Denisova K, Zhao G, Wang Z, et al (2017)

Cortical interactions during the resolution of information processing demands in autism spectrum disorders.

Brain and behavior, 7(2):e00596 pii:BRB3596.

INTRODUCTION: Our flexible and adaptive interactions with the environment are guided by our individual representation of the physical world, estimated through sensation and evaluation of available information against prior knowledge. When linking sensory evidence with higher-level expectations for action, the central nervous system (CNS) in typically developing (TD) individuals relies in part on distributed and interacting cortical regions to communicate neuronal signals flexibly across the brain. Increasing evidence suggests that the balance between levels of signal and noise during information processing may be disrupted in individuals with Autism Spectrum Disorders (ASD).

METHODS: Participants with and without ASD performed a visuospatial interference task while undergoing functional Magnetic Resonance Imaging (fMRI). We empirically estimated parameters characterizing participants' latencies and their subtle fluctuations (noise accumulation) over the 16-min scan. We modeled hemodynamic activation and used seed-based analyses of neural coupling to study dysfunction in interference-specific connectivity in a subset of ASD participants who were nonparametrically matched to TD participants on age, male-to-female ratio, and magnitude of movement during the scan.

RESULTS: Stochastic patterns of response fluctuations reveal significantly higher noise-to-signal levels and a more random and noisy structure in ASD versus TD participants, and in particular ASD adults who have the greatest clinical autistic deficits. While individuals with ASD show an overall weaker modulation of interference-specific functional connectivity relative to TD individuals, in particular between the seeds of Anterior Cingulate Cortex (ACC) and Inferior Parietal Sulcus (IPS) and the rest of the brain, we found that in ASD, higher uncertainty during the task is linked to increased interference-specific coupling between bilateral anterior insula and prefrontal cortex.

CONCLUSIONS: Subtle and informative differences in the structure of experiencing information exist between ASD and TD individuals. Our findings reveal in ASD an atypical capacity to apply previously perceived information in a manner optimal for adaptive functioning, plausibly revealing suboptimal message-passing across the CNS.

RevDate: 2018-04-12
CmpDate: 2018-03-08

Tashi T, Scott Reading N, Wuren T, et al (2017)

Gain-of-function EGLN1 prolyl hydroxylase (PHD2 D4E:C127S) in combination with EPAS1 (HIF-2α) polymorphism lowers hemoglobin concentration in Tibetan highlanders.

Journal of molecular medicine (Berlin, Germany), 95(6):665-670.

Tibetans have lived at high altitude for generations and are thought to be genetically adapted to hypoxic environments. Most are protected from hypoxia-induced polycythemia, and a haplotype of EPAS1, encoding hypoxia-inducible factor (HIF-2α), has been associated with lower hemoglobin levels. We earlier reported a Tibetan-specific EGLN1 haplotype encoding PHD2 which abrogates HIF augmentation in hypoxia. We genotyped 347 Tibetan individuals from varying altitudes for both the Tibetan-specific EGLN1 haplotype and 10 candidate SNPs in the EPAS1 haplotype and correlated their association with hemoglobin levels. The effect of the EGLN1 haplotype on hemoglobin exhibited age dependency at low altitude, while at higher altitudes, it showed a trend to lower hemoglobin levels in the presence of the Tibetan-selected EPAS1 rs142764723 C/C allele. The observed gene-environment and gene-gene interactions and the moderate effect of the EGLN1 and EPAS1 haplotypes on hemoglobin indicate that other modifiers exist. It remains to be determined whether a blunting of erythropoiesis or other physiological consequences of HIF downregulation are the primary drivers of these genetic adaptations among Tibetans.

KEY MESSAGE: Most Tibetans are protected from polycythemia while living in high altitude. An EGLN1 co-adapted haplotype, EGLN1 c.12C>G, c.380G>C is uniquely Tibetan. The Tibetan EPAS1 haplotype has introgressed from the Denisovan genome. While EGLN1 and EPAS1 genotypes lower Hb, this study indicates additional Hb modifiers.

RevDate: 2018-04-07
CmpDate: 2018-01-26

Povysil G, S Hochreiter (2016)

IBD Sharing between Africans, Neandertals, and Denisovans.

Genome biology and evolution, 8(12):3406-3416.

Interbreeding between ancestors of humans and other hominins outside of Africa has been studied intensively, while their common history within Africa still lacks proper attention. However, shedding light on human evolution in this time period about which little is known, is essential for understanding subsequent events outside of Africa. We investigate the genetic relationships of humans, Neandertals, and Denisovans by identifying very short DNA segments in the 1000 Genomes Phase 3 data that these hominins share identical by descent (IBD). By focusing on low frequency and rare variants, we identify very short IBD segments with high confidence. These segments reveal events from a very distant past because shorter IBD segments are presumably older than longer ones. We extracted two types of very old IBD segments that are not only shared among humans, but also with Neandertals and/or Denisovans. The first type contains longer segments that are found primarily in Asians and Europeans where more segments are found in South Asians than in East Asians for both Neandertal and Denisovan. These longer segments indicate complex admixture events outside of Africa. The second type consists of shorter segments that are shared mainly by Africans and therefore may indicate events involving ancestors of humans and other ancient hominins within Africa. Our results from the autosomes are further supported by an analysis of chromosome X, on which segments that are shared by Africans and match the Neandertal and/or Denisovan genome were even more prominent. Our results indicate that interbreeding with other hominins was a common feature of human evolution starting already long before ancestors of modern humans left Africa.

RevDate: 2017-10-26
CmpDate: 2017-07-11

Carus-Cadavieco M, Gorbati M, Ye L, et al (2017)

Gamma oscillations organize top-down signalling to hypothalamus and enable food seeking.

Nature, 542(7640):232-236.

Both humans and animals seek primary rewards in the environment, even when such rewards do not correspond to current physiological needs. An example of this is a dissociation between food-seeking behaviour and metabolic needs, a notoriously difficult-to-treat symptom of eating disorders. Feeding relies on distinct cell groups in the hypothalamus, the activity of which also changes in anticipation of feeding onset. The hypothalamus receives strong descending inputs from the lateral septum, which is connected, in turn, with cortical networks, but cognitive regulation of feeding-related behaviours is not yet understood. Cortical cognitive processing involves gamma oscillations, which support memory, attention, cognitive flexibility and sensory responses. These functions contribute crucially to feeding behaviour by unknown neural mechanisms. Here we show that coordinated gamma (30-90 Hz) oscillations in the lateral hypothalamus and upstream brain regions organize food-seeking behaviour in mice. Gamma-rhythmic input to the lateral hypothalamus from somatostatin-positive lateral septum cells evokes food approach without affecting food intake. Inhibitory inputs from the lateral septum enable separate signalling by lateral hypothalamus neurons according to their feeding-related activity, making them fire at distinct phases of the gamma oscillation. Upstream, medial prefrontal cortical projections provide gamma-rhythmic inputs to the lateral septum; these inputs are causally associated with improved performance in a food-rewarded learning task. Overall, our work identifies a top-down pathway that uses gamma synchronization to guide the activity of subcortical networks and to regulate feeding behaviour by dynamic reorganization of functional cell groups in the hypothalamus.

RevDate: 2018-04-04
CmpDate: 2017-06-29

Khabarova EA, Denisova NP, Rogov DY, et al (2016)

[The preliminary results of subthalamic nucleus stimulation after destructive surgery in Parkinson's disease].

Zhurnal voprosy neirokhirurgii imeni N. N. Burdenko, 80(6):36-41.

OBJECTIVE: To evaluate the efficacy of bilateral electrical stimulation (ES) of the subthalamic nucleus (STN) in patients with Parkinson's disease (PD) after preceding pallidotomy or ventrolateral (VL) thalamotomy.

MATERIAL AND METHODS: The study included 9 patients with bilateral STN ES who had undergone previous unilateral destructive surgery on the subcortical structures: pallidotomy (5 patients) and VL thalamotomy (4). A control group consisted of 9 patients with STN ES, without prior destructive surgery. A clinical and neurological examination included quantitative assessment of motor disturbances using the Hoehn-Yahr scale and Unified Parkinson's disease rating scale (UPDRS). UPDRS was used to evaluate the motor activity (IIIrd part of the scale) and severity of drug-induced dyskinesia and motor fluctuations (IVth part of the scale).

RESULTS: In the group of STN ES with preceding destruction of the subcortical structures, an improvement in motor functions in the early period (6 months) was 45%, and severity of drug-induced complications was decreased by 75%. In a group of STN DBS without destruction, motor disturbances were improved by 61%, and drug-induced complications were decreased by 77%. Improvement in motor functions amounted to 51.9% in patients with preceding pallidotomy (GPi destruction) and 37.5% in a group with preceding VL thalamotomy. The equivalent dose of levodopa was reduced by 51.39%, from 1,008±346 to 490±194, in the study group and by 55.04%, from 963±96 to 433±160, in the control group.

CONCLUSION: Bilateral STN neurostimulation is effective after unilateral stereotaxic destruction of the subcortical structures in PD patients.

RevDate: 2018-06-26
CmpDate: 2018-06-26

Bugaeva LI, Denisova TD, Mazanova YA, et al (2017)


Eksperimental'naia i klinicheskaia farmakologiia, 80(1):28-31.

It is experimentally established that afobazole produces no damaging action on the organogenesis and fetogenic processes registered in the postnatal period of rat offspring development. It was noted that, in rat babies in lactation age, the dynamics of body weight gain was lower on average by 7.4% (p < 0.05) in males and 17.0% (p < 0.001) in females; the rate of muscular force maturing was lower by 2.7% (p < 0.05); and the locomotive activity was lower (by 19.4% for ver- tical standings and by 50% for looking into floor holes, p < 0.05) compared to control values. For the same offspring passed to definitive food, the body weight gain and behavioral activity did not differ from control indicators, while the terms of sexual development were delayed in females and did not change in males. By two-month age, the physical development of rat offspring was completely created and met physiological standards.

RevDate: 2018-06-26
CmpDate: 2017-07-24

Racimo F, Gokhman D, Fumagalli M, et al (2017)

Archaic Adaptive Introgression in TBX15/WARS2.

Molecular biology and evolution, 34(3):509-524.

A recent study conducted the first genome-wide scan for selection in Inuit from Greenland using single nucleotide polymorphism chip data. Here, we report that selection in the region with the second most extreme signal of positive selection in Greenlandic Inuit favored a deeply divergent haplotype that is closely related to the sequence in the Denisovan genome, and was likely introgressed from an archaic population. The region contains two genes, WARS2 and TBX15, and has previously been associated with adipose tissue differentiation and body-fat distribution in humans. We show that the adaptively introgressed allele has been under selection in a much larger geographic region than just Greenland. Furthermore, it is associated with changes in expression of WARS2 and TBX15 in multiple tissues including the adrenal gland and subcutaneous adipose tissue, and with regional DNA methylation changes in TBX15.

RevDate: 2018-01-28
CmpDate: 2017-08-01

Pajic P, Lin YL, Xu D, et al (2016)

The psoriasis-associated deletion of late cornified envelope genes LCE3B and LCE3C has been maintained under balancing selection since Human Denisovan divergence.

BMC evolutionary biology, 16(1):265 pii:10.1186/s12862-016-0842-6.

BACKGROUND: A common, 32kb deletion of LCE3B and LCE3C genes is strongly associated with psoriasis. We recently found that this deletion is ancient, predating Human-Denisovan divergence. However, it was not clear why negative selection has not removed this deletion from the population.

RESULTS: Here, we show that the haplotype block that harbors the deletion (i) retains high allele frequency among extant and ancient human populations; (ii) harbors unusually high nucleotide variation (π, P < 4.1 × 10-3); (iii) contains an excess of intermediate frequency variants (Tajima's D, P < 3.9 × 10-3); and (iv) has an unusually long time to coalescence to the most recent common ancestor (TSel, 0.1 quantile).

CONCLUSIONS: Our results are most parsimonious with the scenario where the LCE3BC deletion has evolved under balancing selection in humans. More broadly, this is consistent with the hypothesis that a balance between autoimmunity and natural vaccination through increased exposure to pathogens maintains this deletion in humans.

RevDate: 2017-08-16
CmpDate: 2017-08-16

Noe F, Polster J, Geithe C, et al (2017)

OR2M3: A Highly Specific and Narrowly Tuned Human Odorant Receptor for the Sensitive Detection of Onion Key Food Odorant 3-Mercapto-2-methylpentan-1-ol.

Chemical senses, 42(3):195-210.

The detection of key food odorants appears to be an important capability of odorant receptors. Here, thiols occupy an outstanding position among the 230 known key food odorants because of their very low odor thresholds. Members of the homologous series of 3-mercapto-2-methylalkan-1-ols have been described as onion key food odorants or food constituents and are detected at logarithmically different thresholds. 3-Mercapto-2-methylpentan-1-ol being the only key food odorant within this series also has the lowest odor threshold. Most odorants typically activate combinations of odorant receptors, which may be narrowly or broadly tuned. Consequently, a specific receptor activation pattern will define an odor quality. In contrast, here we show that just 1 of the 391 human odorant receptors, OR2M3, responded exclusively to 3-mercapto-2-methylpentan-1-ol of the 190 key food odorants tested, with a half maximal effective concentration at submicromolar concentration. Moreover, neither the Denisovan OR2M3 nor the closest OR2M3 homologs from five species did respond to this compound. This outstanding specificity of extremely narrowly tuned human OR2M3 can explain both odor qualities and odor threshold trend within a homologous series of 3-mercapto-2-methylalkan-1-ols and suggests a modern human-specific, food-related function of OR2M3 in detecting a single onion key food odorant.

RevDate: 2018-05-21
CmpDate: 2018-05-21

Torres EB, K Denisova (2016)

Motor noise is rich signal in autism research and pharmacological treatments.

Scientific reports, 6:37422 pii:srep37422.

The human body is in constant motion, from every breath that we take, to every visibly purposeful action that we perform. Remaining completely still on command is a major achievement as involuntary fluctuations in our motions are difficult to keep under control. Here we examine the noise-to-signal ratio of micro-movements present in time-series of head motions extracted from resting-state functional magnetic resonance imaging scans in 1048 participants. These included individuals with autism spectrum disorders (ASD) and healthy-controls in shared data from the Autism Brain Imaging Data Exchange (ABIDE) and the Attention-Deficit Hyperactivity Disorder (ADHD-200) databases. We find excess noise and randomness in the ASD cases, suggesting an uncertain motor-feedback signal. A power-law emerged describing an orderly relation between the dispersion and shape of the probability distribution functions best describing the stochastic properties under consideration with respect to intelligence quotient (IQ-scores). In ASD, deleterious patterns of noise are consistently exacerbated with the presence of secondary (comorbid) neuropsychiatric diagnoses, lower verbal and performance intelligence, and autism severity. Importantly, such patterns in ASD are present whether or not the participant takes psychotropic medication. These data unambiguously establish specific noise-to-signal levels of head micro-movements as a biologically informed core feature of ASD.

RevDate: 2018-01-22
CmpDate: 2018-01-22

Gittelman RM, Schraiber JG, Vernot B, et al (2016)

Archaic Hominin Admixture Facilitated Adaptation to Out-of-Africa Environments.

Current biology : CB, 26(24):3375-3382.

As modern humans dispersed from Africa throughout the world, they encountered and interbred with archaic hominins, including Neanderthals and Denisovans [1, 2]. Although genome-scale maps of introgressed sequences have been constructed [3-6], considerable gaps in knowledge remain about the functional, phenotypic, and evolutionary significance of archaic hominin DNA that persists in present-day individuals. Here, we describe a comprehensive set of analyses that identified 126 high-frequency archaic haplotypes as putative targets of adaptive introgression in geographically diverse populations. These loci are enriched for immune-related genes (such as OAS1/2/3, TLR1/6/10, and TNFAIP3) and also encompass genes (including OCA2 and BNC2) that influence skin pigmentation phenotypes. Furthermore, we leveraged existing and novel large-scale gene expression datasets to show many positively selected archaic haplotypes act as expression quantitative trait loci (eQTLs), suggesting that modulation of transcript abundance was a common mechanism facilitating adaptive introgression. Our results demonstrate that hybridization between modern and archaic hominins provided an important reservoir of advantageous alleles that enabled adaptation to out-of-Africa environments.

RevDate: 2018-02-07
CmpDate: 2017-12-07

Birolo C, Zannin ME, Arsenyeva S, et al (2016)

Comparable Efficacy of Abatacept Used as First-line or Second-line Biological Agent for Severe Juvenile Idiopathic Arthritis-related Uveitis.

The Journal of rheumatology, 43(11):2068-2073.

OBJECTIVE: Abatacept (ABA) has recently been proposed as second-line treatment in patients with juvenile idiopathic arthritis (JIA)-associated uveitis refractory to anti-tumor necrosis factor-α (anti-TNF) agents, but little is known about its efficacy as a first-line approach. The aim of the present study was to compare the safety and efficacy of ABA as a first-line biological agent (ABA-1) with that of ABA as a second-line treatment after 1 or more anti-TNF agents (ABA-2), in patients with severe JIA-related uveitis.

METHODS: In this multicenter study, we collected data on patients with severe JIA-related uveitis treated with ABA as a first-line or second-line biological agent. Changes in frequency of uveitis flares/year and ocular complications before and after ABA treatment, clinical remission, and side effects were recorded.

RESULTS: Thirty-five patients with a mean age of 10.8 years were treated with ABA for a mean period of 19.6 months. In 4 patients, ABA administration was discontinued, owing to inefficacy on arthritis in 3 cases and allergic reaction in 1. Thirty-one patients, 14 in the ABA-1 group and 17 in the ABA-2 group, completed the 12-month followup period; of these, 17 (54.8%) had clinical remission. The mean frequency of uveitis flares decreased from 4.1 to 1.2 in the ABA-1 group (p = 0.002) and from 3.7 to 1.2 in the ABA-2 group (p = 0.004). Preexisting ocular complications improved or remained stable in all but 5 patients, all in the ABA-2 group. No significant difference was found between the efficacy of the 2 treatment modalities. ABA confirmed its good safety profile.

CONCLUSION: ABA, used as first-line biological treatment or after 1 or more anti-TNF agents, induces a comparable improvement in severe refractory JIA-related uveitis.

RevDate: 2017-11-16
CmpDate: 2017-03-02

Voevoda MI, Kovalkova NA, Ragino YI, et al (2016)

[Prevalence of metabolic syndrome in 25-45-year-old Novosibirsk dwellers].

Terapevticheskii arkhiv, 88(10):51-56.

AIM: To study the prevalence of metabolic syndrome (MS) and its components in a 25-45-year-old Novosibirsk population.

SUBJECTS AND METHODS: The Novosibirsk Research Institute of Internal and Preventive Medicine conducted a cross-sectional population-based survey in one of the typical districts of Novosibirsk in 2013-2015. The survey covered 346 men and 408 women. The criteria of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (NCEP-ATP III, 2001), the International Diabetes Federation (IDF, 2005), the Joint Interim Statement (JIS, 2009), and the All-Russian Research Society of Cardiologists (ARRSC, 2009) were used to detect MS. According to the ARRSC criteria, MS was recorded if a waist circumference (WC) was >80 cm for women and >94 cm for men in conjunction with 2 of the following criteria: a blood pressure ≥130/85 mm Hg, triglycerides (TG) ≥1.7 mmol/l, high-density lipoprotein (HDL) cholesterol <1.0 mmol/l for men and <1.2 mmol/l for women, low-density lipoprotein (LDL) cholesterol >3.0 mmol/l, and plasma glucose level ≥6.1 mmol/l.

RESULTS: According to the 2009 ARRSC criteria, the prevalence of abdominal obesity, hypertension, hypertriglyceridemia, HDL hypocholestrolemia, LDL hypercholesterolemia, and high plasma glucose level was 42.6, 33.5, 17.5, 24.3, 64.8, and 29%, respectively. The prevalence of MS in 25-45-year-old Novosibirsk people was 17% (19.9% in men and 14.5% in women) according to the 2001 NCEP-ATP III, 27% (29.5% in men and 24.5% in women) according to the 2005 IDF criteria, 30% (35.8% in men and 25% in women) according to the 2009 JIS criteria, and 29.3% (33.2% in men and 26% in women) according to the 2009 ARRSC criteria, this was higher among men than women. There was an increase in the prevalence of MS with age.

CONCLUSION: The highest prevalence of MS was 30 and 29.3% when using the 2009 JIS and the 2009 ARRSC criteria, respectively. Whatever the criterion was used, MS was more frequently recorded in men than women.

RevDate: 2018-01-30
CmpDate: 2017-12-26

Kozela M, Bobak M, Besala A, et al (2016)

The association of depressive symptoms with cardiovascular and all-cause mortality in Central and Eastern Europe: Prospective results of the HAPIEE study.

European journal of preventive cardiology, 23(17):1839-1847.

BACKGROUND: Studies in western populations have shown a positive association between depression and cardiovascular disease (CVD) and all-cause mortality. The association with depressive symptoms seems to be graded, rather than limited to the presence versus the absence of depression. Evidence from populations with potentially different patterns of confounders helps to address the consistency of these findings. The objective of the study was to investigate the association between depressive symptoms and all-cause and CVD mortality in populations of Central and Eastern Europe.

STUDY DESIGN: This was a prospective cohort study.

METHODS: A total of 24,542 participants aged 45-69 years, randomly selected from populations of Novosibirsk (Russia), Krakow (Poland) and six Czech towns, were included. Depressive symptoms, assessed by the 20-item Center for Epidemiologic Studies Depression (CES-D) scale, were used as both continuous and categorical variables. Data on deaths were obtained from local or national death registers. Associations between depression and mortality were assessed using Cox proportional hazards models.

RESULTS: Over a median of 7 years, 2091 deaths from all causes and 850 CVD deaths occurred in the cohorts. There was a graded association between CES-D score and mortality; the hazard ratio (HR) of CVD mortality for a 1 SD increase in CES-D was 1.20 (95% confidence interval (CI): 1.16-1.24) in men and 1.23 (95% CI: 1.12-1.35) in women; for all-cause mortality, the HRs were 1.13 (95% CI: 1.09-1.18) and 1.17 (95% CI: 1.10-1.25), respectively. The results were similar across countries.

CONCLUSIONS: Depressive symptoms predicted CVD and all-cause mortality independently of a wide range of potential confounders. The association followed a gradient and increased mortality risks were associated with scores below the cut-offs that are commonly used to define 'depression'.

RevDate: 2018-03-28
CmpDate: 2017-06-08

Racimo F, Marnetto D, E Huerta-Sánchez (2017)

Signatures of Archaic Adaptive Introgression in Present-Day Human Populations.

Molecular biology and evolution, 34(2):296-317.

Comparisons of DNA from archaic and modern humans show that these groups interbred, and in some cases received an evolutionary advantage from doing so. This process-adaptive introgression-may lead to a faster rate of adaptation than is predicted from models with mutation and selection alone. Within the last couple of years, a series of studies have identified regions of the genome that are likely examples of adaptive introgression. In many cases, once a region was ascertained as being introgressed, commonly used statistics based on both haplotype as well as allele frequency information were employed to test for positive selection. Introgression by itself, however, changes both the haplotype structure and the distribution of allele frequencies, thus confounding traditional tests for detecting positive selection. Therefore, patterns generated by introgression alone may lead to false inferences of positive selection. Here we explore models involving both introgression and positive selection to investigate the behavior of various statistics under adaptive introgression. In particular, we find that the number and allelic frequencies of sites that are uniquely shared between archaic humans and specific present-day populations are particularly useful for detecting adaptive introgression. We then examine the 1000 Genomes dataset to characterize the landscape of uniquely shared archaic alleles in human populations. Finally, we identify regions that were likely subject to adaptive introgression and discuss some of the most promising candidate genes located in these regions.

RevDate: 2017-08-16

Stankiewicz P (2016)

One pedigree we all may have come from - did Adam and Eve have the chromosome 2 fusion?.

Molecular cytogenetics, 9:72 pii:283.

BACKGROUND: In contrast to Great Apes, who have 48 chromosomes, modern humans and likely Neandertals and Denisovans have and had, respectively, 46 chromosomes. The reduction in chromosome number was caused by the head-to-head fusion of two ancestral chromosomes to form human chromosome 2 (HSA2) and may have contributed to the reproductive barrier with Great Apes.

RESULTS: Next generation sequencing and molecular clock analyses estimated that this fusion arose prior to our last common ancestor with Neandertal and Denisovan hominins ~ 0.74 - 4.5 million years ago.

HYPOTHESES: I propose that, unlike recurrent Robertsonian translocations in humans, the HSA2 fusion was a single nonrecurrent event that spread through a small polygamous clan population bottleneck. Its heterozygous to homozygous conversion, fixation, and accumulation in the succeeding populations was likely facilitated by an evolutionary advantage through the genomic loss rather than deregulation of expression of the gene(s) flanking the HSA2 fusion site at 2q13.

CONCLUSIONS: The origin of HSA2 might have been a critical evolutionary event influencing higher cognitive functions in various early subspecies of hominins. Next generation sequencing of Homo heidelbergensis and Homo erectus genomes and complete reconstruction of DNA sequence of the orthologous subtelomeric chromosomes in Great Apes should enable more precise timing of HSA2 formation and better understanding of its evolutionary consequences.

RevDate: 2017-02-20

Papadakis R, Li H, Bergman J, et al (2016)

Metal-free photochemical silylations and transfer hydrogenations of benzenoid hydrocarbons and graphene.

Nature communications, 7:12962 pii:ncomms12962.

The first hydrogenation step of benzene, which is endergonic in the electronic ground state (S0), becomes exergonic in the first triplet state (T1). This is in line with Baird's rule, which tells that benzene is antiaromatic and destabilized in its T1 state and also in its first singlet excited state (S1), opposite to S0, where it is aromatic and remarkably unreactive. Here we utilized this feature to show that benzene and several polycyclic aromatic hydrocarbons (PAHs) to various extents undergo metal-free photochemical (hydro)silylations and transfer-hydrogenations at mild conditions, with the highest yield for naphthalene (photosilylation: 21%). Quantum chemical computations reveal that T1-state benzene is excellent at H-atom abstraction, while cyclooctatetraene, aromatic in the T1 and S1 states according to Baird's rule, is unreactive. Remarkably, also CVD-graphene on SiO2 is efficiently transfer-photohydrogenated using formic acid/water mixtures together with white light or solar irradiation under metal-free conditions.

RevDate: 2017-05-15
CmpDate: 2017-05-15

Yasukochi Y, J Ohashi (2017)

Elucidating the origin of HLA-B*73 allelic lineage: Did modern humans benefit by archaic introgression?.

Immunogenetics, 69(1):63-67.

A previous study reported that some of the human leukocyte antigen (HLA) alleles and haplotypes in present-day humans were acquired by admixture with archaic humans; specifically, an exceptionally diverged HLA-B*73 allele was proposed to be transmitted from Denisovans, although the DNA sequence of HLA-B*73 has not been detected in the Denisovan genome. Here, we argue against the hypothesis that HLA-B*73 introgressed from Denisovans into early modern humans. A phylogenetic analysis revealed that HLA-B*73:01 formed a monophyletic group with a chimpanzee MHC-B allele, strongly suggesting that the HLA-B*73 allelic lineage has been maintained in humans as well as in chimpanzees since the divergence of humans and chimpanzees. The global distribution of HLA-B*73 allele showed that the population frequency of HLA-B*73 in west Asia (0.24 %)-a possible site of admixture with Denisovans-is lower than that in Europe (0.72 %) and in south Asia (0.69 %). Furthermore, HLA-B*73 is not observed in Melanesia even though the Melanesian genome contains the highest proportion of Denisovan ancestry in present-day human populations. Single nucleotide polymorphisms in HLA-A*11-HLA-C*12:02 or HLA-A*11-C*15 haplotypes, one of which was assumed to be transmitted together with HLA-B*73 from Denisovans by the study of Abi-Rached and colleagues, were not differentiated from those in other HLA-A-C haplotypes in modern humans. These results do not support the introgression hypothesis. Thus, we conclude that it is highly likely that HLA-B*73 allelic lineage has been maintained in the direct ancestors of modern humans.

RevDate: 2018-01-30
CmpDate: 2017-09-05

Kaur A, Denisova OV, Qiao X, et al (2016)

PP2A Inhibitor PME-1 Drives Kinase Inhibitor Resistance in Glioma Cells.

Cancer research, 76(23):7001-7011.

Glioblastoma multiforme lacks effective therapy options. Although deregulated kinase pathways are drivers of malignant progression in glioblastoma multiforme, glioma cells exhibit intrinsic resistance toward many kinase inhibitors, and the molecular basis of this resistance remains poorly understood. Here, we show that overexpression of the protein phosphatase 2A (PP2A) inhibitor protein PME-1 drives resistance of glioma cells to various multikinase inhibitors. The PME-1-elicited resistance was dependent on specific PP2A complexes and was mediated by a decrease in cytoplasmic HDAC4 activity. Importantly, both PME-1 and HDAC4 associated with human glioma progression, supporting clinical relevance of the identified mechanism. Synthetic lethality induced by both PME-1 and HDAC4 inhibition was dependent on the coexpression of proapoptotic protein BAD. Thus, PME-1-mediated PP2A inhibition is a novel mechanistic explanation for multikinase inhibitor resistance in glioma cells. Clinically, these results may inform patient stratification strategies for future clinical trials with selected kinase inhibitors in glioblastoma multiforme. Cancer Res; 76(23); 7001-11. ©2016 AACR.

RevDate: 2017-12-05
CmpDate: 2017-12-05

Wall JD, D Yoshihara Caldeira Brandt (2016)

Archaic admixture in human history.

Current opinion in genetics & development, 41:93-97.

Modern humans evolved in Southern or Eastern Africa, and spread from there across the rest of the world. As they expanded across Africa and Eurasia, they encountered other hominin groups. The extent to which modern and 'archaic' human groups interbred is an area of active research, and while we know that modern humans interbred with Neanderthals and Denisovans, there is not yet agreement on how many admixture events there were or on how much Neanderthal or Denisovan DNA can be found in contemporary genomes. Here we review what is known about archaic admixture in human history, with a focus on what has been discovered in the past 2 years.

RevDate: 2017-02-24

Aarts JM, Alink GM, Scherjon F, et al (2016)

Fire Usage and Ancient Hominin Detoxification Genes: Protective Ancestral Variants Dominate While Additional Derived Risk Variants Appear in Modern Humans.

PloS one, 11(9):e0161102 pii:PONE-D-16-05619.

Studies of the defence capacity of ancient hominins against toxic substances may contribute importantly to the reconstruction of their niche, including their diets and use of fire. Fire usage implies frequent exposure to hazardous compounds from smoke and heated food, known to affect general health and fertility, probably resulting in genetic selection for improved detoxification. To investigate whether such genetic selection occurred, we investigated the alleles in Neanderthals, Denisovans and modern humans at gene polymorphisms well-known to be relevant from modern human epidemiological studies of habitual tobacco smoke exposure and mechanistic evidence. We compared these with the alleles in chimpanzees and gorillas. Neanderthal and Denisovan hominins predominantly possess gene variants conferring increased resistance to these toxic compounds. Surprisingly, we observed the same in chimpanzees and gorillas, implying that less efficient variants are derived and mainly evolved in modern humans. Less efficient variants are observable from the first early Upper Palaeolithic hunter-gatherers onwards. While not clarifying the deep history of fire use, our results highlight the long-term stability of the genes under consideration despite major changes in the hominin dietary niche. Specifically for detoxification gene variants characterised as deleterious by epidemiological studies, our results confirm the predominantly recent appearance reported for deleterious human gene variants, suggesting substantial impact of recent human population history, including pre-Holocene expansions.

RevDate: 2017-08-30
CmpDate: 2017-05-02

Lu D, Lou H, Yuan K, et al (2016)

Ancestral Origins and Genetic History of Tibetan Highlanders.

American journal of human genetics, 99(3):580-594.

The origin of Tibetans remains one of the most contentious puzzles in history, anthropology, and genetics. Analyses of deeply sequenced (30×-60×) genomes of 38 Tibetan highlanders and 39 Han Chinese lowlanders, together with available data on archaic and modern humans, allow us to comprehensively characterize the ancestral makeup of Tibetans and uncover their origins. Non-modern human sequences compose ∼6% of the Tibetan gene pool and form unique haplotypes in some genomic regions, where Denisovan-like, Neanderthal-like, ancient-Siberian-like, and unknown ancestries are entangled and elevated. The shared ancestry of Tibetan-enriched sequences dates back to ∼62,000-38,000 years ago, predating the Last Glacial Maximum (LGM) and representing early colonization of the plateau. Nonetheless, most of the Tibetan gene pool is of modern human origin and diverged from that of Han Chinese ∼15,000 to ∼9,000 years ago, which can be largely attributed to post-LGM arrivals. Analysis of ∼200 contemporary populations showed that Tibetans share ancestry with populations from East Asia (∼82%), Central Asia and Siberia (∼11%), South Asia (∼6%), and western Eurasia and Oceania (∼1%). Our results support that Tibetans arose from a mixture of multiple ancestral gene pools but that their origins are much more complicated and ancient than previously suspected. We provide compelling evidence of the co-existence of Paleolithic and Neolithic ancestries in the Tibetan gene pool, indicating a genetic continuity between pre-historical highland-foragers and present-day Tibetans. In particular, highly differentiated sequences harbored in highlanders' genomes were most likely inherited from pre-LGM settlers of multiple ancestral origins (SUNDer) and maintained in high frequency by natural selection.

RevDate: 2018-03-08
CmpDate: 2017-05-26

Caldararo N (2016)

Denisovans, Melanesians, Europeans, and Neandertals: The Confusion of DNA Assumptions and the Biological Species Concept.

Journal of molecular evolution, 83(1-2):78-87.

A number of recent articles have appeared on the Denisova fossil remains and attempts to produce DNA sequences from them. One of these recently appeared in Science by Vernot et al. (Science 352:235-239, 2016). We would like to advance an alternative interpretation of the data presented. One concerns the problem of contamination/degradation of the determined DNA sequenced. Just as the publication of the first Neandertal sequence included an interpretation that argued that Neandertals had not contributed any genes to modern humans, the Denisovan interpretation has considerable influence on ideas regarding human evolution. The new papers, however, confuse established ideas concerning the nature of species, as well as the use of terms like premodern, Archaic Homo, and Homo heidelbergensis. Examination of these problems presents a solution by means of reinterpreting the results. Given the claims for gene transfer among a number of Mid Pleistocene hominids, it may be time to reexamine the idea of anagenesis in hominid evolution.

RevDate: 2018-01-23
CmpDate: 2017-06-21

Hubbard TD, Murray IA, Bisson WH, et al (2016)

Divergent Ah Receptor Ligand Selectivity during Hominin Evolution.

Molecular biology and evolution, 33(10):2648-2658.

We have identified a fixed nonsynonymous sequence difference between humans (Val381; derived variant) and Neandertals (Ala381; ancestral variant) in the ligand-binding domain of the aryl hydrocarbon receptor (AHR) gene. In an exome sequence analysis of four Neandertal and Denisovan individuals compared with nine modern humans, there are only 90 total nucleotide sites genome-wide for which archaic hominins are fixed for the ancestral nonsynonymous variant and the modern humans are fixed for the derived variant. Of those sites, only 27, including Val381 in the AHR, also have no reported variability in the human dbSNP database, further suggesting that this highly conserved functional variant is a rare event. Functional analysis of the amino acid variant Ala381 within the AHR carried by Neandertals and nonhuman primates indicate enhanced polycyclic aromatic hydrocarbon (PAH) binding, DNA binding capacity, and AHR mediated transcriptional activity compared with the human AHR. Also relative to human AHR, the Neandertal AHR exhibited 150-1000 times greater sensitivity to induction of Cyp1a1 and Cyp1b1 expression by PAHs (e.g., benzo(a)pyrene). The resulting CYP1A1/CYP1B1 enzymes are responsible for PAH first pass metabolism, which can result in the generation of toxic intermediates and perhaps AHR-associated toxicities. In contrast, the human AHR retains the ancestral sensitivity observed in primates to nontoxic endogenous AHR ligands (e.g., indole, indoxyl sulfate). Our findings reveal that a functionally significant change in the AHR occurred uniquely in humans, relative to other primates, that would attenuate the response to many environmental pollutants, including chemicals present in smoke from fire use during cooking.

RevDate: 2018-01-24
CmpDate: 2017-06-14

Söderholm S, Kainov DE, Öhman T, et al (2016)

Phosphoproteomics to Characterize Host Response During Influenza A Virus Infection of Human Macrophages.

Molecular & cellular proteomics : MCP, 15(10):3203-3219.

Influenza A viruses cause infections in the human respiratory tract and give rise to annual seasonal outbreaks, as well as more rarely dreaded pandemics. Influenza A viruses become quickly resistant to the virus-directed antiviral treatments, which are the current main treatment options. A promising alternative approach is to target host cell factors that are exploited by influenza viruses. To this end, we characterized the phosphoproteome of influenza A virus infected primary human macrophages to elucidate the intracellular signaling pathways and critical host factors activated upon influenza infection. We identified 1675 phosphoproteins, 4004 phosphopeptides and 4146 nonredundant phosphosites. The phosphorylation of 1113 proteins (66%) was regulated upon infection, highlighting the importance of such global phosphoproteomic profiling in primary cells. Notably, 285 of the identified phosphorylation sites have not been previously described in publicly available phosphorylation databases, despite many published large-scale phosphoproteome studies using human and mouse cell lines. Systematic bioinformatics analysis of the phosphoproteome data indicated that the phosphorylation of proteins involved in the ubiquitin/proteasome pathway (such as TRIM22 and TRIM25) and antiviral responses (such as MAVS) changed in infected macrophages. Proteins known to play roles in small GTPase-, mitogen-activated protein kinase-, and cyclin-dependent kinase- signaling were also regulated by phosphorylation upon infection. In particular, the influenza infection had a major influence on the phosphorylation profiles of a large number of cyclin-dependent kinase substrates. Functional studies using cyclin-dependent kinase inhibitors showed that the cyclin-dependent kinase activity is required for efficient viral replication and for activation of the host antiviral responses. In addition, we show that cyclin-dependent kinase inhibitors protect IAV-infected mice from death. In conclusion, we provide the first comprehensive phosphoproteome characterization of influenza A virus infection in primary human macrophages, and provide evidence that cyclin-dependent kinases represent potential therapeutic targets for more effective treatment of influenza infections.

RevDate: 2017-04-03
CmpDate: 2017-04-03

Taylor JS, TE Reimchen (2016)

Opsin gene repertoires in northern archaic hominids.

Genome, 59(8):541-549.

The Neanderthals' northern distribution, hunting techniques, and orbit breadths suggest that they were more active in dim light than modern humans. We surveyed visual opsin genes from four Neanderthals and two other archaic hominids to see if they provided additional support for this hypothesis. This analysis was motivated by the observation that alleles responsible for anomalous trichromacy in humans are more common in northern latitudes, by data suggesting that these variants might enhance vision in mesopic conditions, and by the observation that dim light active species often have fewer opsin genes than diurnal relatives. We also looked for evidence of convergent amino acid substitutions in Neanderthal opsins and orthologs from crepuscular or nocturnal species. The Altai Neanderthal, the Denisovan, and the Ust'-Ishim early modern human had opsin genes that encoded proteins identical to orthologs in the human reference genome. Opsins from the Vindija Cave Neanderthals (three females) had many nonsynonymous substitutions, including several predicted to influence colour vision (e.g., stop codons). However, the functional implications of these observations were difficult to assess, given that "control" loci, where no substitutions were expected, differed from humans to the same extent. This left unresolved the test for colour vision deficiencies in Vindija Cave Neanderthals.

RevDate: 2017-02-20
CmpDate: 2016-07-19

Ko KH (2016)

Hominin interbreeding and the evolution of human variation.

Journal of biological research (Thessalonike, Greece), 23:17 pii:54.

Mitochondrial Eve confirms the "out of Africa" theory, but the evidence also supports interbreeding between Homo sapiens and other hominins: Neanderthals, Denisovans, and Homo heidelbergensis. This article explains how interbreeding between early H. sapiens and archaic hominins occurred. The availability of edible insects in East Asia aided the spread of the unaggressive, highly cooperative Neanderthals, who interbred with H. sapiens in Asia, resulting in a higher admixture of Neanderthal DNA in East Asian populations. Geographical variation in degree of interbreeding between H. sapiens and Neanderthals likely contributed to neurological and behavioral differences in modern humans. Similarly, people with Denisovan genetic admixture were better able to dwell in mountainous regions, allowing their genetic legacy to cross the Himalayas and persist in Southeast Asian and Oceanian H. sapiens. In the Sub-Saharan region, unaffected by Denisovan or Neanderthal interbreeding, H. sapiens interbred with H. heidelbergensis, because high humidity militated against fire-making and allowed the survival of these non-fire-making hominins.

RevDate: 2017-11-08
CmpDate: 2017-08-07

Miga KH (2017)

Chromosome-Specific Centromere Sequences Provide an Estimate of the Ancestral Chromosome 2 Fusion Event in Hominin Genomes.

The Journal of heredity, 108(1):45-52.

Human chromosome 2 is a product of a telomere fusion of two ancestral chromosomes and loss/degeneration of one of the two original centromeres. Genomic signatures of this event are limited to inverted telomeric repeats at the precise site of chromosomal fusion and to the small amount of relic centromeric sequences that remain on 2q21.2. Unlike the site of fusion, which is enriched for sequences that are shared elsewhere in the human genome, the region of the nonfunctioning and degenerate ancestral centromere appears to share limited similarity with other sites in the human genome, thereby providing an opportunity to study this genomic arrangement in short, fragmented ancient DNA genomic datasets. Here, chromosome-assigned satellite DNAs are used to study shared centromere sequence organization in Denisovan and Neandertal genomes. By doing so, one is able to provide evidence for the presence of both active and degenerate centromeric satellite profiles on chromosome 2 in these archaic genomes, supporting the hypothesis that the chromosomal fusion event took place prior to our last common ancestor with Denisovan and Neandertal hominins and presenting a genomic reference for predicting karyotype in ancient genomic datasets.

RevDate: 2017-06-21
CmpDate: 2016-08-02

Bogomolov DV, Zbrueva YV, Putintsev VA, et al (2016)

[Forensic medical diagnostics of intra-vitality of the strangulation mark by morphological methods].

Sudebno-meditsinskaia ekspertiza, 59(2):40-43.

The objective of the present study WaS to overview the current domestic and foreign literature concerning the up-to-date methods employed for the expert evaluation of intra-vitality of the strangulation mark. The secondary objective was to propose the new approaches for addressing this problem. The methods of expert diagnostics with a view to determining the time of infliction of injuries as exemplified by mechanical asphyxia are discussed. It is concluded that immunohistochemical and morphometric studies provide the most promising tools for the evaluation of intra-vitality of the strangulation mark for the purpose of forensic medical expertise.

RevDate: 2017-02-20
CmpDate: 2017-01-27

Slatkin M, F Racimo (2016)

Ancient DNA and human history.

Proceedings of the National Academy of Sciences of the United States of America, 113(23):6380-6387.

We review studies of genomic data obtained by sequencing hominin fossils with particular emphasis on the unique information that ancient DNA (aDNA) can provide about the demographic history of humans and our closest relatives. We concentrate on nuclear genomic sequences that have been published in the past few years. In many cases, particularly in the Arctic, the Americas, and Europe, aDNA has revealed historical demographic patterns in a way that could not be resolved by analyzing present-day genomes alone. Ancient DNA from archaic hominins has revealed a rich history of admixture between early modern humans, Neanderthals, and Denisovans, and has allowed us to disentangle complex selective processes. Information from aDNA studies is nowhere near saturation, and we believe that future aDNA sequences will continue to change our understanding of hominin history.

RevDate: 2017-06-21
CmpDate: 2016-06-02

Rabinovich IM, Rabinovich OF, Abramova ES, et al (2016)

[Clinical and pathogenetic aspects of various forms of cheilitis].

Stomatologiia, 95(1):67-72.

RevDate: 2017-07-27
CmpDate: 2017-07-07

Zhao G, Denisova K, Sehatpour P, et al (2016)

Fractal Dimension Analysis of Subcortical Gray Matter Structures in Schizophrenia.

PloS one, 11(5):e0155415 pii:PONE-D-15-22372.

A failure of adaptive inference-misinterpreting available sensory information for appropriate perception and action-is at the heart of clinical manifestations of schizophrenia, implicating key subcortical structures in the brain including the hippocampus. We used high-resolution, three-dimensional (3D) fractal geometry analysis to study subtle and potentially biologically relevant structural alterations (in the geometry of protrusions, gyri and indentations, sulci) in subcortical gray matter (GM) in patients with schizophrenia relative to healthy individuals. In particular, we focus on utilizing Fractal Dimension (FD), a compact shape descriptor that can be computed using inputs with irregular (i.e., not necessarily smooth) surfaces in order to quantify complexity (of geometrical properties and configurations of structures across spatial scales) of subcortical GM in this disorder. Probabilistic (entropy-based) information FD was computed based on the box-counting approach for each of the seven subcortical structures, bilaterally, as well as the brainstem from high-resolution magnetic resonance (MR) images in chronic patients with schizophrenia (n = 19) and age-matched healthy controls (n = 19) (age ranges: patients, 22.7-54.3 and healthy controls, 24.9-51.6 years old). We found a significant reduction of FD in the left hippocampus (median: 2.1460, range: 2.07-2.18 vs. median: 2.1730, range: 2.15-2.23, p<0.001; Cohen's effect size, U3 = 0.8158 (95% Confidence Intervals, CIs: 0.6316, 1.0)), the right hippocampus (median: 2.1430, range: 2.05-2.19 vs. median: 2.1760, range: 2.12-2.21, p = 0.004; U3 = 0.8421 (CIs: 0.5263, 1)), as well as left thalamus (median: 2.4230, range: 2.40-2.44, p = 0.005; U3 = 0.7895 (CIs: 0.5789, 0.9473)) in schizophrenia patients, relative to healthy individuals. Our findings provide in-vivo quantitative evidence for reduced surface complexity of hippocampus, with reduced FD indicating a less complex, less regular GM surface detected in schizophrenia.

RevDate: 2017-12-06
CmpDate: 2016-07-26

Johnston SC, Amarenco P, Albers GW, et al (2016)

Ticagrelor versus Aspirin in Acute Stroke or Transient Ischemic Attack.

The New England journal of medicine, 375(1):35-43.

BACKGROUND: Ticagrelor may be a more effective antiplatelet therapy than aspirin for the prevention of recurrent stroke and cardiovascular events in patients with acute cerebral ischemia.

METHODS: We conducted an international double-blind, controlled trial in 674 centers in 33 countries, in which 13,199 patients with a nonsevere ischemic stroke or high-risk transient ischemic attack who had not received intravenous or intraarterial thrombolysis and were not considered to have had a cardioembolic stroke were randomly assigned within 24 hours after symptom onset, in a 1:1 ratio, to receive either ticagrelor (180 mg loading dose on day 1 followed by 90 mg twice daily for days 2 through 90) or aspirin (300 mg on day 1 followed by 100 mg daily for days 2 through 90). The primary end point was the time to the occurrence of stroke, myocardial infarction, or death within 90 days.

RESULTS: During the 90 days of treatment, a primary end-point event occurred in 442 of the 6589 patients (6.7%) treated with ticagrelor, versus 497 of the 6610 patients (7.5%) treated with aspirin (hazard ratio, 0.89; 95% confidence interval [CI], 0.78 to 1.01; P=0.07). Ischemic stroke occurred in 385 patients (5.8%) treated with ticagrelor and in 441 patients (6.7%) treated with aspirin (hazard ratio, 0.87; 95% CI, 0.76 to 1.00). Major bleeding occurred in 0.5% of patients treated with ticagrelor and in 0.6% of patients treated with aspirin, intracranial hemorrhage in 0.2% and 0.3%, respectively, and fatal bleeding in 0.1% and 0.1%.

CONCLUSIONS: In our trial involving patients with acute ischemic stroke or transient ischemic attack, ticagrelor was not found to be superior to aspirin in reducing the rate of stroke, myocardial infarction, or death at 90 days. (Funded by AstraZeneca; number, NCT01994720.).

RevDate: 2018-04-04
CmpDate: 2016-07-08

Denisova NP, Rogov DY, Rzaev DA, et al (2016)

[Spinal cord stimulation in the treatment of chronic pain syndromes].

Zhurnal voprosy neirokhirurgii imeni N. N. Burdenko, 80(2):47-52.

AIM: The study objective was to estimate the efficacy of chronic epidural spinal cord stimulation in the treatment of patients with neuropathic pain syndrome.

MATERIAL AND METHODS: A system for chronic spinal cord stimulation (St. Jude) was implanted to 75 patients with neuropathic pain syndrome. Fifty three (70.7%) patients were diagnosed with failed back surgery syndrome (FBSS); 9 (12.0%) patients had complex regional pain syndrome type II; 4 (5.3%) patients had diabetic polyneuropathy of the lower limbs; 3 (4.0%) patients had idiopathic pelvic-perineal pain; 2 (2.7%) patients had spinal stroke pain; 2 (2.7%) patients had postherpetic intercostal neuralgia; 1 (1.3%) patient had stump pain; 1 (1.3%) patient had spinal cord injury pain. The treatment efficacy was evaluated using the visual analog scale (VAS) and DN4 questionnaire. The follow-up period ranged from 6 to 18 months.

RESULTS: 136 patients underwent test stimulation at the Center in 2014. A significant reduction in pain was observed in 75 (55.1%) patients. These patients underwent the second stage of surgery that included implantation of permanent electrodes and a generator. The mean VAS score was 6.5 (maximum: 10; minimum: 5) before surgery, 3.2 at discharge, and 3.1 after 3 and 6 months. The VAS score amounted to 3.6 after 12 months. Complications in the form of pain at the generator implantation site and the need for removal of the system occurred in 2 patients (2.6%), electrode migration was observed in 4 (5.3%) cases.

CONCLUSION: Chronic epidural spinal cord stimulation is an effective and safe technique for the treatment of drug-resistant chronic neurogenic pain syndromes.

RevDate: 2018-02-13
CmpDate: 2017-06-12

Houldcroft CJ, SJ Underdown (2016)

Neanderthal genomics suggests a pleistocene time frame for the first epidemiologic transition.

American journal of physical anthropology, 160(3):379-388.

High quality Altai Neanderthal and Denisovan genomes are revealing which regions of archaic hominin DNA have persisted in the modern human genome. A number of these regions are associated with response to infection and immunity, with a suggestion that derived Neanderthal alleles found in modern Europeans and East Asians may be associated with autoimmunity. As such Neanderthal genomes are an independent line of evidence of which infectious diseases Neanderthals were genetically adapted to. Sympathetically, human genome adaptive introgression is an independent line of evidence of which infectious diseases were important for AMH coming in to Eurasia and interacting with Neanderthals. The Neanderthals and Denisovans present interesting cases of hominin hunter-gatherers adapted to a Eurasian rather than African infectious disease package. Independent sources of DNA-based evidence allow a re-evaluation of the first epidemiologic transition and how infectious disease affected Pleistocene hominins. By combining skeletal, archaeological and genetic evidence from modern humans and extinct Eurasian hominins, we question whether the first epidemiologic transition in Eurasia featured a new package of infectious diseases or a change in the impact of existing pathogens. Coupled with pathogen genomics, this approach supports the view that many infectious diseases are pre-Neolithic, and the list continues to expand. The transfer of pathogens between hominin populations, including the expansion of pathogens from Africa, may also have played a role in the extinction of the Neanderthals and offers an important mechanism to understand hominin-hominin interactions well back beyond the current limits for aDNA extraction from fossils alone. Am J Phys Anthropol 160:379-388, 2016. © 2016 Wiley Periodicals, Inc.

RevDate: 2018-03-14
CmpDate: 2018-01-26

Sankararaman S, Mallick S, Patterson N, et al (2016)

The Combined Landscape of Denisovan and Neanderthal Ancestry in Present-Day Humans.

Current biology : CB, 26(9):1241-1247.

Some present-day humans derive up to ∼5% [1] of their ancestry from archaic Denisovans, an even larger proportion than the ∼2% from Neanderthals [2]. We developed methods that can disambiguate the locations of segments of Denisovan and Neanderthal ancestry in present-day humans and applied them to 257 high-coverage genomes from 120 diverse populations, among which were 20 individual Oceanians with high Denisovan ancestry [3]. In Oceanians, the average size of Denisovan fragments is larger than Neanderthal fragments, implying a more recent average date of Denisovan admixture in the history of these populations (p = 0.00004). We document more Denisovan ancestry in South Asia than is expected based on existing models of history, reflecting a previously undocumented mixture related to archaic humans (p = 0.0013). Denisovan ancestry, just like Neanderthal ancestry, has been deleterious on a modern human genetic background, as reflected by its depletion near genes. Finally, the reduction of both archaic ancestries is especially pronounced on chromosome X and near genes more highly expressed in testes than other tissues (p = 1.2 × 10(-7) to 3.2 × 10(-7) for Denisovan and 2.2 × 10(-3) to 2.9 × 10(-3) for Neanderthal ancestry even after controlling for differences in level of selective constraint across gene classes). This suggests that reduced male fertility may be a general feature of mixtures of human populations diverged by >500,000 years.

RevDate: 2017-02-02
CmpDate: 2017-02-02

Brown S, Higham T, Slon V, et al (2016)

Identification of a new hominin bone from Denisova Cave, Siberia using collagen fingerprinting and mitochondrial DNA analysis.

Scientific reports, 6:23559 pii:srep23559.

DNA sequencing has revolutionised our understanding of archaic humans during the Middle and Upper Palaeolithic. Unfortunately, while many Palaeolithic sites contain large numbers of bones, the majority of these lack the diagnostic features necessary for traditional morphological identification. As a result the recovery of Pleistocene-age human remains is extremely rare. To circumvent this problem we have applied a method of collagen fingerprinting to more than 2000 fragmented bones from the site of Denisova Cave, Russia, in order to facilitate the discovery of human remains. As a result of our analysis a single hominin bone (Denisova 11) was identified, supported through in-depth peptide sequencing analysis, and found to carry mitochondrial DNA of the Neandertal type. Subsequent radiocarbon dating revealed the bone to be >50,000 years old. Here we demonstrate the huge potential collagen fingerprinting has for identifying hominin remains in highly fragmentary archaeological assemblages, improving the resources available for wider studies into human evolution.

RevDate: 2017-06-11
CmpDate: 2016-09-05

Árnason Ú (2016)

The Out of Africa hypothesis and the ancestry of recent humans: Cherchez la femme (et l'homme).

Gene, 585(1):9-12.

The Out of Africa hypothesis (OOAH) has been a mainstay in the discussion of human evolution since its presentation in the 1980's. However, recent advances in palaeontology and molecular genetics have made it possible to examine the hypothesis in a manner that was inconceivable at the time of its proposal. The palaeontological progress relates to early Homo finds in the Caucasus, Denisova finds in the Altai Mountains and Neanderthal finds in a wide range of localities from the Altai Mountains, the Caucasus, the Levant, Asia Minor, southern and Central Europe and the Iberian Peninsula. The Eurasian location of these finds and recognition of the principle of Last common ancestor (LCA) lend no support to OOAH. The same conclusion is drawn from genomic findings, which (a) have revealed the presence of Denisovan and Neanderthal nuclear DNA, primarily in the genomes of recent Eurasians and (b) have shown genomic introgression from early modern humans into Neanderthals in the Altai Mountains. Similarly, archaeological finds in Sulawesi and the discovery of ≈100,000years old human teeth in southern China constitute strong independent challenges to OOAH. The genomic and palaeogenomic results and the new palaeontological and archaeological discoveries suggest (a) that the ancestors of modern humans had their origin in a Eurasian (largely Asian) biogeographic region which may also have extended into NE Africa, and (b) that the founders of basal African lineages became separated, geographically and genetically, in the westernmost part of this region and spread from there to different parts of the African continent.

RevDate: 2016-04-29
CmpDate: 2016-05-11

Vernot B, Tucci S, Kelso J, et al (2016)

Excavating Neandertal and Denisovan DNA from the genomes of Melanesian individuals.

Science (New York, N.Y.), 352(6282):235-239.

Although Neandertal sequences that persist in the genomes of modern humans have been identified in Eurasians, comparable studies in people whose ancestors hybridized with both Neandertals and Denisovans are lacking. We developed an approach to identify DNA inherited from multiple archaic hominin ancestors and applied it to whole-genome sequences from 1523 geographically diverse individuals, including 35 previously unknown Island Melanesian genomes. In aggregate, we recovered 1.34 gigabases and 303 megabases of the Neandertal and Denisovan genome, respectively. We use these maps of archaic sequences to show that Neandertal admixture occurred multiple times in different non-African populations, characterize genomic regions that are significantly depleted of archaic sequences, and identify signatures of adaptive introgression.

RevDate: 2017-06-21
CmpDate: 2016-04-21

Kovalkova NA, Denisova DV, Polonskaya YV, et al (2016)

[The incidence of respiratory symptoms and their associations with serum cotinine levels as a marker of tobacco smoking in 25-45-year-old Novosibirsk dwellers].

Terapevticheskii arkhiv, 88(1):70-74.

AIM: To study the incidence of respiratory symptoms and to reveal their associations with serum cotinine levels (SCL) in 25-45-year-old Novosibirsk dwellers.

SUBJECTS AND METHODS: The WHO respiratory symptom questionnaire and the ECRHS screening questionnaire were used for a population-based survey conducted in Novosibirsk to identify respiratory symptoms; 545 people replied to the questions available in the questionnaires. SCL was determined by enzyme immunoassay on a random subsample of 182 examinees.

RESULTS: The incidence of respiratory symptoms was determined among the 25-45-year-old Novosibirsk dwellers: cough (27.7%), more than 3-month cough per year (22%), sputum discharge (25%), forced respiration/wheezing in the past year (22.6%), suffocation fits in the past year (5.3%), and cough/forced respiration/stertor bouts by breathing cold air (14.9%) or contacting animals, plants, or chemical agents (16.5%). There was a significant positive correlation between SCL and the presence of cough, more than 3-month cough per year, sputum discharge, forced respiration/wheezing in the past year (compared to the examinees who did not report these symptoms). The median SCL proved to be significantly higher in the people who complained of cough, more than 3-month cough per year, sputum discharge, and forced respiration/wheezing in the past year (compared to the examinees who did not report these symptoms). The people who had a SCL of more than 3 ng/ml were ascertained to be at higher risk of cough, more than 3-month cough per year, sputum discharge, and forced respiration/wheezing in the past year than those who had a SCL of less than 3 ng/ml.

CONCLUSION: The incidence of respiratory symptoms was determined among the 25-45-year-old Novosibirsk dwellers; SCL was found to be associated with the symptoms characteristic of bronchial obstructive diseases; the expediency of using the SCL threshold of 3 ng/ml as a marker of tobacco smoking was confirmed.

RevDate: 2017-02-20
CmpDate: 2016-04-27

Meyer M, Arsuaga JL, de Filippo C, et al (2016)

Nuclear DNA sequences from the Middle Pleistocene Sima de los Huesos hominins.

Nature, 531(7595):504-507.

A unique assemblage of 28 hominin individuals, found in Sima de los Huesos in the Sierra de Atapuerca in Spain, has recently been dated to approximately 430,000 years ago. An interesting question is how these Middle Pleistocene hominins were related to those who lived in the Late Pleistocene epoch, in particular to Neanderthals in western Eurasia and to Denisovans, a sister group of Neanderthals so far known only from southern Siberia. While the Sima de los Huesos hominins share some derived morphological features with Neanderthals, the mitochondrial genome retrieved from one individual from Sima de los Huesos is more closely related to the mitochondrial DNA of Denisovans than to that of Neanderthals. However, since the mitochondrial DNA does not reveal the full picture of relationships among populations, we have investigated DNA preservation in several individuals found at Sima de los Huesos. Here we recover nuclear DNA sequences from two specimens, which show that the Sima de los Huesos hominins were related to Neanderthals rather than to Denisovans, indicating that the population divergence between Neanderthals and Denisovans predates 430,000 years ago. A mitochondrial DNA recovered from one of the specimens shares the previously described relationship to Denisovan mitochondrial DNAs, suggesting, among other possibilities, that the mitochondrial DNA gene pool of Neanderthals turned over later in their history.

RevDate: 2017-10-05
CmpDate: 2017-05-24

Ghirotto S, Tassi F, Barbujani G, et al (2016)

The Uromodulin Gene Locus Shows Evidence of Pathogen Adaptation through Human Evolution.

Journal of the American Society of Nephrology : JASN, 27(10):2983-2996.

Common variants in the UMOD gene encoding uromodulin, associated with risk of hypertension and CKD in the general population, increase UMOD expression and urinary excretion of uromodulin, causing salt-sensitive hypertension and renal lesions. To determine the effect of selective pressure on variant frequency, we investigated the allelic frequency of the lead UMOD variant rs4293393 in 156 human populations, in eight ancient human genomes, and in primate genomes. The T allele of rs4293393, associated with CKD risk, has high frequency in most modern populations and was the one detected in primate genomes. In contrast, we identified only the derived, C allele in Denisovan and Neanderthal genomes. The distribution of the UMOD ancestral allele did not follow the ancestral susceptibility model observed for variants associated with salt-sensitive hypertension. Instead, the global frequencies of the UMOD alleles significantly correlated with pathogen diversity (bacteria, helminths) and prevalence of antibiotic-resistant urinary tract infections (UTIs). The inverse correlation found between urinary levels of uromodulin and markers of UTIs in the general population substantiates the link between UMOD variants and protection against UTIs. These data strongly suggest that the UMOD ancestral allele, driving higher urinary excretion of uromodulin, has been kept at a high frequency because of its protective effect against UTIs.

RevDate: 2017-06-06
CmpDate: 2017-04-06

Malyarchuk BA, Derenko M, Denisova G, et al (2016)

Y chromosome haplotype diversity in Mongolic-speaking populations and gene conversion at the duplicated STR DYS385a,b in haplogroup C3-M407.

Journal of human genetics, 61(6):491-496.

Y chromosome microsatellite (Y-STR) diversity has been studied in different Mongolic-speaking populations from South Siberia, Mongolia, North-East China and East Europe. The results obtained indicate that the Mongolic-speaking populations clustered into two groups, with one group including populations from eastern part of South Siberia and Central Asia (the Buryats, Barghuts and Khamnigans) and the other group including populations from western part of Central Asia and East Europe (the Mongols and Kalmyks). High frequency of haplogroup C3-M407 (>50%) is present in the Buryats, Barghuts and Khamnigans, whereas in the Mongols and Kalmyks its frequency is much lower. In addition, two allelic combinations in DYS385a,b loci of C3-M407 haplotypes have been observed: the combination 11,18 (as well as 11,17 and 11,19) is frequent in different Mongolic-speaking populations, but the 11,11 branch is present mainly in the Kalmyks and Mongols. Results of locus-specific sequencing suggest that the action of gene conversion is a more likely explanation for origin of homoallelic 11,11 combination. Moreover, analysis of median networks of Y-STR haplotypes demonstrates that at least two gene conversion events can be revealed-one of them has probably occurred among the Mongols, and the other event occurred in the Barghuts. These two events give an average gene conversion rate range of 0.24-7.1 × 10(-3) per generation.


ESP Quick Facts

ESP Origins

In the early 1990's, Robert Robbins was a faculty member at Johns Hopkins, where he directed the informatics core of GDB — the human gene-mapping database of the international human genome project. To share papers with colleagues around the world, he set up a small paper-sharing section on his personal web page. This small project evolved into The Electronic Scholarly Publishing Project.

ESP Support

In 1995, Robbins became the VP/IT of the Fred Hutchinson Cancer Research Center in Seattle, WA. Soon after arriving in Seattle, Robbins secured funding, through the ELSI component of the US Human Genome Project, to create the original ESP.ORG web site, with the formal goal of providing free, world-wide access to the literature of classical genetics.

ESP Rationale

Although the methods of molecular biology can seem almost magical to the uninitiated, the original techniques of classical genetics are readily appreciated by one and all: cross individuals that differ in some inherited trait, collect all of the progeny, score their attributes, and propose mechanisms to explain the patterns of inheritance observed.

ESP Goal

In reading the early works of classical genetics, one is drawn, almost inexorably, into ever more complex models, until molecular explanations begin to seem both necessary and natural. At that point, the tools for understanding genome research are at hand. Assisting readers reach this point was the original goal of The Electronic Scholarly Publishing Project.

ESP Usage

Usage of the site grew rapidly and has remained high. Faculty began to use the site for their assigned readings. Other on-line publishers, ranging from The New York Times to Nature referenced ESP materials in their own publications. Nobel laureates (e.g., Joshua Lederberg) regularly used the site and even wrote to suggest changes and improvements.

ESP Content

When the site began, no journals were making their early content available in digital format. As a result, ESP was obliged to digitize classic literature before it could be made available. For many important papers — such as Mendel's original paper or the first genetic map — ESP had to produce entirely new typeset versions of the works, if they were to be available in a high-quality format.

ESP Help

Early support from the DOE component of the Human Genome Project was critically important for getting the ESP project on a firm foundation. Since that funding ended (nearly 20 years ago), the project has been operated as a purely volunteer effort. Anyone wishing to assist in these efforts should send an email to Robbins.

ESP Plans

With the development of methods for adding typeset side notes to PDF files, the ESP project now plans to add annotated versions of some classical papers to its holdings. We also plan to add new reference and pedagogical material. We have already started providing regularly updated, comprehensive bibliographies to the ESP.ORG site.


Order from Amazon

One of the most intriguing, and philosophically suggestive, recent scientific findings has been the discovery that the human lineage included several branches at the species level in which each species had developed culture (tool making, mastery of fire, burial of the dead). Before the Chicxulub impact that ended the realm of the dinosaurs, sentience and culture had not occurred in any lineage, despite several hundred million years of evolution. However, in the mammalian radiation that occurred afterwards, several primate lineages occurred. In just the last few million years, one of those lineages diverged into several sentient, culture-developing species. This book explores how only one of those species (ours) survived, while the others went extinct. Recommended. R. Robbins

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Papers in Classical Genetics

The ESP began as an effort to share a handful of key papers from the early days of classical genetics. Now the collection has grown to include hundreds of papers, in full-text format.

Digital Books

Along with papers on classical genetics, ESP offers a collection of full-text digital books, including many works by Darwin (and even a collection of poetry — Chicago Poems by Carl Sandburg).


ESP now offers a much improved and expanded collection of timelines, designed to give the user choice over subject matter and dates.


Biographical information about many key scientists.

Selected Bibliographies

Bibliographies on several topics of potential interest to the ESP community are now being automatically maintained and generated on the ESP site.

ESP Picks from Around the Web (updated 07 JUL 2018 )