Decreased recent adaptation at human mendelian disease genes as a possible consequence of interference between advantageous and deleterious variants

Chenlu Di,Jesus Murga Moreno,David Enard,Diego F Salazar-Tortosa,M Elise Lauterbur

doi:10.7554/elife.69026

Abstract

Advances in genome sequencing have improved our understanding of the genetic basis of human diseases, and thousands of human genes have been associated with different diseases. Recent genomic adaptation at disease genes has not been well characterized. Here, we compare the rate of strong recent adaptation in the form of selective sweeps between mendelian, non-infectious disease genes and non-disease genes across distinct human populations from the 1000 Genomes Project. We find that mendelian disease genes have experienced far less selective sweeps compared to non-disease genes especially in Africa. Investigating further the possible causes of the sweep deficit at disease genes, we find that this deficit is very strong at disease genes with both low recombination rates and with high numbers of associated disease variants, but is almost non-existent at disease genes with higher recombination rates or lower numbers of associated disease variants. Because segregating recessive deleterious variants have the ability to interfere with adaptive ones, these observations strongly suggest that adaptation has been slowed down by the presence of interfering recessive deleterious variants at disease genes. These results suggest that disease genes suffer from a transient inability to adapt as fast as the rest of the genome.

Highlights

Advances in genome sequencing have dramatically improved our understanding of the genetic basis of human diseases, and thousands of human genes have been associated with different diseases (Amberger et al, 2019; Pinero et al, 2020)
In contrast with previous studies, we systematically control for a large number of confounding factors when comparing recent adaptation in human mendelian disease and non-disease genes, including evolutionary constraint, mutation rate, recombination rate, the proportion of immune or virus-interacting genes, etc
In agreement with scenario 3, we find a strong deficit of selective sweeps at disease genes compared to non-disease genes in Africa, and weaker deficits in East Asia and Europe

Summary

Introduction

Advances in genome sequencing have dramatically improved our understanding of the genetic basis of human diseases, and thousands of human genes have been associated with different diseases (Amberger et al, 2019; Pinero et al, 2020). Despite our expanding knowledge of mendelian disease gene associations, and despite the fact that multiple evolutionary processes might connect disease and genomic adaptation at the gene level, these connections are yet to be studied more thoroughly, especially in the case of recent genomic adaptation. Different evolutionary processes have the potential to make the occurrence of mendelian disease genes and adaptation not independent from each other in the human genome. There is currently considerable uncertainty about how any of these non-exclusive evolutionary processes, or other processes, might have influenced adaptation at disease genes. It is even not well-known whether human non-infectious disease genes have similar, higher or lower levels of adaptation in human populations compared to genes not involved in diseases

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