ABI Innovation: An Integrative Approach to Identifying Highly Heritable Subtypes of Complex Phenotypes

ABI 创新：识别复杂表型的高度遗传亚型的综合方法

• 批准号: 1356655
• 负责人: Jinbo Bi
• 金额: $ 56.17万
• 依托单位: University of Connecticut
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1356655&HistoricalAwards=false
• 关键词: ABI; Innovation; Integrative; Approach; Identifying

Identifying genetic variation underlying complex phenotypes aids the understanding of their biology. Complex phenotypes characterized by a variety of features are often associated with substantial phenotypic variation. Current statistical methods are ineffective to address this phenotypic heterogeneity, and hence lack of power to associate genetic variants with the phenotype. This project aims to design new algorithms that differentiate homogenous subtypes of a complex phenotype that are most informative in genetic analysis, and identify genetic variants that are associated with the subtypes but cannot be detected by the non-differentiated phenotype. The validity of the subtypes will be proved in multiple scales including the evidence from genomic structure and phenotypic features. The new algorithms will be validated in the areas of genetic selection for complex traits of agriculturally-important animals and plants. This project serves a vehicle to train graduate students in the multidisciplinary methods involving computer science and biology, and allow them to apply the methods in a variety of biological fields. A new course in the bioinformatics field will be developed for senior undergraduate students. High school educational materials will also be developed to educate high school students about how to mathematically model biological data so it solves biological problems.This project will derive novel analytics based on quantitative genetics theory and machine learning theory to refine complex phenotypes for enhanced discovery of genotype-phenotype correlations. Using empirical and statistically rigorous methods, this project will derive composite traits, as functions of multiple phenotypic features, that are optimized with respect to narrow-sense heritability, and that map readily to specific genomic regions. Two statistical models for estimating narrow-sense heritability will be considered: one based on sample pedigrees, and the other directly uses the whole-genome markers. To identify multi-scale evidence of a subtype that is characterized by a composite trait, a new machine learning framework will be derived to jointly analyze genotypes and phenotypes. By testing the algorithms in the analysis of large-scale biological databases, the new algorithms will derive highly heritable composite traits for feed efficiency of dairy cattle and adaptive traits of soybean to improve their genetic selection. The algorithms developed in this project will also advance the machine learning field by defining and addressing new research problems, such as the joint model inference using data from multiple sources, probabilistic clustering based on matrix decomposition, and quadratic optimization for heritability estimation. This project will yield user-friendly software tools that can be broadly deployed to biological research areas that study genetics of complex phenotypes. The validated methods and software will be disseminated through the PI?s laboratory website http://www.labhealthinfo.uconn.edu/home/ which provides more information of this project.

识别复杂表型背后的遗传变异有助于理解它们的生物学。以各种特征为特征的复杂表型往往与显著的表型变异有关。目前的统计方法不能有效地解决这种表型异质性，因此缺乏将遗传变异与表型联系起来的能力。该项目旨在设计新的算法，区分在遗传分析中信息量最大的复杂表型的同质亚型，并识别与亚型相关但不能被未分化表型检测到的遗传变异。亚型的有效性将在多个尺度上得到证明，包括来自基因组结构和表型特征的证据。新算法将在农业上重要的动植物复杂性状的遗传选择领域得到验证。该项目为研究生提供涉及计算机科学和生物学的多学科方法方面的培训，并允许他们将这些方法应用于各种生物学领域。将为高年级本科生开发一门生物信息学领域的新课程。还将开发高中教材，教育高中生如何对生物数据进行数学建模，从而解决生物学问题。该项目将基于数量遗传学理论和机器学习理论推导出新的分析方法，以提炼复杂的表型，以增强对基因-表型相关性的发现。使用经验和统计严格的方法，这个项目将得出复合性状，作为多个表型特征的函数，相对于狭义遗传力进行优化，并容易映射到特定的基因组区域。将考虑两种估计狭义遗传力的统计模型：一种基于样本家系，另一种直接使用全基因组标记。为了识别以复合性状为特征的亚型的多尺度证据，将推导出一种新的机器学习框架来联合分析基因类型和表型。通过对大规模生物数据库的分析测试，新算法将得到奶牛饲料效率的高遗传性组合性状和大豆的适应性性状，以改进其遗传选择。该项目中开发的算法还将通过定义和解决新的研究问题来推动机器学习领域，例如使用多源数据的联合模型推理、基于矩阵分解的概率聚类和遗传力估计的二次优化。该项目将产生用户友好的软件工具，可广泛部署到研究复杂表型遗传学的生物学研究领域。经过验证的方法和软件将通过皮？S实验室网站http://www.labhealthinfo.uconn.edu/home/发布，该网站提供了该项目的更多信息。