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

Abstract

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. Despite our expanding knowledge of gene-disease associations, and despite the medical importance of disease genes, their evolution has not been thoroughly studied across diverse human populations. In particular, recent genomic adaptation at disease genes has not been well characterized, even though multiple evolutionary processes are expected to connect disease and adaptation at the gene level. Understanding the relationship between disease and adaptation at the gene level in the human genome is severely hampered by the fact that we do not even know whether disease genes have experienced more, less, or as much adaptation as non-disease genes during recent human evolution. Here, we compare the rate of strong recent adaptation in the form of selective sweeps between disease genes and non-disease genes across 26 distinct human populations from the 1,000 Genomes Project. We find that disease genes have experienced far less selective sweeps compared to non-disease genes during recent human evolution. This sweep deficit at disease genes is particularly visible in Africa, and less visible in East Asia or Europe, likely due to more intense genetic drift in the latter populations creating more spurious selective sweeps signals. 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 inexistent at disease genes with higher recombination rates or lower numbers of associated disease variants. Because 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 clarify the evolutionary relationship between disease genes and recent genomic adaptation, and suggest that disease genes suffer not only from a higher load of segregating deleterious mutations, but also from an inability to adapt as much, and/or as fast as the rest of the genome.

Mixture Density Regression reveals frequent recent adaptation in the human genome

“…These mutations can interfere with adaptation when they are in linkage with advantageous mutations. This would be especially relevant for genomic regions with low recombination, where the linkage between deleterious and advantageous mutations is more likely (Di et al 2021). Therefore, a higher coding density could favor or hinder positive selection depending on the circumstances, complicating the detection of an association between coding density and selection with our approach.…”

“…In contrast, this pattern is more readily visible in the other populations studied despite showing smaller selected components. A potential, but still speculative explanation at this point could be the fact that bottlenecks related to the migration out of Africa may have removed segregating recessive deleterious variants, which may reduce their interference over advantageous mutations, thus making it easier for positive selection to act on coding regions (Di et al 2021). In contrast, there were no similar bottlenecks to decrease the genetic interference in the Yoruba, and regions of the genome with high a coding density may still experience stronger interference from recessive deleterious mutations.…”