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Distinct patterns of complex rearrangements and a mutational signature of microhomeology are frequently observed in PLP1 copy number gain structural variants

V. Bahrambeigi, X. Song, K. Sperle, CR. Beck, H. Hijazi, CM. Grochowski, S. Gu, P. Seeman, KJ. Woodward, CMB. Carvalho, GM. Hobson, JR. Lupski,

. 2019 ; 11 (1) : 80. [pub] 20191209

Jazyk angličtina Země Velká Británie

Typ dokumentu časopisecké články, Research Support, N.I.H., Extramural, práce podpořená grantem

Perzistentní odkaz   https://www.medvik.cz/link/bmc20023345

Grantová podpora
R35 GM133600 NIGMS NIH HHS - United States
UM1 HG006542 NHGRI NIH HHS - United States
R35 NS105078 NINDS NIH HHS - United States
GM106373 NIGMS NIH HHS - United States
R01 GM106373 NIGMS NIH HHS - United States
R01 NS058529 NINDS NIH HHS - United States
R00 GM120453 NIGMS NIH HHS - United States
R01 NS058978 NINDS NIH HHS - United States
UM1HG006542 National Heart, Lung, and Blood Institute (US)/National Human Genome Research Institute - International
P30 GM114736 NIGMS NIH HHS - United States
NV16-30206A MZ0 CEP - Centrální evidence projektů

BACKGROUND: We investigated the features of the genomic rearrangements in a cohort of 50 male individuals with proteolipid protein 1 (PLP1) copy number gain events who were ascertained with Pelizaeus-Merzbacher disease (PMD; MIM: 312080). We then compared our new data to previous structural variant mutagenesis studies involving the Xq22 region of the human genome. The aggregate data from 159 sequenced join-points (discontinuous sequences in the reference genome that are joined during the rearrangement process) were studied. Analysis of these data from 150 individuals enabled the spectrum and relative distribution of the underlying genomic mutational signatures to be delineated. METHODS: Genomic rearrangements in PMD individuals with PLP1 copy number gain events were investigated by high-density customized array or clinical chromosomal microarray analysis and breakpoint junction sequence analysis. RESULTS: High-density customized array showed that the majority of cases (33/50; ~ 66%) present with single duplications, although complex genomic rearrangements (CGRs) are also frequent (17/50; ~ 34%). Breakpoint mapping to nucleotide resolution revealed further previously unknown structural and sequence complexities, even in single duplications. Meta-analysis of all studied rearrangements that occur at the PLP1 locus showed that single duplications were found in ~ 54% of individuals and that, among all CGR cases, triplication flanked by duplications is the most frequent CGR array CGH pattern observed. Importantly, in ~ 32% of join-points, there is evidence for a mutational signature of microhomeology (highly similar yet imperfect sequence matches). CONCLUSIONS: These data reveal a high frequency of CGRs at the PLP1 locus and support the assertion that replication-based mechanisms are prominent contributors to the formation of CGRs at Xq22. We propose that microhomeology can facilitate template switching, by stabilizing strand annealing of the primer using W-C base complementarity, and is a mutational signature for replicative repair.

Clinical and Molecular Genetics Unit Institute of Child Health London UK Present address Diagnostic Genomics PathWest Laboratory Medicine Perth WA Australia School of Biomedical Sciences University of Western Australia Perth WA Australia

Department of Molecular and Human Genetics Baylor College of Medicine One Baylor Plaza Room 604B Houston TX USA

Department of Molecular and Human Genetics Baylor College of Medicine One Baylor Plaza Room 604B Houston TX USA Present address Department of Genetics and Genome Sciences University of Connecticut Health Center and the Jackson Laboratory for Genomic Medicine Farmington CT USA

DNA Laboratory Department of Pediatric Neurology 2nd Faculty of Medicine Charles University Prague and University Hospital Motol 150 06 Prague Czech Republic

Graduate Program in Diagnostic Genetics School of Health Professions The University of Texas MD Anderson Cancer Center Houston TX USA Department of Molecular and Human Genetics Baylor College of Medicine One Baylor Plaza Room 604B Houston TX USA Department of Pediatrics Baylor College of Medicine Houston TX USA Human Genome Sequencing Center Baylor College of Medicine Houston TX USA Texas Children's Hospital Houston TX USA

Graduate Program in Diagnostic Genetics School of Health Professions The University of Texas MD Anderson Cancer Center Houston TX USA Present address Graduate School of Biomedical Sciences The University of Texas MD Anderson Cancer Center UTHealth Houston TX USA

Nemours Biomedical Research Nemours Alfred 1 DuPont Hospital for Children 1600 Rockland Road RC1 Wilmington DE USA

Nemours Biomedical Research Nemours Alfred 1 DuPont Hospital for Children 1600 Rockland Road RC1 Wilmington DE USA Jefferson Medical College Thomas Jefferson University Philadelphia PA USA Department of Biological Sciences University of Delaware Newark DE USA

School of Biomedical Sciences Faculty of Medicine The Chinese University of Hong Kong Shatin NT Hong Kong SAR

Citace poskytuje Crossref.org

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$a BACKGROUND: We investigated the features of the genomic rearrangements in a cohort of 50 male individuals with proteolipid protein 1 (PLP1) copy number gain events who were ascertained with Pelizaeus-Merzbacher disease (PMD; MIM: 312080). We then compared our new data to previous structural variant mutagenesis studies involving the Xq22 region of the human genome. The aggregate data from 159 sequenced join-points (discontinuous sequences in the reference genome that are joined during the rearrangement process) were studied. Analysis of these data from 150 individuals enabled the spectrum and relative distribution of the underlying genomic mutational signatures to be delineated. METHODS: Genomic rearrangements in PMD individuals with PLP1 copy number gain events were investigated by high-density customized array or clinical chromosomal microarray analysis and breakpoint junction sequence analysis. RESULTS: High-density customized array showed that the majority of cases (33/50; ~ 66%) present with single duplications, although complex genomic rearrangements (CGRs) are also frequent (17/50; ~ 34%). Breakpoint mapping to nucleotide resolution revealed further previously unknown structural and sequence complexities, even in single duplications. Meta-analysis of all studied rearrangements that occur at the PLP1 locus showed that single duplications were found in ~ 54% of individuals and that, among all CGR cases, triplication flanked by duplications is the most frequent CGR array CGH pattern observed. Importantly, in ~ 32% of join-points, there is evidence for a mutational signature of microhomeology (highly similar yet imperfect sequence matches). CONCLUSIONS: These data reveal a high frequency of CGRs at the PLP1 locus and support the assertion that replication-based mechanisms are prominent contributors to the formation of CGRs at Xq22. We propose that microhomeology can facilitate template switching, by stabilizing strand annealing of the primer using W-C base complementarity, and is a mutational signature for replicative repair.
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