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

项目总结 更好地理解形成观察到的遗传变异的种群基因组过程是 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比率 以及重组模式、种群人口历史(调节基因漂移)和自然选择。 然而，由于未能纳入结构变体(插入、删除、重复、易位和 长度为≥50bp的倒位)，可遗传变异的最大来源往往被忽视， 解决了许多复杂表型研究中所面临的“遗传缺失”问题。由于它们的体型， 结构变异经常扰乱蛋白质编码基因和/或改变基因表达，因此它们 定性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在人类群体中；然而，类似的 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(如 在生物医学和行为研究中的广泛应用。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曾使 全面量化全基因组结构变异是不可能的。然而，尖端的单人- 分子长阅读测序技术现在使我们能够以相当高的分辨率研究这一主题。 在接下来的五年里，Pfeifer实验室将结合新的长时间阅读的基因组数据集的开发 用进化推理的计算方法：(I)全面表征全谱 基因组变异(包括不同类型结构变异的相对频率) 与生物医学相关的灵长类物种，(Ii)与人类进行基因组范围的比较，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)描述分子和 决定结构变异的应计和命运的进化过程(四)决定 与先前表征的临床表型的相关性，以及(V)调查 (结构性)突变与另一个塑造基因组结构的群体遗传过程，重组。 总而言之，这项研究将提高这些物种在生物医学研究中作为模型的实用性， 提供对疾病病因的新见解，并允许更深入地了解疾病的模式和节奏 整个灵长类物种的进化变化。

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.