Mutational bias in spermatogonia impacts the anatomy of regulatory sites in the human genome.
Mutational bias in spermatogonia impacts the anatomy of regulatory sites in the human genome.
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DOI：
10.1101/gr.275407.121
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发表时间：
2021-11
期刊：
影响因子：
7
通讯作者：
Semple CA
中科院分区：
文献类型：
--
作者：
Kaiser VB;Talmane L;Kumar Y;Semple F;MacLennan M;Deciphering Developmental Disorders Study;FitzPatrick DR;Taylor MS;Semple CA
生殖系中的突变是遗传变异的最终来源，但对生殖系染色质结构对突变过程的影响知之甚少。使用ATAC-seq，我们描述了人类精原细胞的开放染色质图谱，人类精原细胞是生殖系中增殖最多的细胞类型，确定了转录因子结合位点(TFBs)和PRDM9结合位点，其中的一部分将启动减数分裂重组。我们观察到在PRDM9结合位点上罕见的结构变异(SV)断裂点的增加，暗示减数分裂重组在结构变异的产生中。许多生殖系TFBS，如NRF1，也与SV断裂点的增加有关，显然不依赖于重组。单态短插入片段(≥5碱基)在TFBs处高度丰富，尤其是在睾丸活动因子结合的部位，其比率与结构变异断裂点的比率相关。短插入经常复制TFBS基序，导致在这一男性驱动的进化过程中调控区域附近的基序位点聚集。生殖系TFBs突变负荷的增加不成比例地影响精原细胞中具有活性的神经增强器，潜在地改变神经发育调节结构。因此，精原细胞中的局部染色质结构在形成进化和疾病方面是普遍存在的。
Mutation in the germline is the ultimate source of genetic variation, but little is known about the influence of germline chromatin structure on mutational processes. Using ATAC-seq, we profile the open chromatin landscape of human spermatogonia, the most proliferative cell type of the germline, identifying transcription factor binding sites (TFBSs) and PRDM9 binding sites, a subset of which will initiate meiotic recombination. We observe an increase in rare structural variant (SV) breakpoints at PRDM9-bound sites, implicating meiotic recombination in the generation of structural variation. Many germline TFBSs, such as NRF1, are also associated with increased rates of SV breakpoints, apparently independent of recombination. Singleton short insertions (≥5 bp) are highly enriched at TFBSs, particularly at sites bound by testis active TFs, and their rates correlate with those of structural variant breakpoints. Short insertions often duplicate the TFBS motif, leading to clustering of motif sites near regulatory regions in this male-driven evolutionary process. Increased mutation loads at germline TFBSs disproportionately affect neural enhancers with activity in spermatogonia, potentially altering neurodevelopmental regulatory architecture. Local chromatin structure in spermatogonia is thus pervasive in shaping both evolution and disease.
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影响因子：
64.5
作者：
de la Torre-Ubieta L;Stein JL;Won H;Opland CK;Liang D;Lu D;Geschwind DH
通讯作者：
Geschwind DH
DOI：
10.1093/bioinformatics/btv562
发表时间：
2016-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Gel B;Díez-Villanueva A;Serra E;Buschbeck M;Peinado MA;Malinverni R
通讯作者：
Malinverni R
影响因子：
56.9
作者：
An, Joon-Yong;Lin, Kevin;Sanders, Stephan J.
通讯作者：
Sanders, Stephan J.
影响因子：
30.8
作者：
Francioli, Laurent C.;Menelaou, Andronild;Wijmenga, Cisca
通讯作者：
Wijmenga, Cisca
模因套件：用于发现和搜索的工具。
影响因子：
14.9
作者：
Bailey TL;Boden M;Buske FA;Frith M;Grant CE;Clementi L;Ren J;Li WW;Noble WS
通讯作者：
Noble WS