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Journal article
Optical mapping of the 22q11.2DS region reveals complex repeat structures and preferred locations for non-allelic homologous recombination (NAHR)
Scientific reports, v 10(1), pp 12235-12235
22 Jul 2020
PMID: 32699385
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
The most prevalent microdeletion in humans occurs at 22q11.2, a region rich in chromosome-specific low copy repeats (LCR22s). The structure of this region has defied elucidation due to its size, regional complexity, and haplotype diversity, and is not well represented in the human genome reference. Most individuals with 22q11.2 deletion syndrome (22q11.2DS) carry a de novo hemizygous deletion of ~ 3 Mbp occurring by non-allelic homologous recombination (NAHR) mediated by LCR22s. In this study, optical mapping has been used to elucidate LCR22 structure and variation in 88 individuals in thirty 22q11.2DS families to uncover potential risk factors for germline rearrangements leading to 22q11.2DS offspring. Families were optically mapped to characterize LCR22 structures, NAHR locations, and genomic signatures associated with the deletion. Bioinformatics analyses revealed clear delineations between LCR22 structures in normal and deletion-containing haplotypes. Despite no explicit whole-haplotype predisposing configurations being identified, all NAHR events contain a segmental duplication encompassing FAM230 gene members suggesting preferred recombination sequences. Analysis of deletion breakpoints indicates that preferred recombinations occur between FAM230 and specific segmental duplication orientations within LCR22A and LCR22D, ultimately leading to NAHR. This work represents the most comprehensive analysis of 22q11.2DS NAHR events demonstrating completely contiguous LCR22 structures surrounding and within deletion breakpoints.
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Details
- Title
- Optical mapping of the 22q11.2DS region reveals complex repeat structures and preferred locations for non-allelic homologous recombination (NAHR)
- Creators
- Steven Pastor - Children's Hospital of PhiladelphiaOanh Tran - Children's Hospital of PhiladelphiaAndrea Jin - Children's Hospital of PhiladelphiaDanielle Carrado - Children's Hospital of PhiladelphiaBenjamin A Silva - University of PennsylvaniaLahari Uppuluri - Drexel UniversityHeba Z Abid - Drexel UniversityEleanor Young - Drexel UniversityT Blaine Crowley - Children's Hospital of PhiladelphiaAlice G Bailey - Children's Hospital of PhiladelphiaDaniel E McGinn - Children's Hospital of PhiladelphiaDonna M McDonald-McGinn - University of PennsylvaniaElaine H Zackai - University of PennsylvaniaMichael Xie - Children's Hospital of PhiladelphiaDeanne Taylor - Children's Hospital of PhiladelphiaBernice E Morrow - Albert Einstein College of MedicineMing Xiao - Drexel UniversityBeverly S Emanuel - University of Pennsylvania
- Publication Details
- Scientific reports, v 10(1), pp 12235-12235
- Publisher
- Springer Nature
- Grant note
- R01 GM125757 / NIGMS NIH HHS R01 HG005946 / NHGRI NIH HHS GM125757 / NIH HHS HD070454 / NIH HHS
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- School of Biomedical Engineering, Science, and Health Systems
- Web of Science ID
- WOS:000556403500016
- Scopus ID
- 2-s2.0-85088403664
- Other Identifier
- 991019167623904721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Genetics & Heredity