Characterizing the full spectrum of genomic variation in biomedically-relevant primates

表征生物医学相关灵长类动物的全谱基因组变异

• 批准号: 10713954
• 负责人: Susanne P Pfeifer
• 金额: $ 39.25万
• 依托单位: ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10713954
• 关键词: Behavioral Research; Biology; Biomedical Research; Catalogs; Code; Complex; Computing Methodologies; Data Set; Development; Disease; Etiology; Evolution; Frequencies; Gene Expression; Genes; Genetic Drift; Genetic Processes; Genetic Recombination; Genetic Variation; Genome; Genomics; Health; Heart; Heritability; Historical Demography; Human; Knowledge; Length; Modeling; Molecular; Mutation; Natural Selections; Nucleotides; Pathogenesis; Pattern; Phenotype; Play; Point Mutation; Population; Population Genetics; Primates; Process; Proteins; Research; Resolution; Role; Sampling; Shapes; Source; Structure; Technology; Variant; Work; clinical phenotype; genome-wide; genomic data; genomic variation; improved; insight; neglect; nonhuman primate; novel; single molecule

PROJECT SUMMARY Gaining a better understanding of the population genomic processes that shape observed genetic variation is at the heart of evolutionary biology. Over the past decades, much previous genomics work has focused on studying the causes and consequences of point mutations, utilizing single nucleotide variation to infer rates and patterns of recombination, population demographic history (modulating genetic drift), and natural selection. However, by failing to incorporate structural variants (insertions, deletions, duplications, translocations, and inversions with a length of ≥ 50 bp), the greatest source of heritable variation was often neglected, contributing to the 'missing heritability' problem faced in many studies of complex phenotypes. Owing to their size, structural variants frequently disrupt protein-coding genes and/or modify gene expression, thus their characterization is crucially important to elucidate factors related to health and disease. Several population- specific structural variant catalogues have recently started to emerge for human populations; yet, similar datasets remain limited for most non-human primates, despite their importance to evolutionary research (as outgroups to the human lineage) and extensive usage in biomedical and behavioral research. This neglect is largely owing to historical reasons, as short-read sequencing and limited sampling previously made a comprehensive quantification of genome-wide structural variation impossible. However, cutting-edge single- molecule long-read sequencing technologies now allow us to investigate the topic with considerable resolution. Over the next five years, the Pfeifer lab will combine the development of novel long-read genomics datasets with computational methods for evolutionary inference to: (i) comprehensively characterize the full spectrum of genomic variation (including the relative frequencies of different types of structural variants) in three biomedically-relevant primate species, (ii) conduct genomic-wide comparisons with hominoids to gain a better understanding of the diversity within and divergence between species, (iii) characterize the molecular and evolutionary processes determining the accrual, and dictating the fate, of structural variants, (iv) determine associations with previously characterized clinical phenotypes, as well as (v) investigate the interplay of (structural) mutation with another population genetic process that shapes genome structure, recombination. Taken together, this research will improve the utility of these species as models in biomedical research, provide new insights into the etiology of disease, and allow for a deeper understanding of the mode and tempo of evolutionary changes across the primate clade.

项目概要 更好地了解影响观察到的遗传变异的群体基因组过程是 在过去的几十年里，许多先前的基因组学工作都集中在进化生物学的核心。 研究点突变的原因和后果，利用单核苷酸变异来推断比率 重组模式、人口统计历史（调节遗传漂变）和自然选择。 然而，由于未能合并结构变异（插入、删除、重复、易位和 长度≥ 50 bp的倒位），可遗传变异的最大来源经常被忽视，导致 由于复杂表型的大小，许多研究都面临“遗传性缺失”的问题， 结构变异经常破坏蛋白质编码基因和/或改变基因表达，因此它们的 表征对于阐明与健康和疾病相关的因素至关重要。 最近开始出现针对人类的特定结构变异目录； 对于大多数非人类灵长类动物来说，数据集仍然有限，尽管它们对进化研究很重要（如 人类谱系的外群体）并在生物医学和行为研究中广泛使用。 很大程度上归因于历史原因，因为之前的短读长测序和有限采样使得 然而，对全基因组结构变异进行全面量化是不可能的。 分子长读长测序技术现在使我们能够以相当大的分辨率研究该主题。 未来五年，Pfeifer 实验室将结合新型长读基因组学数据集的开发 使用进化推理的计算方法：（i）全面表征 三种基因组变异（包括不同类型结构变异的相对频率） 生物医学相关的灵长类物种，(ii) 与类人猿进行全基因组比较，以获得更好的结果 了解物种内部的多样性和物种之间的差异，（iii）表征分子和 进化过程决定结构变异的累积并决定其命运，（iv）决定 与先前表征的临床表型的关联，以及 (v) 研究 （结构）突变与另一个群体遗传过程形成基因组结构、重组。 总而言之，这项研究将提高这些物种作为生物医学研究模型的效用， 为疾病的病因学提供新的见解，并可以更深入地了解疾病的模式和节奏 整个灵长类进化枝的进化变化。