The fitness effects of de novo structural variants

项目总结/摘要 NIH Pathway to Independence Award（K99/R 00）的提案主要针对孙炳勋博士的培训。 Hsieh成为大规模基因组学和人类群体遗传学的独立研究者。博士 Hsieh是一名训练有素的人口遗传学家，拟议中的研究将把他的训练推进到长期阅读中。 基于测序技术和新的机器学习方法来研究 新的突变，重点是结构变异（SV），在人类和非人类灵长类动物。另一 重要的一部分将是开发资源，哪些类型的新SV最有可能成为 致病性，因此最值得医学研究人员进一步努力。在这项工作中开发的方法 将使其他研究人员能够在疾病病因学中对SV进行更多的无假设分析。 具体来说，培训计划将集中在新SV的健身效果分布的研究， 人和非人灵长类动物使用高质量的SV调用和基因型，从几个大规模的长期和 短读测序项目。指导工作将在主要负责人的监督下进行 导师Evan Eichler博士和共同导师Sharon布朗宁博士都在华盛顿大学（UW）。 指导者和共同指导者都是基因组变异表征方面的公认专家， 高通量技术和大规模遗传学随机建模方法的发展 数据，分别。谢博士还将从一个正式的咨询委员会以及通过 由基因组科学系（GS）安排的活动，这是指导的最佳场所 培训为候选人提供接触包括模型遗传学在内的领域的杰出科学家的机会 生物、疾病、群体遗传学和高通量基因组技术的发展。 虽然在自然界中发现并且鉴于其大小通常被认为是有害的，但SV可以是有益的，并且 因此，新SV的适应性效应（DFE）的分布（即，有益的、中性的和 有害的SV）仍然难以捉摸。在拟议的研究中，我们将推断新SV和其他变体的DFE 以评估它们在自然界中的相对重要性，这反过来有助于区分变体的优先级（例如，SV vs.单身- 核苷酸变异[SNV]）。具体而言，在K99/R 00阶段，我们将（1）推断DFE 使用约100个长读段和约4，000个短读段高覆盖率的多样化面板， 人类和非人类灵长类动物基因组;（2）比较灵长类动物中新突变的DFE， 现代和古代的DNA基因组;（3）研究适应性效应和选择性约束， 在超过20，000个基因组的大型队列中，不同突变类别的疾病。在这个过程中学到的技能 建议书是最前沿的，是为候选人量身定制的，以积累大量的知识， 基因组学的新领域，这将适用于许多生物体和疾病， 未来的独立实验室。

PROJECT SUMMARY/ABSTRACT This proposal for the NIH Pathway to Independence Award (K99/R00) focuses on the training of Dr. PingHsun Hsieh to become an independent investigator of large-scale genomics and human population genetics. Dr. Hsieh is a population geneticist by training, and the proposed studies will advance his training into long-read- based sequencing technologies and novel machine-learning approaches to study the fitness consequences of new mutations, with a focus on structural variants (SVs), in humans and nonhuman primates. Another essential piece will be the development of resources on which types of new SVs are most likely to be pathogenic and hence most worth further effort by medical researchers. The methods developed in this work will enable other researchers to do more hypothesis-free analysis of SVs in disease etiology. Specifically, the training program will center on the study of the distribution of fitness effects of new SVs in human and nonhuman primates using high-quality SV calls and genotypes from several large-scale long- and short-read sequencing projects. The mentored work will take place under the supervision of the primary mentor, Dr. Evan Eichler, and the co-mentor, Dr. Sharon Browning, both at the University of Washington (UW). The mentor and co-mentor are well-established experts in the characterization of genomic variations using high-throughput technologies and the development of stochastic modeling methods for large-scale genetic data, respectively. Dr. Hsieh will also gain advice from a formal advisory committee as well as through activities arranged by the Department of Genome Sciences (GS), which is an optimal place for the mentored training providing the candidate with access to outstanding scientists in areas including genetics of model organisms, disease, population genetics, and the development of high-throughput genomic technologies. While found in nature and yet generally deemed to be deleterious given their size, SVs can be beneficial, and thus, the distribution of fitness effects (DFE) of new SVs (i.e., the relative frequencies of beneficial, neutral, and deleterious SVs) remains elusive. In the proposed studies, we will infer the DFE of new SVs and other variants to assess their relative importance in nature, which in turn helps prioritize variants (e.g., SVs vs. single- nucleotide variants [SNVs]) in medical genetics. Specifically, in the K99/R00 phases we will (1) infer the DFE of new SVs and SNVs using a diverse panel of ~100 long-read and ~4,000 short-read high-coverage human and nonhuman primate genomes; (2) compare the DFE of new mutations among primates using contemporary and ancient DNA genomes; and (3) study the fitness effects and selective constraints on diseases in different mutation categories in large cohorts of >20,000 genomes. The skills learned in this proposal are on the cutting-edge and are tailored for the candidate to amass a great amount of knowledge in new areas of genomics, which will be applicable to many organisms and diseases and critical to the candidate’s future independent laboratory.