Fetal de novo mutations and preterm birth.
Fetal de novo mutations and preterm birth.
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DOI：
10.1371/journal.pgen.1006689
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发表时间：
2017-04
期刊：
影响因子：
4.5
通讯作者：
Shaw GM
中科院分区：
文献类型：
--
作者：
Li J;Oehlert J;Snyder M;Stevenson DK;Shaw GM
早产（PTB）影响美国约12%的妊娠。尽管PTB的发病率和死亡率很高，但其分子病因学尚不清楚。许多研究致力于鉴定母体和胎儿基因组中的遗传因素，但到目前为止，很少有基因组位点与PTB相关。通过分析816个三人家系的全基因组测序数据，我们首次观察了胎儿新生突变在PTB中的作用。我们观察到PTB胎儿基因组中从头突变负荷显著增加。我们的基因组分析进一步揭示了受PTB从头突变影响的基因是剂量敏感的，对基因组缺失不耐受，并且它们的小鼠直系同源物可能是发育必需的。这些基因显著参与早期胎儿脑发育，这进一步得到了我们对从独立PTB队列中鉴定的拷贝数变异的分析的支持。我们的研究表明PTB发生的一种新机制独立于胎儿基因组，从而为未来PTB的研究开辟了一条新的途径。早产是一种普遍的妊娠状况，导致大量的发病率和死亡率。其遗传关联已被很好地观察到，但潜在的病因仍不清楚。目前的研究重点是确定母体基因组中的风险因素。在这项研究中，我们测试了一个未经探索的假设，即早产可能独立地受到胎儿基因组的影响。我们分析了来自816个三人家庭的胎儿新生突变，这些突变不是从父母那里遗传的，发现早产儿与足月出生的婴儿相比，新生突变率往往增加。重要的是，我们还观察到，这些早产相关的从头突变优先影响胚胎发育所必需的剂量敏感基因，这些受影响的基因参与早期胎儿脑发育。总的来说，我们的研究首次显示了胎儿遗传对早产的贡献，并提出胎儿发育异常是早产的潜在原因。
Preterm birth (PTB) affects ~12% of pregnancies in the US. Despite its high mortality and morbidity, the molecular etiology underlying PTB has been unclear. Numerous studies have been devoted to identifying genetic factors in maternal and fetal genomes, but so far few genomic loci have been associated with PTB. By analyzing whole-genome sequencing data from 816 trio families, for the first time, we observed the role of fetal de novo mutations in PTB. We observed a significant increase in de novo mutation burden in PTB fetal genomes. Our genomic analyses further revealed that affected genes by PTB de novo mutations were dosage sensitive, intolerant to genomic deletions, and their mouse orthologs were likely developmentally essential. These genes were significantly involved in early fetal brain development, which was further supported by our analysis of copy number variants identified from an independent PTB cohort. Our study indicates a new mechanism in PTB occurrence independently contributed from fetal genomes, and thus opens a new avenue for future PTB research. Preterm birth is a prevalent pregnancy condition and leads to substantial morbidity and mortality. Its genetic association has been well observed, but the underlying etiology remains unclear. Current research has been focused on identifying risk factors in maternal genomes. In this study, we tested an unexplored hypothesis that preterm birth could be independently influenced by fetal genomes. We analyzed fetal de novo mutations, those not inherited from parents, from 816 trio families, and found preterm infants tended to have increased de novo mutation rates compared to infants born at term. Importantly, we also observed that these preterm-associated de novo mutations preferentially affect dosage sensitive genes that are essential in embryonic development, and these affected genes are involved in early fetal brain development. Overall, our study for the first time showed the fetal genetic contribution to preterm birth, and suggested abnormal fetal development as a potential cause for preterm birth.