A time-invariant principle of genome evolution
A time-invariant principle of genome evolution
复制标题
DOI：
10.1073/pnas.0914454107
复制
发表时间：
2010-07-20
影响因子：
11.1
通讯作者：
Babu, M. Madan
中科院分区：
文献类型：
--
作者：
De, Subhajyoti;Babu, M. Madan
揭示基因组进化的一般原则是时间不变的，并在生殖细胞和体细胞中运作，对全基因组关联研究（GWAS），基因治疗和疾病基因组学有影响。在这里，我们研究了结构改变之间的关系（例如，插入和缺失）和单核苷酸取代，通过比较以下在不同时间在生殖细胞和体细胞谱系中分化的基因组：（i）参考人类和黑猩猩基因组（百万年），（ii）参考人类和个人基因组（数万年），以及（iii）癌症和遗传工程细胞中结构改变的区域（天）。在物种水平上，在附近区域发生结构改变的基因显示出增加的单核苷酸变化，并且往往进化得更快。在个人基因组中，结构改变位点附近的单核苷酸取代率较高，并随着距离的增加而降低。在人类癌细胞群和使用锌指核酸酶基因工程的细胞中，单核苷酸变化经常发生在结构改变的位点附近。我们提出了结构改变会诱导附近区域单核苷酸变化的证据，并讨论了导致这种现象的可能分子机制。我们提出，在插入或缺失过程中使用的非复制性易错修复聚合酶的低保真度导致结构改变附近的断裂修复诱导的单核苷酸突变。因此，在突变景观中，结构改变与体细胞和生殖细胞谱系中不同时间尺度的单核苷酸变化有关。我们讨论了基因组进化，GWAS，疾病基因组学和基因治疗的影响，并强调需要在一个单一的框架内调查两种类型的突变。
Uncovering general principles of genome evolution that are time-invariant and that operate in germ and somatic cells has implications for genome-wide association studies (GWAS), gene therapy, and disease genomics. Here we investigate the relationship between structural alterations (e.g., insertions and deletions) and single-nucleotide substitutions by comparing the following genomes that diverged at different times across germ-and somatic-cell lineages: (i) the reference human and chimpanzee genome (in million years), (ii) the reference human and personal genomes (in tens of thousands of years), and (iii) structurally altered regions in cancer and genetically engineered cells (in days). At the species level, genes with structural alteration in nearby regions show increased single-nucleotide changes and tend to evolve faster. In personal genomes, the single-nucleotide substitution rate is higher near sites of structural alteration and decreases with increasing distance. In human cancer cell populations and in cells genetically engineered using zinc-finger nucleases, single-nucleotide changes occur frequently near sites of structural alterations. We present evidence that structural alteration induces single-nucleotide changes in nearby regions and discuss possible molecular mechanisms that contribute to this phenomenon. We propose that the low fidelity of nonreplicative error-prone repair polymerases, which are used during insertion or deletion, result in break-repair-induced single-nucleotide mutations in the vicinity of structural alteration. Thus, in the mutational landscape, structural alterations are linked to single-nucleotide changes across different time scales in both somatic-and germ-cell lineages. We discuss implications for genome evolution, GWAS, disease genomics, and gene therapy and emphasize the need to investigate both types of mutations within a single framework.