Adaptive Structural Variants Contributing to Human Brain Development Revealed by 1,026 Rhesus Macaque Genomes

Clarifying structural variants (SV) profiles in nonhuman primates could provideinsights into the genetic background underlying human-specific traits, but suchresources are largely lacking. Here, we report the largest SV atlas generated to date from a population of 1,026 macaques, verified by genome assembly for one of them. This accurate, quantitative map indicates stronger purifying selection on inversions located in regulatory regions, suggesting a strategy for prioritizing those with the most important functions. We then identified 75 human-specific inversions and prioritized them. Notably, the top-ranked inversions have substantially shaped the transcriptome through their dual-effects of reconfiguring the ancestral genomic architecture and introducing regional mutation hotspots. As a proof-of-concept, the overexpression of APCDD1, located on one of these inversions and downregulated during human evolution, significantly accelerated neuronal maturation, while its depletion in mice delays the neuronal maturation and subsequently improved their cognitive ability. This study thus provides a valuable resource to explore human evolution and diseases,and broaden the understanding of the contribution of SVs in shaping the distinct features in human brain development. scRNA-seq of wild type and Apcdd1+/- mouse embryonic brain at E10.5阐明非人灵长类的结构变异（Structural Variant，SV）谱特征，可为解析人类特异性性状背后的遗传背景提供科学洞见，但目前此类研究资源仍极度匮乏。本研究报道了迄今为止规模最大的猕猴群体SV图谱，该图谱基于1026只猕猴的群体测序数据构建，并通过其中一只个体的基因组组装结果完成验证。这份精准定量的图谱显示，调控区域内的倒位受到更强的纯化选择，这为筛选功能至关重要的倒位提供了可行策略。随后本研究鉴定出75个人类特异性倒位，并对其进行了优先级排序。值得注意的是，排名靠前的倒位通过重塑祖先基因组架构与引入区域突变热点的双重效应，极大地塑造了转录组特征。作为概念验证实验，定位于此类倒位区域且在人类进化过程中表达下调的APCDD1基因过表达，可显著加速神经元成熟；而在小鼠体内敲除该基因则会延迟神经元成熟，却最终提升了小鼠的认知能力。因此，本研究为探索人类进化与疾病机制提供了宝贵的研究资源，并加深了学界对结构变异在塑造人类大脑发育独特特征中作用的认知。包含E10.5时期野生型与Apcdd1+/-小鼠胚胎脑组织的单细胞RNA测序（single-cell RNA sequencing，scRNA-seq）数据。