The fitness effects of de novo structural variants

从头结构变异的适应度效应

• 批准号: 10733508
• 负责人: PingHsun Hsieh
• 金额: $ 24.71万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-09 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10733508
• 关键词: Advisory Committees; Affect; Area; Award; Base Pairing; Benchmarking; Categories; Communities; Complex; Copy Number Polymorphism; DNA; DNA Sequence; Data; Demography; Development; Diploidy; Disease; Etiology; Evolution; Frequencies; Future; Genes; Genetic; Genetic Diseases; Genetic Drift; Genetic Models; Genetic Polymorphism; Genome; Genomics; Genotype; Goals; Human; Human Genome; Individual; Knowledge; Laboratories; Learning Skill; Machine Learning; Medical; Medical Genetics; Mentors; Methods; Modeling; Modernization; Mutation; Natural Selections; Nature; Organism; Outcome; Parents; Pathogenicity; Pathway interactions; Phase; Phylogenetic Analysis; Population; Population Genetics; Primates; Public Health; Quantitative Trait Loci; Recurrence; Relaxation; Research; Research Personnel; Resource Development; Resources; Sample Size; Sampling; Scientist; Shapes; Signal Transduction; Single Nucleotide Polymorphism; Supervision; Technology; Testing; Training; Training Programs; Uncertainty; United States National Institutes of Health; Universities; Variant; Washington; Work; autism spectrum disorder; biological systems; biomedical resource; career; cohort; disease-causing mutation; expectation; fitness; genetic variant; genome sciences; genome sequencing; genome wide association study; genomic locus; genomic variation; high throughput technology; human population genetics; improved; machine learning method; model organism; nonhuman primate; novel; pressure; simulation; skills; trait

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.

项目摘要/摘要 NIH独立奖（K99/R00）的这项提议重点介绍Pinghsun博士的培训 HSIEH成为大规模基因组学和人类遗传学的独立研究者。博士 HSIEH是培训的人群遗传学家，拟议的研究将把他的培训推向长阅读 - 基于测序技术和新型的机器学习方法来研究适应性后果 新的突变，重点是人类和非人类隐私的结构变体（SVS）。其他 必不可少的部分是发展资源的开发 致病性，因此医学研究人员最值得进一步的努力。这项工作中开发的方法 将使其他研究人员能够对疾病病因中的SV进行更多假设分析。 具体而言，培训计划将集中于研究新SV的健身效应的分布 人类和非人类的私人使用高质量的SV调用和基因型，来自几个大规模的长期和基因型 短阅读测序项目。修订工作将在主要的监督下进行 导师埃文·艾希勒（Evan Eichler）博士和华盛顿大学（UW）的院长莎朗·布朗宁（Sharon Browning）博士。 导师和同事是使用基因组变异表征的良好专家 高通量技术和大规模遗传的随机建模方法的开发 数据分别。 Hsieh博士还将从正式的咨询委员会以及通过 基因组科学系（GS）安排的活动，这是此事的最佳场所 培训为候选人提供在包括模型遗传学的领域的杰出科学家的机会 生物，疾病，种群遗传学以及高通量基因组技术的发展。 虽然在自然界中发现，但鉴于它们的尺寸，但通常被认为是被删除的，但SV可能是有益的，并且 因此，新SV的适应性效应（DFE）的分布（即有益，中性和 有害的SVS）仍然难以捉摸。在拟议的研究中，我们将推断出新的SV和其他变体的DFE 评估它们在自然界中的相对重要性，这反过来有助于优先考虑变体 医学遗传学中的核苷酸变体[SNVS]）。具体而言，在K99/R00阶段，我们将（1）推断DFE 使用〜100长阅读和〜4,000个短读高覆盖的潜水员面板的新SV和SNV 人类和非人类灵长类动物基因组； （2）比较使用灵长类动物之间的新突变的DFE 当代和古老的DNA基因组； （3）研究适应性效果和选择性约束 大量> 20,000个基因组中不同突变类别的疾病。在这方面学到的技能 提案是在尖端的 基因组学的新领域，这些领域将适用于许多生物和疾病，对 候选人的未来独立实验室。