Genomic hypomethylation in the human germline associates with selective structural mutability in the human genome.
Genomic hypomethylation in the human germline associates with selective structural mutability in the human genome.
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DOI：
10.1371/journal.pgen.1002692
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发表时间：
2012
期刊：
影响因子：
4.5
通讯作者：
Milosavljevic A
中科院分区：
文献类型：
--
作者：
Li J;Harris RA;Cheung SW;Coarfa C;Jeong M;Goodell MA;White LD;Patel A;Kang SH;Shaw C;Chinault AC;Gambin T;Gambin A;Lupski JR;Milosavljevic A
人类基因组中结构多态性和结构变异的热点仍有待从机制上解释。我们研究了结构突变与种系 DNA 甲基化以及低拷贝重复序列 (LCR) 介导的非等位同源重组 (NAHR) 之间的关联。来自四个人类精子甲基化图谱、人类基因组进化、人类结构多态性以及之前的基因组和疾病研究的综合证据一致表明，种系低甲基化与基因组不稳定性之间存在密切关联。具体来说，甲基化荒漠（人类基因组中种系甲基化程度最低的部分）显示出自黑猩猩分支以来人类基因组中发生的结构重排的十倍富集，并且高度富集了调节组织特异性基因表达的快速进化位点。使用定制设计的阵列比较基因组杂交 (aCGH) 芯片对 400 个人类样本中的拷贝数变异 (CNV) 进行分析，并结合公开的结构变异数据，表明结构变异与种系低甲基化的关联程度与结构变异与 LCR 介导的 NAHR 的关联程度相当。此外，在被诊断患有精神分裂症、双相情感障碍和发育迟缓的个体的基因组中出现的罕见CNV以及在被诊断患有自闭症的个体中出现的从头CNV明显更加集中在低甲基化区域。这些发现表明表观基因组、选择性突变、进化和人类疾病之间存在新的联系。人类基因组包含许多结构突变发生率高的位点，包括染色体片段的插入和缺失。这种过度的变异加速了进化并导致了人类疾病，但尚未得到解释。先前已发现以低拷贝数 (LCR) 重复的 DNA 片段会促进特定疾病相关位点的结构突变。此前，基因组 DNA 缺乏甲基化（低甲基化）已被认为与长臂猿和人类癌细胞的高结构突变性有关，但在本研究之前尚未探讨其与人类种系结构突变性的关联。我们的分析证实了LCR在促进基因组规模结构突变中的作用，但也揭示了基因组不稳定性与低甲基化之间惊人的强关联。具体来说，进化分析表明，甲基化荒漠（人类基因组中约 1% 的部分，在人类精子中甲基化程度最低）的结构突变数量比全基因组平均水平高出十倍。此外，被诊断患有精神分裂症、双相情感障碍、发育迟缓和自闭症的个体的结构突变明显更集中在低甲基化区域。我们的研究结果表明基因组 DNA 甲基化、选择性结构突变、进化和人类疾病之间存在新的联系。
The hotspots of structural polymorphisms and structural mutability in the human genome remain to be explained mechanistically. We examine associations of structural mutability with germline DNA methylation and with non-allelic homologous recombination (NAHR) mediated by low-copy repeats (LCRs). Combined evidence from four human sperm methylome maps, human genome evolution, structural polymorphisms in the human population, and previous genomic and disease studies consistently points to a strong association of germline hypomethylation and genomic instability. Specifically, methylation deserts, the ∼1% fraction of the human genome with the lowest methylation in the germline, show a tenfold enrichment for structural rearrangements that occurred in the human genome since the branching of chimpanzee and are highly enriched for fast-evolving loci that regulate tissue-specific gene expression. Analysis of copy number variants (CNVs) from 400 human samples identified using a custom-designed array comparative genomic hybridization (aCGH) chip, combined with publicly available structural variation data, indicates that association of structural mutability with germline hypomethylation is comparable in magnitude to the association of structural mutability with LCR–mediated NAHR. Moreover, rare CNVs occurring in the genomes of individuals diagnosed with schizophrenia, bipolar disorder, and developmental delay and de novo CNVs occurring in those diagnosed with autism are significantly more concentrated within hypomethylated regions. These findings suggest a new connection between the epigenome, selective mutability, evolution, and human disease. The human genome contains many loci with high incidence of structural mutations, including insertions and deletions of chromosomal segments. This excessive mutability has accelerated evolution and contributed to human disease but has yet to be explained. Segments of DNA repeated in low-copy numbers (LCRs) have been previously implicated in promoting structural mutability in specific disease-associated loci. Lack of methylation (hypomethylation) of genomic DNA has been previously associated with high structural mutability in gibbons and in human cancer cells, but the association with structural mutability in the human germline has not been explored prior to this study. Our analyses confirm the role of LCRs in promoting structural mutability on the genome scale but also reveal a surprisingly strong association of genomic instability with hypomethylation. Specifically, evolutionary analyses reveal that methylation deserts, the ∼1% fraction of the human genome with the lowest methylation in human sperm, harbor a tenfold higher number of structural mutations than genome-wide average. Moreover, the structural mutations in individuals diagnosed with schizophrenia, bipolar disorder, developmental delay, and autism are significantly more concentrated within hypomethylated regions. Our findings suggest a new connection between methylation of genomic DNA, selective structural mutability, evolution, and human disease.