Balancing selection on genomic deletion polymorphisms in humans

Abstract

A key question in biology is why genomic variation persists in a population for extended periods. Recent studies have identified examples of genomic deletions that have remained polymorphic in the human lineage for hundreds of millennia, ostensibly owing to balancing selection. Nevertheless, genome-wide investigations of ancient and possibly adaptive deletions remain an imperative exercise. Here, we used simulations to show an excess of ancient allele sharing between modern and archaic human genomes that cannot be explained solely by introgression or ancient structure under neutrality. We identified 63 deletion polymorphisms that emerged before the divergence of humans and Neanderthals and are associated with GWAS traits. We used empirical and simulation-based analyses to show that the haplotypes that harbor these functional ancient deletions have likely been evolving under time- and geography-dependent balancing selection. Collectively, our results suggest that balancing selection may have maintained at least 27% of the functional deletion polymorphisms in humans for hundreds of thousands of years.

Distilling functional variations for human UGT2B4 upstream region based on selection signals and implications for phenotypes of Neanderthal and Denisovan

“…In contrast, it seems that the deletion can cause a higher UGT2B11 expression but fail to reach statistical significance (r 2 = 0.11, P = 0.17, n = 161 in total), which might be due to some outliers with extremely low expression. When these outliers are removed from analysis, a significant association can be obtained (r 2 = 0.20, P = 0.022, n = 150 in total), which is consistent with previous report 23 .…”

“…Therefore, the heterozygous individuals at this locus might have a better chance to keep a proper sex hormone level and further present selection advantage in reproduction, which deserves further investigation. In this regard, it is interesting to observe that balancing selection is also observed in other members in this gene family, including UGT2B17 45 , UGT2B28 and UGT2A1 23 . Moreover, a search in Open Targets Genetics database indicates that this haplotype (tagged by rs11723463) is significantly associated with multiple diseases in reproductive system, including primary ovarian failure (P = 0.034), postpartum depression (P = 0.017), haemorrhage in early pregnancy (P = 0.024) and spontaneous (P = 0.013) and other (P = 0.034) abortion (most results from FinnGen [https:// www.…”

“…In UGT cluster, there are two structure variations (SV, or copy number variation), esv3600896 (~ 184.2 kb upstream UGT2B4) and esv3600917 (~ 108.5 kb downstream UGT2B4), showing signals for balancing selection 23 . We were wondering whether these two SVs are also within our LD block.…”

“…Our results substantiate the regulation of this locus under balancing selection on UGT2B4 expression. SV esv3600896 contains entire UGT2B28 gene and is supposed to be under balancing selection 23 . Therefore, the association between esv3600896 genotype and UGT2B28 or UGT2B11 expression was also investigated in abovementioned LCL cohort.…”

Resurrecting the Alternative Splicing Landscape of Archaic Hominins using Machine Learning

“…No SAVs private to Vindija or Chagyrskaya nor shared between both late Neanderthals were identified as introgressed, even though Neanderthal ancestry in most modern humans is most closely related to Vindija and Chagyrskaya [3,4]. This is consistent with weaker selection on lineage-specific SAVs and previous work suggesting that older introgressed archaic variants were more tolerated in humans [55][56][57].…”