Modeling and Analysis of Genomic Imprinting and Maternal Effects

遗传印迹和母体基因型效应是两种表观遗传现象，它们可能导致基因表达或细胞表型的遗传变化，而不改变潜在的DNA序列。这些表观遗传因素，也被称为亲本效应，作为寻找“缺失的遗传性”的共同努力的一部分，它们在复杂性状中的作用已被越来越多地探索。随着下一代测序技术的广泛应用，对亲本效应的研究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，但统计方法却落后了。大多数现有的研究印迹/母体效应的方法都局限于来自核心家庭的数据。这些方法的适用性进一步受到阻碍，因为需要作出强有力但不切实际的假设，以减少参数的数量，以避免过度参数化。此外，印迹效应和母体效应被混淆，母体效应被认为是异质的；所有这些都进一步使建模和分析工作复杂化。本项目解决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，而不会做出强烈但不切实际的假设。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中未受影响的兄弟姐妹的内部控制。这种新颖的设计使得制定部分似然方法成为可能，其中感兴趣的似然成分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谱系，重点是开发一种方法来整合异质性母系效应并解决数据缺失问题，这在扩展谱系中很常见。所提出的方法将在公开可用的软件中实现。表观遗传学在21世纪的重要性怎么强调也不为过。借用科学作家大卫·申克的话说，表观遗传学“可能是自基因发现以来遗传科学中最重要的发现”。在这方面，基因组印记和母性效应作为表观遗传过程的两个方面，具有重要作用，因为它们对哺乳动物的正常生长和发育至关重要，但也可能导致毁灭性疾病和出生缺陷。遗传印记是指基因的亲本起源的表观遗传标记，它导致相同的DNA序列的表达不同，取决于它是遗传自母亲还是父亲。众所周知，普莱德？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，这种影响可能源于儿童携带的某些基因的表达水平被母亲在怀孕期间传递的额外遗传物质所改变。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。该项目旨在开发新的统计方法和计算软件，以克服利用核心和扩展家庭数据识别具有印记和/或母系影响的基因的困难。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。该项目还将有助于培养融合生物学、统计学和计算机科学知识的前沿跨学科研究领域的下一代研究人员。

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.