Fine-Scale Characterization of Genomic Structural Variation in the Human Genome Reveals Adaptive and Biomedically Relevant Hotspots
Fine-Scale Characterization of Genomic Structural Variation in the Human Genome Reveals Adaptive and Biomedically Relevant Hotspots
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DOI：
10.1093/gbe/evz058
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发表时间：
2019-04-01
影响因子：
3.3
通讯作者：
Gokcumen, Omer
中科院分区：
文献类型：
--
作者：
Lin, Yen-Lung;Gokcumen, Omer
基因组结构变异(SVS)在人类基因组中的分布是非随机的。SVS的“热点”与进化创新和医疗条件有关。然而，这些热点的进化和生物医学特征仍然不完全清楚。在这里，我们分析了2,504个基因组的数据，构建了人类基因组中1,148个SV热点的精细化图谱。我们证实节段性复制相关的非等位基因同源重组是SV热点形成的重要机制驱动因素。然而，令我们惊讶的是，我们也发现热点中的大多数SVS并不是通过这种基于重组的机制形成的，这表明不同的机制和选择性力量塑造了热点。事实上，我们的进化分析表明，大多数SV热点位于基因缺乏的区域，并在宽松的负选择或中性条件下进化。然而，我们仍然发现了一小部分SV热点，这些热点含有丰富的人类学关键功能基因，并在地理特定和平衡的适应力量下进化。这包括位于不同染色体上的两个独立的热点，它们影响着α和β血红蛋白基因簇。在生物医学上，我们发现SV热点与临床相关的大型新生SVS的断点重合，明显高于全基因组的预期。例如，我们证明了导致特发性矮小的多个大型SVS的断点与SV热点重合。因此，SV火锅中的突变不稳定性可能导致染色体断裂，从而导致致病结构变异的形成。总体而言，我们的研究有助于更好地理解基因组的突变和适应性格局。
Genomic structural variants (SVs) are distributed nonrandomly across the human genome. The "hotspots" of SVs have been implicated in evolutionary innovations, as well as medical conditions. However, the evolutionary and biomedical features of these hotspots remain incompletely understood. Here, we analyzed data from 2,504 genomes to construct a refined map of 1,148 SV hotspots in human genomes. We confirmed that segmental duplication-related nonallelic homologous recombination is an important mechanistic driver of SV hotspot formation. However, to our surprise, we also found that a majority of SVs in hotspots do not form through such recombination-based mechanisms, suggesting diverse mechanistic and selective forces shaping hotspots. Indeed, our evolutionary analyses showed that the majority of SV hotspots are within gene-poor regions and evolve under relaxed negative selection or neutrality. However, we still found a small subset of SV hotspots harboring genes that are enriched for anthropologically crucial functions and evolve under geography-specific and balancing adaptive forces. These include two independent hotspots on different chromosomes affecting alpha and beta hemoglobin gene clusters. Biomedically, we found that the SV hotspots coincide with breakpoints of clinically relevant, large de novo SVs, significantly more often than genome-wide expectations. For example, we showed that the breakpoints of multiple large SVs, which lead to idiopathic short stature, coincide with SV hotspots. Therefore, the mutational instability in SV hotpots likely enables chromosomal breaks that lead to pathogenic structural variation formations. Overall, our study contributes to a better understanding of the mutational and adaptive landscape of the genome.