Enhancing Evolution: Charting regulatory changes across primate evolution

Abstract

Development and speciation are directed by changes in gene expression programs, which are in turn controlled by regulatory elements such as enhancers, that act in a cell-type and temporal-specific manner. Recent whole genome sequencing of different primate species has identified genomic alterations that could account for the phenotypic differences between humans and other primate species. Moreover, as most of this variation resides in the non-coding part of the genome, they potentially affect the activity of these enhancer elements. Here, we charted active regulatory elements in the common marmoset and analyzed the regulatory rewiring that occurred during primate evolution. Comparison with other primates showed that a set of regulatory elements emerged upon the split of the great apes from the rest of the primate lineage. These elements emerged preferentially in oligodendrocytes and were found to be more often deregulated in autism spectrum disorder. This hints towards a link between oligodendrocytes, the evolution of a more complex brain and increased susceptibility to neurological disorders. Focusing more closely on evolutionary novel enhancers, we showed that these are mostly variable between individuals. They more often reside in inactive genomic compartments and seem to be devoid of functional contacts with other regulatory elements suggesting a lack of function. Instead, analysis of trait associated nucleotide variants showed that these are more often located in evolutionary conserved enhancers, providing valuable information on which variations can be modelled in non-human primates. Together these findings contribute to the understanding on the role of regulatory elements in evolution and disease.