Archaic hominin genomics provides a window into gene expression evolution

Abstract

Differences in gene expression are thought to account for most phenotypic differences within and between species. Consequently, gene expression is a powerful lens through which to study divergence between modern humans and our closest evolutionary relatives, the Neanderthals and Denisovans. Such insights complement biological knowledge gleaned from the fossil record, while also revealing general features of the mode and tempo of regulatory evolution. Because of the degradation of ancient RNA, gene expression profiles of archaic hominins must be studied by indirect means. As such, conclusions drawn from these studies are often laden with assumptions about the genetic architecture of gene expression, the complexity of which is increasingly apparent. Despite these challenges, rapid technical and conceptual advances in the fields of ancient genomics, functional genomics, statistical genomics, and genome engineering are revolutionizing understanding of hominin gene expression evolution.

Figure 1:. Approaches for studying archaic gene expression.

Modern humans diverged from Neanderthals and Denisovans approximately 500 kya, with subsequent admixture among these lineages <100 kya [10]. Differences in gene expression between modern and archaic hominins likely contributed to their phenotypic differences, as well as the phenotypic impacts of introgressed sequences. Due to the degradation of ancient RNA, assaying the expression of archaic alleles requires indirect methods. a, Heterogeneity in the genomic landscape of introgressed haplotypes in modern human populations serves as a signature of positive, negative, and balancing selection targeting genes and regulatory elements following introgression. b, Associations between introgressed haplotypes and modern human gene expression can be tested directly in contemporary samples. c, Statistical methods can be used to predict archaic gene expression by training models with features such as genotype-expression associations, DNA sequence features, and methylation status. d, Massively parallel reporter assays allow thousands of archaic (and non-archaic) alleles to be introduced episomally or by genome editing into human cell lines or model organisms, then tested simultaneously for effects on gene expression.