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Cross-comparison of the genome sequences from human, chimpanzee, Neanderthal and a Denisovan hominin identifies novel potentially compensated mutations.

ABSTRACT: The recent publication of the draft genome sequences of the Neanderthal and a ?50,000-year-old archaic hominin from Denisova Cave in southern Siberia has ushered in a new age in molecular archaeology. We previously cross-compared the human, chimpanzee and Neanderthal genome sequences with respect to a set of disease-causing/disease-associated missense and regulatory mutations (Human Gene Mutation Database) and succeeded in identifying genetic variants which, although apparently pathogenic in humans, may represent a 'compensated' wild-type state in at least one of the other two species. Here, in an attempt to identify further 'potentially compensated mutations' (PCMs) of interest, we have compared our dataset of disease-causing/disease-associated mutations with their corresponding nucleotide positions in the Denisovan hominin, Neanderthal and chimpanzee genomes. Of the 15 human putatively disease-causing mutations that were found to be compensated in chimpanzee, Denisovan or Neanderthal, only a solitary F5 variant (Val1736Met) was specific to the Denisovan. In humans, this missense mutation is associated with activated protein C resistance and an increased risk of thromboembolism and recurrent miscarriage. It is unclear at this juncture whether this variant was indeed a PCM in the Denisovan or whether it could instead have been associated with disease in this ancient hominin.

SUBMITTER: Zhang G

PROVIDER: S-EPMC3525967 | biostudies-literature | 2011 Jul

REPOSITORIES: biostudies-literature

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Cross-comparison of the genome sequences from human, chimpanzee, Neanderthal and a Denisovan hominin identifies novel potentially compensated mutations.

Zhang Guojie G Pei Zhang Z Ball Edward V EV Mort Matthew M Kehrer-Sawatzki Hildegard H Cooper David N DN

Human genomics 20110701 5

The recent publication of the draft genome sequences of the Neanderthal and a ∼50,000-year-old archaic hominin from Denisova Cave in southern Siberia has ushered in a new age in molecular archaeology. We previously cross-compared the human, chimpanzee and Neanderthal genome sequences with respect to a set of disease-causing/disease-associated missense and regulatory mutations (Human Gene Mutation Database) and succeeded in identifying genetic variants which, although apparently pathogenic in hum ...[more]

PMID: 21807602

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Project description:BackgroundThe 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.ResultsThe 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.ConclusionAlthough 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.

Project description:BackgroundIntrogression from extinct Neanderthal and Denisovan human species has been shown to contribute to the genetic pool of modern human populations and their phenotypic spectrum. Evidence of how Neanderthal introgression shaped the genetics of human traits and diseases has been extensively studied in populations of European descent, with signatures of admixture reported for instance in genes associated with pigmentation, immunity, and metabolic traits. However, limited information is currently available about the impact of archaic introgression on other ancestry groups. Additionally, to date, no study has been conducted with respect to the impact of Denisovan introgression on the health and disease of modern populations. Here, we compare the way evolutionary pressures shaped the genetics of complex traits in East Asian and European populations, and provide evidence of the impact of Denisovan introgression on the health of East Asian and Central/South Asian populations.ResultsLeveraging genome-wide association statistics from the Biobank Japan and UK Biobank, we assessed whether Denisovan and Neanderthal introgression together with other evolutionary genomic signatures were enriched for the heritability of physiological and pathological conditions in populations of East Asian and European descent. In EAS, Denisovan-introgressed loci were enriched for coronary artery disease heritability (1.69-fold enrichment, p=0.003). No enrichment for archaic introgression was observed in EUR. We also performed a phenome-wide association study of Denisovan and Neanderthal alleles in six ancestry groups available in the UK Biobank. In EAS, the Denisovan-introgressed SNP rs62391664 in the major histocompatibility complex region was associated with albumin/globulin ratio (beta=-0.17, p=3.57×10-7). Neanderthal-introgressed alleles were associated with psychiatric and cognitive traits in EAS (e.g., "No Bipolar or Depression"-rs79043717 beta=-1.5, p=1.1×10-7), and with blood biomarkers (e.g., alkaline phosphatase-rs11244089 beta=0.1, p=3.69×10-116) and red hair color (rs60733936 beta=-0.86, p=4.49×10-165) in EUR. In the other ancestry groups, Neanderthal alleles were associated with several traits, also including the use of certain medications (e.g., Central/South East Asia: indapamide - rs732632 beta=-2.38, p=5.22×10-7).ConclusionsOur study provides novel evidence regarding the impact of archaic introgression on the genetics of complex traits in worldwide populations, highlighting the specific contribution of Denisovan introgression in EAS populations.

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Cross-comparison of the genome sequences from human, chimpanzee, Neanderthal and a Denisovan hominin identifies novel potentially compensated mutations.

Publications

Cross-comparison of the genome sequences from human, chimpanzee, Neanderthal and a Denisovan hominin identifies novel potentially compensated mutations.

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