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 recent evolution has not been thoroughly studied across diverse human populations. In particular, recent genomic adaptation at disease genes has not been characterized as well as purifying selection and long-term adaptation. Understanding the relationship between disease and adaptation at the gene level in the human genome is hampered by the fact that we don’t know whether disease genes have experienced more, less, or as much adaptation as non-disease genes during the last ~50,000 years of recent human evolution. 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 26 distinct human populations from the 1,000 Genomes Project. We find that mendelian disease genes have experienced far less selective sweeps compared to non-disease genes especially in Africa. This sweep deficit at mendelian disease genes is less visible in East Asia or Europe. 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. This is further supported by population simulations that show that interference at disease genes is expected to be lower in East Asia and Europe. 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 a transient inability to adapt as much, and/or as fast as the rest of the genome.

Summary Many crops are polyploid or have a polyploid ancestry. Recent phylogenetic analyses have found that polyploidy often preceded the domestication of crop plants. One explanation for this observation is that increased genetic diversity following polyploidy may have been important during the strong artificial selection that occurs during domestication. In order to test the connection between domestication and polyploidy, we identified and examined candidate genes associated with the domestication of the diverse crop varieties of Brassica rapa. Like all ‘diploid’ flowering plants, B. rapa has a diploidized paleopolyploid genome and experienced many rounds of whole genome duplication (WGD). We analyzed transcriptome data of more than 100 cultivated B. rapa accessions. Using a combination of approaches, we identified > 3000 candidate genes associated with the domestication of four major B. rapa crop varieties. Consistent with our expectation, we found that the candidate genes were significantly enriched with genes derived from the Brassiceae mesohexaploidy. We also observed that paleologs were significantly more diverse than non‐paleologs. Our analyses find evidence for that genetic diversity derived from ancient polyploidy played a key role in the domestication of B. rapa and provide support for its importance in the success of modern agriculture.

Many crops are polyploid or have a polyploid ancestry. Recent phylogenetic analyses have found that polyploidy often preceded the domestication of crop plants. One explanation for this observation is that increased genetic diversity following polyploidy may have been important during the strong artificial selection that occurs during domestication. To test the connection between domestication and polyploidy, we identified and examined candidate genes associated with the domestication of the diverse crops of Brassica rapa . Like all "diploid" flowering plants, B. rapa has a diploidized paleopolyploid genome and experienced many rounds of whole genome duplication (WGD). We analyzed transcriptome data of more than hundred cultivated B. rapa accessions. Using a combination of approaches, we identified more than 3,000 candidate genes associated with the domestication of four major B. rapa crops. Consistent with our expectation, we found that the candidate genes were significantly enriched with genes derived from the Brassiceae mesohexaploidy. We also observed that paleologs contained significantly more genetic diversity than non-paleologs, suggesting that elevated genetic variation may explain why paleologs are enriched among domestication candidate genes. Our analyses demonstrate the key role of polyploidy in the domestication of B. rapa and provide support for its importance in the success of modern agriculture.

Pathogens were a major driver of genetic adaptation during human evolution. Viruses in particular were a dominant driver of adaptation in the thousands of proteins that physically interact with viruses (VIPs for Virus-Interacting Proteins). This however poses a conundrum. The best understood cases of virus-driven adaptation in specialized immune antiviral factors or in host viral receptors are numerically vastly insufficient to explain abundant adaptations in VIPs. What adaptive mechanisms can then at least partly close this gap? VIPs tend to be broadly conserved proteins with conserved host native molecular functions. Because many amino acid changes in a protein can alter its stability --the balance between the folded and unfolded forms of a protein-- without destroying conserved native activities, here we ask if stability evolution was an important mechanism of virus-driven human protein adaptation. Using predictions of protein stability changes based on Alphafold 2 structures and validated by multiple lines of evidence, we find that amino acid changes that altered stability experienced highly elevated adaptative evolution in VIPs, compared to changes with a weaker impact on stability. We further find that RNA viruses, rather DNA viruses, predominantly drove strong adaptation through stability changes in VIPs. We also observe that stability in immune antiviral VIPs preferentially evolved under directional selection. Conversely, stability in proviral VIPs needed by viruses evolved under compensatory evolution following viral epidemics. Together, these results suggest that stability evolution, and thus functional host protein abundance evolution, was a prominent mechanism of host protein adaptation during viral epidemics.

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.