Modeling and Analysis of Genomic Imprinting and Maternal Effects

基因组印记和母体效应的建模和分析

• 批准号: 1208968
• 负责人: Shili Lin
• 金额: $ 22万
• 依托单位: Ohio State University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2018-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1208968&HistoricalAwards=false
• 关键词: Modeling; Analysis; Genomic; Imprinting; Maternal

Genetic imprinting and maternal genotype effects are two epigenetic phenomenon, which may lead to heritable changes in gene expression or cellular phenotype without altering the underlying DNA sequence. These epigenetic factors, also known as parent-of-origin effects, have been increasingly explored for their roles in complex traits as part of a concerted effort to find the "missing heritability". Research on parent-of-origin effects has taken on a new dimension as the next generation sequencing technology becomes wildly available. However, despite the great biological and technological progress and innovation, statistical methods are lacking behind. Most existing methods for studying imprinting/maternal effects are restricted to data from nuclear families. The applicability of such methods is further hindered by the need to make strong but unrealistic assumptions to reduce the number of parameters to avoid overparametrization. In addition, imprinting and maternal effects are confounded and maternal effect is believed to be heterogeneous; all these further complicate modeling and analysis efforts. This project takes up this challenging problem and aims to develop novel statistical and computational models/methods and software for extended families and nuclear families without making the strong but unrealistic assumptions. For nuclear family data from retrospective studies, in addition to case families, the study design also considers controls, which can be in the form of control nuclear families or internal controls from unaffected siblings of case families. This novel design makes it possible to formulate a partial likelihood approach, wherein the likelihood component of interest is free of the nuisance parameters. This circumvents the problem of overparametrization and unrealistic assumptions that plague existing methods. For extended pedigrees from prospective studies, the focus is on the development of a method for incorporating heterogeneous maternal effects and addressing the issue of missing data, which is common for extended pedigrees. Methods proposed will be implemented in software that will be made publicly available.The importance of epigenetics in the twenty first century cannot be overstated. To borrow science writer David Shenk's words, epigenetics is ``perhaps the most important discovery in the science of heredity since the gene''. In this regard, genomic imprinting and maternal effects, two aspects of the epigenetic process, holds important roles as they are essential for normal mammalian growth and development but can also cause devastating diseases and birth defects. Genetic imprinting refers to the epigenetic marking of the parental origin of a gene, which leads to the same DNA sequence being expressed differently depending on whether it is inherited from the mother or from the father. It is well known that Prader?Willi syndrome and Angelman syndrome are genetic disorders involving genetic imprinting. Maternal effect refers to the influence of the prenatal environment provided by a mother, which may arise from the expression levels of some genes carried by the child being altered by the additional genetic materials passed from the mother during pregnancy. Biological research increasingly reveals the presence and importance of maternal effect in many diseases such as childhood cancer and birth defects. This projects aims to develop novel statistical methods and computational software that circumvent difficulties in identifying genes that bear imprinting and/or maternal effects using nuclear and extended family data. The tools developed will be made available to the larger scientific community to aid scientific discoveries and finding treatments for genetic diseases. This project will also contribute to the training of the next generation of researchers in a cutting-edge interdisciplinary research area that fuses knowledge in biology, statistics and computer science.

遗传印记和母体基因型效应是两种表观遗传现象，它们可以在不改变DNA序列的情况下导致基因表达或细胞表型的可遗传变化。这些表观遗传因素，也被称为父母的原产地的影响，已越来越多地探讨其在复杂的性状作为一个共同努力的一部分，以找到“丢失的遗传力”。随着下一代测序技术的广泛应用，对起源父母效应的研究已经进入了一个新的层面。然而，尽管生物和技术取得了巨大的进步和创新，但统计方法却落后于人。 大多数现有的方法研究印迹/母亲的影响仅限于核心家庭的数据。由于需要作出强有力但不切实际的假设来减少参数数目以避免过度参数化，这类方法的适用性进一步受到阻碍。此外，印迹和母体效应是混淆和母体效应被认为是异质性的，所有这些进一步复杂化建模和分析工作。 该项目承担了这一具有挑战性的问题，旨在为大家庭和核心家庭开发新的统计和计算模型/方法和软件，而不会做出强有力但不切实际的假设。对于来自回顾性研究的核心家庭数据，除了病例家庭外，研究设计还考虑了对照，其形式可以是对照核心家庭或病例家庭未受影响兄弟姐妹的内部对照。 这种新颖的设计使得有可能制定部分似然方法，其中感兴趣的似然分量不受干扰参数的影响。 这避免了困扰现有方法的过度参数化和不切实际的假设问题。 对于来自前瞻性研究的扩展家系，重点是开发一种方法，用于纳入异质性母体效应并解决缺失数据的问题，这在扩展家系中很常见。 所提出的方法将在软件中实现，这些软件将公开提供。表观遗传学在二十一世纪的重要性怎么强调都不过分。 借用科学作家大卫申克的话，表观遗传学是"自基因以来遗传科学中最重要的发现“。 在这方面，基因组印记和母体效应，表观遗传过程的两个方面，具有重要的作用，因为它们对于正常哺乳动物的生长和发育是必不可少的，但也可能导致毁灭性的疾病和出生缺陷。遗传印记是指基因的亲本来源的表观遗传标记，其导致相同的DNA序列根据其是从母亲还是从父亲遗传而不同地表达。 众所周知，普拉德？Willi综合征和Angelman综合征是涉及遗传印记的遗传性疾病。母体效应是指母亲提供的产前环境的影响，这种影响可能是由于母亲在怀孕期间传递的额外遗传物质改变了儿童携带的某些基因的表达水平。生物学研究越来越多地揭示了母亲效应在许多疾病中的存在和重要性，如儿童癌症和出生缺陷。该项目的目的是开发新的统计方法和计算软件，以避免在识别基因的困难，承担印迹和/或使用核和大家庭数据的母亲的影响。 开发的工具将提供给更大的科学界，以帮助科学发现和寻找遗传疾病的治疗方法。 该项目还将有助于在融合生物学、统计学和计算机科学知识的前沿跨学科研究领域培训下一代研究人员。