Analysis of evolutionary origins of genomic loci harboring 59,732 candidate human-specific regulatory sequences identifies genetic divergence patterns during evolution of Great Apes

TL;DR

This study investigates the evolutionary origins of human-specific regulatory sequences by analyzing conservation patterns across primate genomes, revealing inheritance from extinct ancestors and de novo creation, with implications for human brain development.

Contribution

It identifies two major evolutionary pathways for regulatory sequences, highlighting the complex mosaic nature of human genome evolution and the role of extinct ancestors and de novo sequences.

Findings

Thousands of HSRS inherited from extinct ancestors.

De novo HSRS contributed significantly to human-specific traits.

Conserved regulatory regions linked to brain development.

Abstract

Our view of the universe of genomic regions harboring various types of candidate human-specific regulatory sequences (HSRS) has been markedly expanded in recent years. To infer the evolutionary origins of loci harboring HSRS, analyses of conservations patterns of 59,732 loci in Modern Humans, Chimpanzee, Bonobo, Gorilla, Orangutan, Gibbon, and Rhesus genomes have been performed. Two major evolutionary pathways have been identified comprising thousands of sequences that were either inherited from extinct common ancestors (ECAs) or created de novo in humans after human/chimpanzee split. Thousands of HSRS appear inherited from ECAs yet bypassed genomes of our closest evolutionary relatives, presumably due to the incomplete lineage sorting and/or species-specific loss or regulatory DNA. The bypassing pattern is prominent for HSRS associated with development and functions of human brain. Common genomic loci that may contributed to speciation during evolution of Great Apes comprise 248 insertions sites of African Great Ape-specific retrovirus PtERV1 (45.9%; p = 1.03E-44) intersecting regions harboring 442 HSRS, which are enriched for HSRS associated with human-specific (HS) changes of gene expression in cerebral organoids. Among non-human primates (NHP), most significant fractions of candidate HSRS associated with HS expression changes in both excitatory neurons (347 loci; 67%) and radial glia (683 loci; 72%) are highly conserved in Gorilla genome. Modern Humans acquired unique combinations of regulatory sequences highly conserved in distinct species of six NHP separated by 30 million years of evolution. Concurrently, this unique mosaic of regulatory sequences inherited from ECAs was supplemented with 12,486 created de novo HSRS. These observations support the model of complex continuous speciation process during evolution of Great Apes that is not likely to occur as an instantaneous event.