High level of complexity and global diversity of the 3q29 locus revealed by optical mapping and long-read sequencing

Genome Medicine

Research

Umamaheswaran Gurusamy¹  Yulia Mostovoy¹  Pui-Yan Kwok²  Michael E. Zwick³  Tamim H. Shaikh⁴  Jennifer G. Mulle⁵  Trenell J. Mosley⁶  Ryan H. Purcell⁷  Kwondo Kim⁸  Pille Hallast⁸  Charles Lee⁸  Feyza Yilmaz⁸ 

[1] Cardiovascular Research Institute and Institute for Human Genetics, UCSF School of Medicine, 513 Parnassus Ave, 94143, San Francisco, CA, USA;Cardiovascular Research Institute and Institute for Human Genetics, UCSF School of Medicine, 513 Parnassus Ave, 94143, San Francisco, CA, USA;Department of Dermatology, UCSF School of Medicine, 1701 Divisadero Street, 94115, San Francisco, CA, USA;Department of Genetics, Rutgers University–New Brunswick, Rutgers University, Piscataway, 08901, New Brunswick, NJ, USA;Department of Pediatrics, Section of Genetics and Metabolism, University of Colorado School of Medicine, 13123 E 16Th Ave, 80045, Aurora, CO, USA;Department of Psychiatry, Robert Wood Johnson Medical School, Rutgers Biomedical and Health Sciences, Rutgers University, 671 Hoes Lane, 08901, New Brunswick, NJ, USA;Graduate Program in Genetics and Molecular Biology, Laney Graduate School, Emory University, 201 Dowman Drive, 30322, Atlanta, GA, USA;Laboratory of Translational Cell Biology, Department of Cell Biology, Emory University School of Medicine, 100 Woodruff Circle, 30322, Atlanta, GA, USA;The Jackson Laboratory for Genomic Medicine, 10 Discovery Drive, 06032, Farmington, CT, USA;

关键词: 3q29;    Structural variations;    Genomic disorders;    Schizophrenia;    NAHR;    Copy number variant(s);   

DOI  :  10.1186/s13073-023-01184-5

 received in 2022-10-17, accepted in 2023-04-20,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundHigh sequence identity between segmental duplications (SDs) can facilitate copy number variants (CNVs) via non-allelic homologous recombination (NAHR). These CNVs are one of the fundamental causes of genomic disorders such as the 3q29 deletion syndrome (del3q29S). There are 21 protein-coding genes lost or gained as a result of such recurrent 1.6-Mbp deletions or duplications, respectively, in the 3q29 locus. While NAHR plays a role in CNV occurrence, the factors that increase the risk of NAHR at this particular locus are not well understood.MethodsWe employed an optical genome mapping technique to characterize the 3q29 locus in 161 unaffected individuals, 16 probands with del3q29S and their parents, and 2 probands with the 3q29 duplication syndrome (dup3q29S). Long-read sequencing-based haplotype resolved de novo assemblies from 44 unaffected individuals, and 1 trio was used for orthogonal validation of haplotypes and deletion breakpoints.ResultsIn total, we discovered 34 haplotypes, of which 19 were novel haplotypes. Among these 19 novel haplotypes, 18 were detected in unaffected individuals, while 1 novel haplotype was detected on the parent-of-origin chromosome of a proband with the del3q29S. Phased assemblies from 44 unaffected individuals enabled the orthogonal validation of 20 haplotypes. In 89% (16/18) of the probands, breakpoints were confined to paralogous copies of a 20-kbp segment within the 3q29 SDs. In one del3q29S proband, the breakpoint was confined to a 374-bp region using long-read sequencing. Furthermore, we categorized del3q29S cases into three classes and dup3q29S cases into two classes based on breakpoints. Finally, we found no evidence of inversions in parent-of-origin chromosomes.ConclusionsWe have generated the most comprehensive haplotype map for the 3q29 locus using unaffected individuals, probands with del3q29S or dup3q29S, and available parents, and also determined the deletion breakpoint to be within a 374-bp region in one proband with del3q29S. These results should provide a better understanding of the underlying genetic architecture that contributes to the etiology of del3q29S and dup3q29S.

【 授权许可】

CC BY   
© The Author(s) 2023

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