Analysis of genomic loci harboring 59,732 human-specific regulatory sequences reveals unique to human regulatory patterns associated with brain development

Abstract

AbstractExtensive searches for genomic regions harboring various types of candidate human-specific regulatory sequences (HSRS) identified thousands’ HSRS using high-resolution next-generation sequencing technologies and methodologically diverse comparative analyses of human and non-human primates’ reference genomes. Here, a comprehensive catalogue of 59,732 genomic loci harboring candidate HSRS has been assembled to facilitate the systematic analyses of genomic sequences that were either inherited from extinct common ancestors (ECAs) or created de novo in human genomes. Present analyses identified thousands of HSRS that appear inherited from ECAs yet absent in genomes of our closest evolutionary relatives, Chimpanzee and Bonobo, presumably due to the incomplete lineage sorting and/or species-specific loss or regulatory DNA. This pattern is particularly prominent for HSRS that have been putatively associated with human-specific (HS) gene expression changes in cerebral organoid models. Significant fractions of retrotransposon-derived loci transcriptionally-active in human dorsolateral prefrontal cortex (DLPFC) are highly conserved in genomes of Gorilla, Orangutan, Gibbon, and Rhesus (1,688; 1,371; 1,148; and 1,045 loci, respectively), yet they are absent in genomes of both Chimpanzee and Bonobo. A prominent majority of regions harboring HS mutations associated with HS expression changes during brain development is highly conserved in Chimpanzee, Bonobo, and Gorilla genomes. Among non-human primates (NHP), dominant fractions of HSRS associated with HS gene expression in both excitatory neurons (347 loci; 67%) and radial glia (683 loci; 72%) are highly conserved in the Gorilla genome. Analysis of 4,433 genes encoding virus-interacting proteins (VIPs) revealed that 95.9% of human VIPs are components of HS regulatory networks that appear to operate in distinct types of human cells from preimplantation embryos to adult DLPFC. Present analyses demonstrate that Modern Humans captured unique combinations of regulatory sequences, divergent subsets of which are highly conserved in distinct species of six NHP separated by 30 million years of evolution. Concurrently, this unique-to-human mosaic of genomic regulatory patterns inherited from ECAs was supplemented with 12,486 created de novo HSRS. Present analyses of HSRS support the model of complex continuous speciation process during evolution of the human lineage that is not likely to occur as an instantaneous event. Genes encoding VIPs may represent a principal genomic target of HS regulatory networks, thus affecting a functionally diverse spectrum of biological processes controlled by VIP-containing liquid-liquid phase separated condensates.