The landscape of tolerated genetic variation in humans and primates
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Abstract
Personalized genome sequencing has revealed millions of genetic differences between individuals, but our understanding of their clinical relevance remains largely incomplete. To systematically decipher the effects of human genetic variants, we obtained whole-genome sequencing data for 809 individuals from 233 primate species and identified 4.3 million common protein-altering variants with orthologs in humans. We show that these variants can be inferred to have nondeleterious effects in humans based on their presence at high allele frequencies in other primate populations. We use this resource to classify 6% of all possible human protein-altering variants as likely benign and impute the pathogenicity of the remaining 94% of variants with deep learning, achieving state-of-the-art accuracy for diagnosing pathogenic variants in patients with genetic diseases.
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Humans have adapted to a much longer lifespan compared with other primate species, which have a median lifespan of 20-30 years, suggesting that increased selection on TERT may have occurred as part of human adaption towards extended longevity
Is it clear what the relative telomere lengths are in these species and whether they are correlated with selection on TERT?
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The remaining 19 variants appear to be truly pathogenic in human, and are presumably tolerated in primate because of primate-human differences, such as interactions with changes in the neighboring sequence context (45, 46).
Have you considered the possibility that these deleterious influences in humans might be modified by differences between humans and primates that act at a larger range. For example, a change in a specific transcription factor binding site might have a compensatory shift in the transcription factor. These types of interactions could act at long range and may underlie some of these species-species differences in deleterious effect.
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However, deleterious variants were incompletely removed in humans, consistent with the shorter amount of time they were exposed to natural selection.
It would be great to hear alternative explanations for the presence of 'deleterious' variants in humans. For example, it might be true that the deleterious effect of a variant may be different across species.
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