The 12th International Symposium on 3D Genomics

67 / 2026-04-04 21:40:22

Genomic structural variations distinguishing archaic and modern humans are associated with human brain evolution

Structural variation,Archaic hominins,Neanderthal,Denisovans,Brain evolution

Understanding the genetic mechanisms underlying the differences in neurodevelopment and brain functional complexity between modern humans and extinct archaic hominins (Neanderthals and Denisovans) is one of the central questions in modern human evolution research. Many studies have focused on single nucleotide variants (SNVs) to explain neuro-related phenotypic differences between archaic and modern humans. Compared to SNVs, structural variants (SVs, typically defined as large-scale genomic alterations longer than 50 bp, such as insertions and deletions) often have more pronounced effects on phenotypes (e.g., by affecting protein function, cis-regulatory elements, or altering three-dimensional genome architecture). However, due to technical limitations such as scarce and fragmented ancient DNA samples, research on SVs that distinguish archaic hominin from modern human is relatively scarce compared to SNV studies, limiting our understanding of how SVs contribute to phenotypic differences between the two groups. Based on publicly available data, this study integrated published high-quality sequencing data from four archaic hominin samples (one Denisovan and three Neanderthals) and a dataset of non-human primate (NHP) lineage-specific SVs to genotype NHP SVs across the four archaic hominin genomes. Through screening, we identified a set of high-confidence SVs that are present in archaic hominins but absent in modern humans, defined as Archaic Hominin Structural Variants (AHSVs), totaling 951. These AHSVs are evenly distributed across the genome, with an average length of approximately 493 bp. Functional and disease enrichment analyses revealed that genes associated with AHSVs are significantly enriched in biological processes and diseases closely related to brain development and function. 39 AHSVs overlap with cis‑regulatory elements (CREs) in the primate brain. Additionally, in 3 neural-related genes (PDE10A, RAPGEF4, and DCTN4), chromatin loop anchors specific to modern humans coincide with deletion (DEL) regions shared by archaic hominins and chimpanzees. This suggests that AHSVs may have influenced three-dimensional chromatin structure: due to these DELs, archaic hominins and chimpanzees may be unable to form chromatin loop anchors at the same positions as modern humans, leading to differences in gene regulatory patterns and ultimately shaping the key distinctions in brain neurodevelopment and functional complexity between modern humans and archaic hominins. Overall, this work provides a novel perspective based on SVs for understanding the adaptive evolution of the modern human brain.