Large-scale functional screen identifies genetic variants with splicing effects in modern and archaic humans

Abstract

Our study reveals the impact of genetic differences in pre-mRNA splicing between modern and archaic humans. We used a massively parallel experiment to identify 962 splicing variants that differ between modern and archaic humans, including potentially pathogenic splicing variants unique to Neanderthals and Denisovans, and introgressed splicing variants that may explain differences in modern human traits. Our findings indicate that purifying selection acted against splicing variants in modern human populations, whereas positive selection favored splicing variants in adaptive introgression. By distinguishing causal from linked variants, our study contributes to understanding the functional consequences of genetic variation within extant and extinct hominins and of introgressed variation in modern human populations.