Rhesus macaque is an Old World monkey that shared a common ancestor with human ∼25 Myr ago and is an important animal model for human disease studies. A deep understanding of its genetics is therefore required for both biomedical and evolutionary studies. Among structural variants, inversions represent a driving force in speciation and play an important role in disease predisposition. Here we generated a genome-wide map of inversions between human and macaque, combining single-cell strand sequencing with cytogenetics. We identified 375 total inversions between 859 bp and 92 Mbp, increasing by eightfold the number of previously reported inversions. Among these, 19 inversions flanked by segmental duplications overlap with recurrent copy number variants associated with neurocognitive disorders. Evolutionary analyses show that in 17 out of 19 cases, the Hominidae orientation of these disease-associated regions is always derived. This suggests that duplicated sequences likely played a fundamental role in generating inversions in humans and great apes, creating architectures that nowadays predispose these regions to disease-associated genetic instability. Finally, we identified 861 genes mapping at 156 inversions breakpoints, with some showing evidence of differential expression in human and macaque cell lines, thus highlighting candidates that might have contributed to the evolution of species-specific features. This study depicts the most accurate fine-scale map of inversions between human and macaque using a two-pronged integrative approach, such as single-cell strand sequencing and cytogenetics, and represents a valuable resource toward understanding of the biology and evolution of primate species.

中文翻译：

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猕猴基因组的单细胞链测序揭示了灵长类动物进化过程中的多个嵌套倒位和断点重用

恒河猴是一种旧世界的猴子，在大约 25 Myr 之前与人类有着共同的祖先，是人类疾病研究的重要动物模型。因此，生物医学和进化研究都需要对其遗传学有深入的了解。在结构变异中，倒位代表了物种形成的驱动力，并在疾病易感性中发挥重要作用。在这里，我们生成了人类和猕猴之间倒位的全基因组图谱，将单细胞链测序与细胞遗传学相结合。我们确定了 859 bp 和 92 Mbp 之间的 375 个总倒置，增加了先前报告的倒置数量的八倍。其中，19 个侧翼有节段重复的倒位与与神经认知障碍相关的复发性拷贝数变异重叠。进化分析表明，在 19 个案例中的 17 个中，这些疾病相关区域的人科方向总是派生出来的。这表明，重复序列可能在人类和类人猿体内产生倒位方面发挥了重要作用，创造了如今使这些区域易患与疾病相关的遗传不稳定性的结构。最后，我们在 156 个反转断点处确定了 861 个基因定位，其中一些显示了人类和猕猴细胞系中差异表达的证据，从而突出了可能有助于物种特异性特征进化的候选基因。本研究使用单细胞链测序和细胞遗传学等双管齐下的综合方法描绘了人类和猕猴之间最准确的精细倒置图，