Regulatory regions and human evolution: linking mutations and phenotypic effects

FRANCHINI L.F.

Conferencia; EMBO Workshop: The Evolution of Animal Genomes; 2021

EMBO

It has been proposed that the phenotypic differences in cognitive abilities among modern and archaic humans and also with our closest living relatives, the chimpanzees, are largely due to changes in the regulation of genes involved in brain development. To investigate this hypothesis, we study noncoding conserved regions that underwent accelerated evolution in the human lineage known as Human Accelerated Regions (HARs). We have mapped HARs in the human genome and found that they are not distributed randomly but they accumulate in particular genes and genomic territories. We have identified the gene Neuronal PAS Domain Protein 3 (NPAS3) as the one that accumulates the largest number of HARs in its transcriptional unit. We have functionally characterized the 14 NPAS3-HARs through a transgenic zebrafish enhancer assay comparing the function of the human and the chimpanzee version of each sequence. Through this approach we have identified at least three HARs that lost or gained function in the human lineage. We have particularly focused on HAR202, since its human version displays a loss of function compared to the rest of vertebrate orthologs tested (chimpanzee, macaque, mouse, chicken and zebrafish). Remarkably, we also found that the HAR202 Homo neanderthalensis ortholog sequence, displaying just one substitution compared to the H. sapiens, showed also strong expression in the brain. We also observed this modern human-specific loss of activity in mouse transgenic reporter assays, comparing human and neanderthal HAR202 enhancer activity. Our results suggest that the HAR202 element lost its enhancer function constituting one of the few examples of a HAR that displays functional evolution in the brain as a result of the fast molecular evolution process undergone in the H. sapiens lineage.