Abstract
BackgroundRecent paleogenomic studies have highlighted a very small set of proteins carrying modern human-specific missense changes in comparison to our closest extinct relatives. Despite being frequently alluded to as highly relevant, species-specific differences in regulatory regions remain understudied. Here, we integrate data from paleogenomics, chromatin modification and physical interaction, and single-cell gene expression of neural progenitor cells to identify derived regulatory changes in the modern human lineage in comparison to Neanderthals/Denisovans. We report a set of genes whose enhancers and/or promoters harbor modern human single nucleotide changes and are active at early stages of cortical development.ResultsWe identified 212 genes controlled by regulatory regions harboring modern human changes where Neanderthals/Denisovans carry the ancestral allele. These regulatory regions significantly overlap with putative modern human positively-selected regions and schizophrenia-related genetic loci. Among the 212 genes, we identified a substantial proportion of genes related to transcriptional regulation and, specifically, an enrichment for the SETD1A histone methyltransferase complex, known to regulate WNT signaling for the generation and proliferation of intermediate progenitor cells.ConclusionsThis study complements previous research focused on protein-coding changes distinguishing our species from Neanderthals/Denisovans and highlights chromatin regulation as a functional category so far overlooked in modern human evolution studies. We present a set of candidates that will help to illuminate the investigation of modern human-specific ontogenetic trajectories.
Highlights
Recent paleogenomic studies have highlighted a very small set of proteins carrying modern humanspecific missense changes in comparison to our closest extinct relatives
By integrating data from paleogenomics and chromatin interaction and modification, we identified a set of genes controlled by regulatory regions that are active during early cortical development and contain single nucleotide changes that appeared in the modern human lineage after the split from the Neanderthal/Denisovan lineage
The regulatory regions reported here significantly overlap with putative modern human positively-selected regions and schizophrenia genomic loci, and control a set of genes among which we find a high number related to chromatin regulation, and most the SETD1A/Histone methyltransferase complex (HMT) complex
Summary
Recent paleogenomic studies have highlighted a very small set of proteins carrying modern humanspecific missense changes in comparison to our closest extinct relatives. We integrated data on chromatin immunoprecipitation and open chromatin regions identifying enhancers and promoters active during human cortical development, and the genes regulated by them as revealed by chromatin physical interaction data, together with paleogenomic data of single-nucleotide changes (SNC) distinguishing modern humans and Neanderthal/Denisovan lineages. This allowed us to uncover those enhancer and promoters that harbor modern human SNC (thereafter, mSNC) at fixed or nearly fixed frequency (as defined by [6]) in present-day human populations and where the Neanderthals/Denisovans carry the ancestral allele (Methods section). This complex, which has not figured prominently in the modern human evolution literature until now, appears to have been targeted in modern human evolution and regulates the indirect mode of neurogenesis through the control of WNT/β-CATENIN signaling
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