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.
Highlights
The recent publication of the draft sequence of the Neanderthal genome[1] ushered in a new age in molecular archaeology.[2,3] This achievement was followed closely by the publication of the draft genome sequence (1.9-fold coverage) of a50,000-year old archaic hominin from Denisova Cave in southern Siberia.[4]
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
From the remaining 3,075,115 sites, we identified 117 sites for which the apparent wild-type nucleotide in the Denisovan or chimpanzee was logged in the Human Gene Mutation Database (HGMD) as disease causing or disease associated in either the Denisovan or chimpanzee (Table 3)
Summary
The recent publication of the draft sequence of the Neanderthal genome[1] ushered in a new age in molecular archaeology.[2,3] This achievement was followed closely by the publication of the draft genome sequence (1.9-fold coverage) of a. Access to DNA sequence data from ancient hominins promises to revolutionise our knowledge of hominin relationships, but is potentially informative in the context of exploring the molecular basis of human genetic disease.[8,9] We have previously cross-compared the human, chimpanzee and Neanderthal genome sequences with a set of disease-causing/disease-associated missense and regulatory mutations in order to identify genetic variants which, apparently pathogenic in humans, may represent a ‘compensated’ wild-type state in at least one of the other two species (‘potentially compensated mutations’ [PCMs]).[10] PCMs correspond to variants that may have been deleterious for a certain period of evolutionary time but which persisted long enough in a given population or species to have become positively selected upon the introduction of a ‘compensatory’ nucleotide change.8,11 – 14 Such compensatory changes are thought to be localised in the same gene as the PCM.[15] do PCMs represent excellent candidates for recent population-specific selection (with different alleles having exhibited differential functional importance in different environments), but they may furnish us with new insights into the genetic basis of susceptibility to common diseases.[8,14] Here, in an attempt to identify further PCMs of interest, we have compared a dataset of human mutations of putative pathological significance with their corresponding nucleotide positions in the Neanderthal, Denisovan and chimpanzee genomes.
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