Sequence resolution of complex human genome structural variation

复杂人类基因组结构变异的序列解析

• 批准号: 10656792
• 负责人: Evan Eichler
• 金额: $ 44.1万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-06 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10656792
• 关键词: 1q21; Adult; Age Years; Base Sequence; Child; Childhood; Chromosomes; Complement; Complex; Copy Number Polymorphism; Coupled; DNA; Data; Disease; Event; Evolution; Frequencies; Future; Gene Frequency; Genetic; Genetic Diseases; Genetic Polymorphism; Genetic Variation; Genome; Genomic Segment; Genomics; Genotype; Goals; Haplotypes; Human; Human Genetics; Human Genome; Human Genome Project; Individual; Location; Maps; Methods; Modeling; Mutation; Parents; Patients; Pattern; Phase; Population; Population Genetics; Property; Recurrence; Research; Resolution; Resources; Sampling; Single Nucleotide Polymorphism; Structure; Technology; Testing; Validation; Variant; Work; de novo mutation; disorder risk; homologous recombination; human disease; human pangenome; improved; insight; nonhuman primate; rapid technique; reference genome; sample collection; success; telomere; whole genome

ABSTRACT Understanding the genetic basis of human disease requires a comprehensive assessment of the full spectrum of human genetic variation. While the majority of structural variation can now be routinely discovered by application of long reads and phased genome assembly, inversions have proven more difficult to characterize due to their association with repetitive DNA and their location/structure in the genome. These represent some of the largest forms of naturally occurring human genetic variation but are the least understood. That is because these loci are preferentially associated with gaps and are frequently subject to the highest frequency of recurrent mutation making them difficult to genotype using standard approaches. In this competing renewal, we focus on the complete sequence resolution of inversion hotspots of structural variation flanked by multi- copy segmental duplications. We apply long-read high-fidelity sequencing, ultra-long-read sequencing, and Strand-seq data to fully phase and assemble all inversion polymorphisms and flanking sequence for 120 human genomes (Aim 1). We use the associated haplotype data to develop methods to identify inversions associated with recurrent mutation and then test whether recurrent mutations are preferentially associated with altered structural configurations of flanking segmental duplications by genotyping these variants in a diversity panel of 3,200 human genomes where short-read whole-genome sequence data are available (Aim 2). Finally, we use the sequence-resolved haplotype structures coupled to long-read sequencing of patients to delineate breakpoints of rearrangements identified in 125 individuals harboring de novo large-scale deletions or duplications (Aim 3). This aim will test whether certain structural configurations are predisposed to recurrent rearrangement and improve breakpoint mapping associated with de novo rearrangement events. New sequence-based methods will also be developed to characterize more complex forms of human genetic variation and provide fundamental insight into their diversity, mechanism of origin, and mutational properties. This research has the additional benefit that it will improve genome assembly, characterize a large class of missing genetic variation, and provide us with the ability to more systematically explore this form of human genetic variation as part of future disease-association studies.

摘要

项目成果

The variation and evolution of complete human centromeres.

完整人类着丝粒的变异和进化。

• DOI: 10.1101/2023.05.30.542849
• 发表时间: 2023
• 期刊: bioRxiv : the preprint server for biology
• 作者: Logsdon,GlennisA;Rozanski,AllisonN;Ryabov,Fedor;Potapova,Tamara;Shepelev,ValeryA;Mao,Yafei;Rautiainen,Mikko;Koren,Sergey;Nurk,Sergey;Porubsky,David;Lucas,JulianK;Hoekzema,Kendra;Munson,KatherineM;Gerton,JenniferL;Phillipp
• 通讯作者: Phillipp

Alpha Satellite Insertion Close to an Ancestral Centromeric Region.

• DOI: 10.1093/molbev/msab244
• 发表时间: 2021-12-09
• 期刊: Molecular biology and evolution
• 影响因子: 10.7
• 作者: Giannuzzi G;Logsdon GA;Chatron N;Miller DE;Reversat J;Munson KM;Hoekzema K;Bonnet-Dupeyron MN;Rollat-Farnier PA;Baker CA;Sanlaville D;Eichler EE;Schluth-Bolard C;Reymond A
• 通讯作者: Reymond A

The Dynamic Structure and Rapid Evolution of Human Centromeric Satellite DNA.

• DOI: 10.3390/genes14010092
• 发表时间: 2022-12-28
• 期刊: Genes
• 影响因子: 3.5