The trait specific timing of accelerated genomic change in the human lineage

Abstract

It remains an open question when and why psychiatric and other disease evolved in human evolutionary history. We harness large genome-wide association studies and recent studies that have identified human-gained epigenetic marks, selective sweeps, archaic introgression, and accelerated evolution to help tackle this question by assessing the enrichment of heritability in these sequence elements for 41 complex traits. We find that human-gained epigenetic elements in the fetal brain harbor variants affecting skeletal, dermatological, and respiratory traits early and psychiatric traits later in development, that genomic sequences under selection since our divergence with Neanderthals are enriched in heritability for autism, and that regions depleted in ancestry from other hominids contribute more to heritability for psychiatric than other traits. Psychiatric disease may be a concomitant outcome of the evolutionary processes that made us uniquely human.

The genetic architecture of the human skeletal form

“…5D). These results suggests that specific skeletal proportions, but not overall height or several other quantitative and disease traits examined by us or (58) underwent human lineage-specific evolution since the separation of humans from the great apes. intervals mark epigenetic annotations while the other color intervals mark genetic annotations.…”

“…Second, we examined heritability enrichment using LD score regression on genomic annotations reflecting divergence at different time points in human evolution ( Fig. 5B ) following an approach outlined in Sohail and Hujoel et al ( 58, 59 ). These annotations include regions that differ in gene regulation between humans and primates through stages of early development ( 60 ), regions that differ in expression between adult humans and macaques ( 61 ), and regions that are enriched and depleted of ancestry from archaic humans ( 62, 63 ) ( Methods: LDScore heritability enrichment in regions of evolutionary context ).…”

“…Meta-analyzing across all our skeletal proportion traits we found enrichment in fetal human-gained enhancers and promoters in early time points (7, 8.5, and 12 post-conception weeks (PCW), h 2 ( C ) = 8.08, p = 5.91 × 10 -44 ; h 2 ( C ) = 3.60, p = 2.55 × 10 -4 ; h 2 ( C ) = 3.65, p = 3.55 × 10 -4 , Table S24 ) but not in adults suggesting that genes associated with skeletal proportions are differentially expressed in early development between apes and humans. While we acknowledge that the annotations of differentially regulated elements are from developing brain and not skeletal tissues, fetal human-gained brain regulatory elements and adult human skeletal regulatory elements are correlated at 58% ( 58, 67 ). Moreover, our observation of only observing enrichment in developing but not adult tissues suggests that enrichment is not driven by confounders of tissue type but by differences in development between the two species.…”

The genetic architecture and evolution of the human skeletal form

“…Second, we examined heritability enrichment using LDSC on genomic annotations that reflect divergence at different time points in human evolution (Fig. 5B) following an approach outlined in Sohail ( 56 ) and Hujoel et al . ( 57 ).…”

The genetic architecture of cerebellar lobules: Insights from the UK Biobank

“…We used stratified LDSC (S-LDSC) [31] to compute the contribution of variants within each specific genomic region towards trait variation, and assess whether this contribution was larger or smaller than would be expected given the relative proportion of variants in that region. We considered six human-gained genetic and epigenetic sequence elements as genomic annotations marking different evolutionary periods (similar to the approach taken in [32, 68]): fetal brain Human Gained Enhancers (HGE) [33], adult HGE and promoters in the cerebellum [69], Human Accelerated Regions [34], Ancient Selective Sweeps [35], SNPs introgressed from other hominins [36] and genomic regions depleted from such introgression signals (so-called “introgression deserts”) [37]).…”