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.

项目摘要 更好地理解形成观察到的遗传变异的群体基因组过程， 进化生物学的核心在过去的几十年里，以前的基因组学工作主要集中在 研究点突变的原因和后果，利用单核苷酸变异来推断 重组模式、人口统计学历史（调节遗传漂变）和自然选择。 然而，由于未能纳入结构变异（插入、缺失、重复、易位和 长度≥ 50 bp的倒位），遗传变异的最大来源往往被忽视， 许多复杂表型研究中所面临的“遗传力缺失”问题。由于它们的大小， 结构变体经常破坏蛋白质编码基因和/或修饰基因表达，因此它们 表征对于阐明与健康和疾病相关的因素至关重要。几个人口- 特定的结构变异目录最近开始出现的人群;然而，类似的 数据集对于大多数非人类灵长类动物来说仍然有限，尽管它们对进化研究很重要（如 人类谱系的外群体），并广泛用于生物医学和行为研究。这种忽视是 这在很大程度上是由于历史原因，因为短读测序和有限的采样以前使 全基因组结构变异的全面量化是不可能的。然而，尖端的单一- 分子长读测序技术现在允许我们以相当高的分辨率研究该主题。 在接下来的五年里，Pfeifer实验室将联合收割机结合新型长读基因组数据集的开发， 用进化推理的计算方法：（i）全面表征 基因组变异（包括不同类型的结构变异的相对频率）在三个 生物医学相关的灵长类物种，（ii）进行全基因组与类人猿比较，以获得更好的 了解物种内部的多样性和物种之间的差异，（iii）表征分子和 进化过程决定的应计，并决定命运，结构变异，（四）决定 与先前表征的临床表型的关联，以及（v）研究以下因素的相互作用： （结构）突变与另一个塑造基因组结构的群体遗传过程，重组。 总之，这项研究将提高这些物种作为生物医学研究模型的实用性， 为疾病的病因学提供了新的见解，并允许更深入地了解疾病的模式和克里思 灵长类进化的变化。