DMS/NIGMS 1: Multilayer network approach to tandem repeat variation in genomes

DMS/NIGMS 1：基因组串联重复变异的多层网络方法

基本信息

批准号：
10592458
负责人：
Naoki Masuda
金额：
$ 14.84万
依托单位：
STATE UNIVERSITY OF NEW YORK AT BUFFALO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-24 至 2025-06-30
项目状态：
未结题

项目摘要

Understanding the genetic bases of biological function is a fundamental quest ion in biological sciences. Traditionally, the conservation of genetic sequences across species and populations has been a primary concept with which to measure functionality. However, recent biochemical characterizations of the DNA have challenged this definition of functionality and argued up to 80% of the human genome to be functional. Several studies have pursued the possibility that biological function evolves as an adaptive response to rapid changes under environmental pressures whe reby sequence conservation does not directly predict function. By integrating -omics datasets and multilayer network approaches, we will specifically test the following four hypotheses: (1) Among the millions of tandem repeats, a small portion, still corresponding to thousands of loci, are functionally relevant. We further hypothesize that majority of these functional tandem repeats will be evolving under negative selection and pr imarily cluster together in multilayer networks of tandem repeat units. (2) Exonic tandem repeats have evolved as molecular tools to regulate the dosage of a particular functional motif. Thus, we expect that these functional tandem repeats will retain sequence conservation among paralogs as well as among species. (3) There are hundreds of tandem repeats in the mammalian genome that evolve under lineage-specific positive selection. We expect that such positively selected tandem re peats show unusual species-specific copy number expansions or contractions, and may affect gene expression and phenotypic traits more often than neutrally evolving tandem repeats. (4) Tandem-repeat copy numbe r variation, if functional, primarily effects phenotypic variation related to immunity and metabolism in humans. We expect that these repeat loci evolve under positive selection. To test these hypotheses, we will develop mathematical/computational methods to find groups of core nodes in multilayer genetic networks, and then apply them to multilayer networks that we will build, in which each network layer is based on a specific type of relationships between tandem repeat units. RELEVANCE (See instructions): Understanding genetic bases of biological function can alleviate ou r ability to understand and treat human disease. However, variable tandem repeats in the human genome have been difficult to characterize for functional and biomedical relevance. This research will leverage recently available long-read sequencing datasets to develop mathematical methods to investigate tandemly repeated sequences in the human genome, thus providing potentially transformative insights into genetic basis of human disease. P ROJ ECT/ P E R FO R M A N C E SI T E(S) (if ad di tional space is need ed , use

了解生物学功能的遗传基础是生物科学中的基本探索。传统上，跨物种和种群的遗传序列的保存一直是主要的衡量功能的概念。但是，DNA的最新生化特征已经挑战了对功能的定义，并认为人类的80％是功能。几项研究追求了生物功能作为适应性发展的可能性在环境压力下，对雷比序列保存下的快速变化的响应没有直接预测功能。通过集成 - 组数据集和多层网络方法，我们将专门检验以下四个假设：（1）在数百万串联重复序列中，一小部分，仍然与数千个基因座相对应，在功能上是相关的。我们进一步假设大多数这些功能串联重复将在负面选择下演变，并将其聚集在一起串联重复单元的多层网络。（2）外显子串联重复已作为分子工具演变为调节特定功能基序的剂量。因此，我们期望这些功能性串联重复将在旁系同源物以及物种之间保留序列保守。（3）有数百个在谱系特异性阳性选择下进化的哺乳动物基因组中的串联重复。我们预计这种积极选择的串联泥炭显示出异常的特定物种拷贝数扩张或收缩，可能会影响基因表达和表型特征的频率比中性演变的串联重复。（4）串联重复复制numbe r变化，如果功能，则主要是影响与人类免疫和代谢有关的表型变异。我们希望这些重复基因座在正选择下进化。为了检验这些假设，我们将发展在多层遗传网络中查找核心节点组的数学/计算方法，并然后将它们应用于我们将构建的多层网络，其中每个网络层都基于串联重复单元之间的特定类型的关系。相关性（请参阅说明）：了解生物功能的遗传基础可以减轻理解和治疗人的能力疾病。但是，人类基因组中的可变串联重复很难表征功能性和生物医学相关性。这项研究将利用最近可用的长阅读测序数据集开发数学方法来研究人类中的串联重复序列基因组，因此将潜在的变革性见解带入了人类疾病的遗传基础。 p roj ect/ p e r fo r m a n c e si t e（S）