Thecis-regulatory effects of modern human-specific variants

Abstract

The Neanderthal and Denisovan genomes enabled the discovery of sequences that differ between modern and archaic humans, the majority of which are noncoding. However, our understanding of the regulatory consequences of these differences remains limited, in part due to the decay of regulatory marks in ancient samples. Here, we used a massively parallel reporter assay in embryonic stem cells, neural progenitor cells and bone osteoblasts to investigate the regulatory effects of the 14,042 single-nucleotide modern human-specific variants. Overall, 1,791 (13%) of sequences containing these variants showed active regulatory activity, and 407 (23%) of these drove differential expression between human groups. Differentially active sequences were associated with divergent transcription factor binding motifs, and with genes enriched for vocal tract and brain anatomy and function. This work provides insight into the regulatory function of variants that emerged along the modern human lineage and the recent evolution of human gene expression.

Fine-grained temporal mapping of derived high-frequency variants supports the mosaic nature of the evolution ofHomo sapiens

“…Our analysis highlights the importance of a temporal window between 300-500k that may well correspond to a significant behavioral shift in our lineage, corresponding to the Jebel Irhoud fossil, but also in other parts of the African continent, to increased ecological resource variability [53], and evidence of long-distance stone transport and pigment use [54]. Other aspects of our cognitive and anatomical modernity emerged much more recently, in the last 150000 years, and for these our analysis points to the relevance of gene expression regulation differences in recent human evolution, in line with [55,56,57].…”

“…analysis points to the relevance of gene expression regulation differences in recent human evolution, in line with [55,56,57].…”

A distinct brain expression profile for genes within large introgression deserts and under positive selection inHomo sapiens

“…This adds complementary evidence for the perinatal globularization phase as a species-specific ontogenic innovation [33]. It also provides new evidence for the claim that the cerebellum, the striatum, and the thalamus significantly contribute to this phenotype [21, 34–37].…”

Harnessing pluripotent stem cells as models to decipher human evolution

“…These approaches combine traditional reporter assay designs with molecular barcoding, allowing the simultaneous testing of 10,000s of variants in a Accepted Article single experiment [174]. Above we highlighted two applications of MPRAs to the study of human-chimpanzee DNA differences [121,122]; another example is the work of Weiss et al, who combined human iPSCs and their differentiated progeny with an MPRA to test for differences in gene regulatory potential of 14,042 fixed DNA differences between Neandertals, Denisovans and humans, identifying 407 where the modern and archaic alleles had a significantly different ability to drive reporter gene expression [175]. Some of these variants impact genes implicated in cerebellum size, or cranial anatomy, although others were not as easily parsed.…”