Resurrecting the Alternative Splicing Landscape of Archaic Hominins using Machine Learning

Abstract

Alternative splicing contributes to adaptation and divergence in many species. However, it has not been possible to directly compare splicing between modern and archaic hominins. Here, we unmask the recent evolution of this previously unobservable regulatory mechanism by applying SpliceAI, a machine-learning algorithm that identifies splice altering variants (SAVs), to high-coverage genomes from three Neanderthals and a Denisovan. We discover 5,950 putative archaic SAVs, of which 2,343 are archaic-specific and 3,607 also occur in modern humans via introgression (237) or shared ancestry (3,370). Archaic-specific SAVs are enriched in genes that contribute to many traits potentially relevant to hominin phenotypic divergence, such as perspiration, platelet volume, and spinal rigidity. Compared to shared SAVs, archaic-specific SAVs occur in sites under weaker selection and are more common in genes with tissue-specific expression. Further underscoring the importance of negative selection on SAVs, Neanderthal lineages with low effective population sizes are enriched for SAVs compared to Denisovan and shared SAVs. Finally, we find that nearly all introgressed SAVs in humans were shared across Neanderthals, suggesting that older SAVs were more tolerated in modern human genomes. Our results reveal the splicing landscape of archaic hominins and identify potential contributions of splicing to phenotypic differences among hominins.

Archaic Introgression Shaped Human Circadian Traits

“…We identified 36 archaic-specific splice altering variants, defined as those variants absent from 1KGP, among 28 circadian genes. Next, we tested for enrichment among this gene set using an empirical null approach (Brand, Colbran, and Capra 2022; McArthur et al 2022). We shuffled the maximum deltas among 1,607,350 variants 10,000 times and counted the number of circadian genes with a splice altering variant each iteration.…”

“…We used a set of archaic variants annotated with the splice altering probabilities to identify circadian genes that may be differentially spliced between archaic hominins and AMH (Brand, Colbran, and Capra 2022). We considered variants from four archaic individuals: the Altai, Chagyrskaya, and Vindija Neanderthals and the Altai Denisovan.…”

Human-specific genetics: new tools to explore the molecular and cellular basis of human evolution

“…In the future, multi-omic studies that jointly interrogate chromatin modifications, transcript abundance, splicing and protein abundance will help to uncover the mechanisms that underlie differential expression and the resulting phenotypic differences. Coupled with advances in artificial intelligence, functional genomics datasets will enable refinement and testing of predictions of the influence of individual mutations, or many combinations from a set of mutations, across levels of gene regulation [132][133][134] .…”