Large scale genome sequencing and integrative analyses to define genomic predictors of recurrent pregnancy loss

大规模基因组测序和综合分析以确定复发性流产的基因组预测因素

基本信息

  • 批准号:
    10226657
  • 负责人:
  • 金额:
    $ 152.42万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-04-15 至 2026-03-31
  • 项目状态:
    未结题

项目摘要

SUMMARY: Recurrent pregnancy loss (RPL) occurs in approximately 5% of clinically recognized pregnancy losses. The etiology of RPL is not well characterized: after excluding the known etiologies, approximately half of women with RPL still have no identifiable cause. The fact that RPL is, in fact, recurrent suggests a strong genetic component, however there is currently a very limited understanding of the genomic contributions to RPL. Previous studies are typically deficient in their design, limited by small sample size, incomplete clinical phenotyping and/or the recruitment of singletons only. In this proposal, we put forward our plan to recruit 1000 rigorously-phenotyped RPL trios including from diverse and underrepresented backgrounds across the US and to apply WGS and sophisticated variant detection and interpretation methods developed by our labs to identify pathogenic and likely pathogenic variants for RPL. We will then perform comprehensive integrative data analyses to define the genetic basis of unexplained RPL and map the genes and regions of the chromosome that are absolutely required for human development and a successful pregnancy. Our variant interpretation pipeline includes cutting edge approaches to map likely pathogenic noncoding and structural variants rarely assessed in any pregnancy loss study. We will also perform a pilot RNA-seq study to assess the utility of this approach for gene discovery in the pregnancy loss setting. We will first look for recessive pathogenic variation, including compound heterozygosity and then test for models for de novo mosaicism, mitochondrial mutations, regulatory noncoding variation and overall mutational burden. From these combined analyses, we expect to uncover many variants in genes and regions of the chromosome that are intolerable to functional variation, which we define as the human intolerome. We will build on our previous studies to map the intolerome by combining i) available data from all clinical studies to define the genetic etiology of unexplained pregnancy loss, including data generated in this proposal and in our prior work, ii) network-based approaches to prioritize variants genes important for human development and pregnancy, iii) mouse (KOMP, DMDD/MGI) and cell line knockout studies iv) rare and common disease sequencing studies including Centers for Mendelian Genomics (CMG), Center for Common Disease Genomics (CCDG) and Pediatric Cardiac Genomics Consortium (PCGC), iv) emerging human pangenome studies HPP, and v) population-scale biobank projects such as UK BioBank and All of Us. We will then confirm these predictions via collaborator-led functional studies and retrospective analyses of RPL first losses, siblings and grandparents. The sharing of early, unpublished data from the Yale CMG and HPP enabled by our leadership in these projects is a significant strength of what will be by far the largest and most comprehensive study of RPL performed to date. Our findings will take great strides towards the goal of comprehensively mapping the human intolerome and will further expand and refine the exploratory space in which to investigate the genes and chromosomal regions essential for human development.
摘要:复发性妊娠丢失(RPL)发生在大约5%的临床确认的妊娠中。 损失。RPL的病因没有得到很好的描述:排除已知的病因后,大约有一半 患有RPL的女性中,仍没有可识别的原因。事实上,RPL是复发性的,这一事实表明 遗传成分,但目前对基因组的贡献了解非常有限 RPL。以前的研究通常在设计上存在缺陷,受样本量小、临床不完整等因素的限制 仅限于表型分析和/或招募单身人士。在这份提案中,我们提出了招聘1000人的计划 严格表型的RPL三人组,包括来自美国各地不同和代表性不足的背景 应用我们实验室开发的WGS和复杂的变异检测和解释方法来识别 RPL的致病和可能致病变异体。然后我们将进行全面的综合数据 分析未解释的RPL的遗传基础并定位染色体的基因和区域 这些都是人类发展和成功怀孕所绝对需要的。我们的不同解释 流水线包括尖端方法,以定位可能的致病非编码和罕见的结构变体 在任何妊娠丢失研究中进行评估。我们还将进行一项试验性的rna-seq研究,以评估这一方法的实用性。 在妊娠丢失环境中发现基因的方法。我们将首先寻找隐性致病变异, 包括复合杂合性,然后测试从头开始的嵌合体,线粒体突变, 调节性非编码变异和总体突变负担。从这些综合分析中,我们预计 发现基因和染色体区域中的许多变异是无法忍受功能变异的, 我们把它定义为人类的不耐烦。我们将在以前研究的基础上,通过以下方式绘制不耐受组图 结合所有临床研究的现有数据,确定不明原因妊娠的遗传病因 损失,包括本建议书和我们先前工作中产生的数据,ii)基于网络的方法来确定优先顺序 对人类发育和怀孕重要的变异基因,III)小鼠(KOMP,DMDD/MGI)和细胞系 基因敲除研究IV)罕见和常见疾病测序研究,包括孟德尔基因组学中心 (CMG)、常见病基因组学中心(CCDG)和儿科心脏基因组学联盟(PCGC), 四)新兴的人类生物基因组研究HPP,以及五)人口规模的生物库项目,如英国生物库 还有我们所有人。然后,我们将通过合作者主导的功能研究和回顾来证实这些预测 RPL第一损失、兄弟姐妹和祖父母的分析。分享耶鲁大学早期未发表的数据 CMG和HPP在这些项目中的领导地位是我们的显著优势,到目前为止 到目前为止对RPL进行的最大规模和最全面的研究。我们的发现将在以下方面取得重大进展 目标是全面绘制人类不耐受组图,并将进一步扩大和细化探索性 研究人类发育所必需的基因和染色体区域的空间。

项目成果

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Ira M Hall其他文献

GEM: crystal-clear DNA alignment
宝石:清晰如水晶的 DNA 比对
  • DOI:
    10.1038/nmeth.2256
  • 发表时间:
    2012-12-07
  • 期刊:
  • 影响因子:
    32.100
  • 作者:
    Gregory G Faust;Ira M Hall
  • 通讯作者:
    Ira M Hall

Ira M Hall的其他文献

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{{ truncateString('Ira M Hall', 18)}}的其他基金

Large scale genome sequencing and integrative analyses to define genomic predictors of recurrent pregnancy loss
大规模基因组测序和综合分析以确定复发性流产的基因组预测因子
  • 批准号:
    10393656
  • 财政年份:
    2021
  • 资助金额:
    $ 152.42万
  • 项目类别:
The WashU-UCSC-EBI Human Genome Reference Center
华盛顿大学-UCSC-EBI 人类基因组参考中心
  • 批准号:
    10456056
  • 财政年份:
    2019
  • 资助金额:
    $ 152.42万
  • 项目类别:
The WashU-UCSC-EBI Human Genome Reference Center
华盛顿大学-UCSC-EBI 人类基因组参考中心
  • 批准号:
    10689153
  • 财政年份:
    2019
  • 资助金额:
    $ 152.42万
  • 项目类别:
A Platform for Large-Scale Discovery in Common Disease
常见疾病大规模发现的平台
  • 批准号:
    9924136
  • 财政年份:
    2016
  • 资助金额:
    $ 152.42万
  • 项目类别:
Extent, Origin, and Control of Structural Variation in Mammalian Genomes
哺乳动物基因组结构变异的范围、起源和控制
  • 批准号:
    7852159
  • 财政年份:
    2009
  • 资助金额:
    $ 152.42万
  • 项目类别:

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