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

• Type of Material: Article
• Authors: Feyza Yilmaz, Jackson Lab Genom Med; Umamaheswaran Gurusamy, UCSF School of Medicine; Trenell J Mosley, Emory University; Pille Hallast, The Jackson Laboratory for Genomic Medicine; Kwondo Kim, The Jackson Laboratory for Genomic Medicine; Yulia Mostovoy, UCSF School of Medicine; Ryan Purcell, Emory University; Tamim H Shaikh, University of Colorado School of Medicine; Michael Zwick, Emory University; Pui-Yan Kwok, UCSF School of Medicine; Charles Lee, Jackson Lab Genom Med; Jennifer Mulle, Emory University
• Language: English
• Date: 2023-05-10
• Publisher: BMC
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2023
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1186/s13073-023-01184-5
• Title of Journal or Parent Work: GENOME MEDICINE
• Volume: 15
• Issue: 1
• Start Page: 35
• End Page: 35
• Grant/Funding Information: C.L., F.Y., and P.H. were supported by the National Institute of Health (NIH) U24HG007497; K.K. was supported by the Jackson Laboratory Postdoctoral Scholar Award. T.H.S. and P-Y.K. were supported by grant # GM120772, from the National Institute of General Medical Sciences of the National Institutes of Health (NIH).; Human Pangenome Reference Consortium support comes from NHGRI: A Human Genome Reference Center (HGRC; RFA-HG-19–004), High-Quality Human Reference Genomes (HGRQ; RFA-HG-19–002), Genome Reference Representations (GRR; RFA-HG-19–003), and Technology development for complete sequencing of genomes (NOT-HG-19–011). JGM was supported by R01 MH110701.
• Keywords: Genetics & Heredity; MECHANISMS; Schizophrenia; MICRODELETION SYNDROME; Structural variations; MICRODUPLICATION; Genomic disorders; Copy number variant(s); INVERSION POLYMORPHISM; REARRANGEMENTS; GENE; NAHR; Life Sciences & Biomedicine; DE-NOVO; Science & Technology; 3q29
• Research Categories: Health Sciences, Medicine and Surgery; Biology, Cell

Abstract

Background: High 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. Methods: We 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. Results: In 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. Conclusions: We 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.