Differential DNA methylation of vocal and facial anatomy genes in modern humans

Abstract

Changes in potential regulatory elements are thought to be key drivers of phenotypic divergence. However, identifying changes to regulatory elements that underlie humanspecific traits has proven very challenging. Here, we use 63 reconstructed and experimentally measured DNA methylation maps of ancient and present-day humans, as well as of six chimpanzees, to detect differentially methylated regions that likely emerged in modern humans after the split from Neanderthals and Denisovans. We show that genes associated with face and vocal tract anatomy went through particularly extensive methylation changes. Specifically, we identify widespread hypermethylation in a network of face-and voiceassociated genes (SOX9, ACAN, COL2A1, NFIX and XYLT1). We propose that these repression patterns appeared after the split from Neanderthals and Denisovans, and that they might have played a key role in shaping the modern human face and vocal tract.

Loss of Extreme Long-Range Enhancers in Human Neural Crest Drives a Craniofacial Disorder

“…It is therefore tempting to speculate that some of this morphological divergence could be mediated by regulatory changes leading to minor differences in SOX9 expression levels during CNCC development. In fact, EC1.45, featured in this study, overlaps a Neanderthal-specific hypomethylated region from bone samples (based on reconstructed DNA methylation maps; Gokhman et al., 2014 , 2020 ; Figures 7 A, 7D, and S6 I). Although somewhat speculative, this suggests that the Neanderthal enhancer element might have retained regulatory activity longer during development (because DNA methylation is generally associated with silencing) compared with the human enhancer, which becomes decommissioned during chondrogenesis and is hypermethylated in human bones of various origins ( Figures 3 C–3E).…”

“…A Neanderthal-specific significantly hypomethylated region was identified at genomic coordinates chr17:68668482-68674772 (hg19) from previously published datasets ( Gokhman et al., 2014 , 2020 ) that overlaps the EC1.45 enhancer cluster. A heatmap was generated representing DNA methylation at CpG dinucleotides spanning the DMR locus for one chimp (rib), seven anatomically modern humans (femur, crania, teeth), one Denisovan (finger) and two Neanderthal (femur and toe) bone samples.…”

“…A heatmap was generated representing DNA methylation at CpG dinucleotides spanning the DMR locus for one chimp (rib), seven anatomically modern humans (femur, crania, teeth), one Denisovan (finger) and two Neanderthal (femur and toe) bone samples. DNA methylation levels were determined by whole genome bisulfite sequencing (WGBS) or reconstructed using previously published methods which leverages spontaneous C → T deamination for ancient samples ( Gokhman et al., 2014 , 2020 ). For reconstructed DNA methylation maps, the C → T ratio was calculated for each CpG dinucleotide and then translated via a linear transformation (based on modern fully hypomethylated or fully methylated sites) to a methylation percentage.…”

DNA Hypermethylation and Unstable Repeat Diseases: A Paradigm of Transcriptional Silencing to Decipher the Basis of Pathogenic Mechanisms

“…As consequences of hypermethylation, the expression level of the expanded XYLT1 allele was found being severely reduced in BSS fibroblasts. Notably, XYLT1 is a gene related to vocal and facial anatomy and it has been recently demonstrated that changes in DNA methylation in this gene correlate with the evolution of vocal tract in humans [ 23 ]. Remarkably, most patients with BSS have variations in pitch and voice quality associated to mild or moderate cognition delay [ 22 ].…”

Innate fear responses are reflected in the blood epigenome of rhesus macaques

“…A broad body of evidence suggests that environmental and experiential factors can trigger cascades of epigenetic modification that in turn mediate downstream molecular and behavioral phenotypes. In this study, we focused on DNA methylation in rhesus macaque and human blood samples using the flexibility of Illumina DNA methylation arrays as a translational platform to investigate DNA methylation in both human and non-human primate species [42][43][44][45] . In fact, we were able to identify Moreover, a DMR in PM20D1 similar to our results was recently identified in human blood samples in a longitudinal study of post-traumatic stress disorder 48 , and CAMK2A is one of the most well-understood genes mediating synaptic plasticity underlying fear learning in a variety of paradigms 49 .…”