Modern human alleles differentially regulate gene expression across brain regions: implications for brain evolution

Abstract

8The high-quality sequence of the genomes of our extinct relatives, Ne-9 anderthals and Denisovans, became recently public. At the same time, 10 we have seen the emergence of big databases of modern human genetic 11 variation. However, linking human genetic variation, neuronal phenotypes 12 and, eventually, behaviour, is only possible if we understand how variation 13 and genetic regulation interact. We used two publicly available datasets, 14 the GTEX cis-eQTL database (v7) and a catalog of high-frequency Homo 15 Sapiens specific alleles relative to the Neanderthals and Denisovan se-16 quences, to understand how high-frequency Homo Sapiens derived alleles 17 affect gene expression regulation. The resulting dataset shows that genes 18 associated with brain development are affected by Homo sapiens-specific 19 eQTL in brain areas key in human evolution such as the cerebellum. We 20 also show that some of these eQTL overlap significantly with putative 21 regions of positive selection relative to archaic humans [Peyrégne et al., 22 2017]. Additionally, we tested whether any of the variants are associated 23 with clinical conditions in modern human populations. These findings can 24 inform future experimental work and enrich current venues of research of 25 the Homo Sapiens brain evolution, such as the relationship between clini-26 cal and evolutionary research and the recent expansion of the cerebellum 27 in Homo Sapiens [Gunz et al., 2010].28 Keywords-Human evolution, eQTL, brain evolution 29 and Boeckx, 2019]). 75 Our results show differential regulation by derived cis-eQTLs in key brain 76 areas and circuits that are claimed to have changed significantly during the 77 emergence of Homo sapiens, such as the cerebellum and olfactory signalling 78 pathway [Bastir et al., 2011]. We also found genetic regulation of cellular pro-79 cesses that can potentially impact neurodevelopment and disease, such as fo-80 late one-carbon metabolism, aerobic glycolysis regulation, cell-cell adhesion and 81 regulation of cytoskeleton dynamics. Some of these processes, such as aerobic 82 glycolysis, have already been discussed in other studies in the context of human 83 evolution and human-specific diseases such as Alzheimer's Disease [Bufill et al., 84 2011]. While we limited the scope of our study to brain tissue, we found as 85 well eQTLs associated with neural crest cell development and the craniofacial 86 complex. This is of special interest, as the Homo sapiens face has a distinct re-87 tracted profile compared to that of archaic humans [Lacruz et al., 2019]. Some 88 of the genes that affect brain development might exert an influence in adjacent 89 tissues [Boeckx, 2017]. 90 Since the eQTLs affect genes previously identified as under selective sweep in 91 modern humans relative to archaic humans, we tested whether the eQTLs affect 92 128 2015]. In this case, the effect of an eQTL is understood as the relative gene 129 expression difference between the minor, ancestral allele and the high-frequency 130 derived allele. As shown ...