Sex-specific recombination patterns predict parent of origin for recurrent genomic disorders

• Type of Material: Article
• Authors: Trenell J Mosley, Emory University; Richard H Johnston, Emory University; David Cutler, Emory University; Michael Zwick, Emory University; Jennifer Mulle, Emory University
• Language: English
• Date: 2021-06-09
• Publisher: BMC
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2021
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1186/s12920-021-00999-8
• Title of Journal or Parent Work: BMC MEDICAL GENOMICS
• Volume: 14
• Issue: 1
• Start Page: 154
• End Page: 154
• Grant/Funding Information: This study was supported in part by the Emory Integrated Genomics Core (EIGC), which is subsidized by the Emory University School of Medicine and is one of the Emory Integrated Core Facilities. Additional support was provided by the Georgia Clinical & Translational Science Alliance of the National Institutes of Health under Award Number UL1TR002378. The content is solely the responsibility of the authors and does not necessarily reflect the official views of the National Institutes of Health. Funding support includes Emory University, Grant/Award Number: Treasure Your Exceptions Project; National Institutes of Health, Grant/Award Numbers: 1R01MH110701-01A1, F31GM131609, T32GM008490. The funding bodies played no role in the design of the study nor in the collection, analysis, and interpretation of the data, nor the writing of the manuscript.
• Keywords: Science & Technology; UNEQUAL MEIOTIC CROSSOVERS; Genetics & Heredity; Meiotic recombination; MOLECULAR CHARACTERIZATION; Copy number variants; SMITH-MAGENIS-SYNDROME; 17Q21.31 MICRODELETION; CONGENITAL HEART-DEFECTS; Parent of origin; COPY-NUMBER VARIANTS; 22Q11.2 DELETIONS; MATERNAL ORIGIN; 3q29 deletion; WILLIAMS-BEUREN-SYNDROME; STRUCTURAL VARIATION; Life Sciences & Biomedicine
• Research Categories: Biology, Molecular; Health Sciences, Epidemiology

Abstract

Background: Structural rearrangements of the genome, which generally occur during meiosis and result in large-scale (> 1 kb) copy number variants (CNV; deletions or duplications ≥ 1 kb), underlie genomic disorders. Recurrent pathogenic CNVs harbor similar breakpoints in multiple unrelated individuals and are primarily formed via non-allelic homologous recombination (NAHR). Several pathogenic NAHR-mediated recurrent CNV loci demonstrate biases for parental origin of de novo CNVs. However, the mechanism underlying these biases is not well understood. Methods: We performed a systematic, comprehensive literature search to curate parent of origin data for multiple pathogenic CNV loci. Using a regression framework, we assessed the relationship between parental CNV origin and the male to female recombination rate ratio. Results: We demonstrate significant association between sex-specific differences in meiotic recombination and parental origin biases at these loci (p = 1.07 × 10–14). Conclusions: Our results suggest that parental origin of CNVs is largely influenced by sex-specific recombination rates and highlight the need to consider these differences when investigating mechanisms that cause structural variation.