Natural selections on both amino acid sequences and expression levels are determinants of ohnolog retention

The mechanism of ohnolog retention is a subject of concern in evolutionary biology. Natural selections on coding sequences and gene dosages have been proposed to be determinants of ohnolog retention. However, the relationship between the two models is not widely accepted, and the role of regulatory sequences on ohnolog retention has long been neglected. In this study, based on a model of complex traits genetic architecture, we compared the natural selections strength on corresponding sequences between ohnologs and non-ohnologs by comparing complex traits heritability enrichments. We showed that complex traits regulatory sequences heritability enrichments (p = 1.1 x 10-5 in 5 kb flanking regions) and expression-mediated heritability enrichments (p = 2.1 x 10-5) of ohnologs were significantly higher than non-ohnologs. Then, we deduced that regulatory sequences of ohnologs were under substantial natural selection, which was also a determent of ohnolog retention. Meanwhile, we showed that in coding sequences, the complex traits heritability enrichments of ohnologs were significantly higher than of non-ohnologs (p = 9.9 x 10-5), supporting the ohnolog retention model of natural selection on coding sequences. We also showed that complex traits causal gene expression effect sizes of ohnologs were significantly larger than of non-ohnologs (p = 8.8 x 10-6), supporting the ohnolog retention model of natural selection on gene dosages. In conclusion, we provide the first unified framework to show that both amino acid sequences and expression levels of ohnologs are under substantial selection, which may end the long-standing debate on ohnolog retention models.