Distinct patterns of complex rearrangements and a mutational signature of microhomeology are frequently observed in PLP1 copy number gain structural variants
Rattachement africain : us, hk, cz, au. Niveau de preuve : code pays fourni par la source.
Le résumé fourni par la source
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.
Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.
Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- Distinct patterns of complex rearrangements and a mutational signature of microhomeology are frequently observed in PLP1 copy number gain structural variants
- Date Crossref
- 01/12/2019
- Éditeur
- Springer Science and Business Media LLC
- Type
- journal-article
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
-
The University of Texas MD Anderson Cancer Center pays non établi dans la noticeÉtablissement de santé
-
Baylor College of Medicine Department of Molecular and Human Genetics pays non établi dans la noticeUniversité ou école supérieure
-
DuPont (United States) pays non établi dans la noticeEntreprise
-
Alfred I. duPont Hospital for Children Nemours Biomedical Research pays non établi dans la noticeÉtablissement de santé
-
Jackson Laboratory Present address: Department of Genetics and Genome Sciences pays non établi dans la noticeOrganisation à but non lucratif
-
The Jackson Laboratory for Genomic Medicine pays non établi dans la noticeOrganisation à but non lucratif
-
UConn Health pays non établi dans la noticeÉtablissement de santé
-
Chinese University of Hong Kong pays non établi dans la noticeUniversité ou école supérieure
-
Charles University DNA Laboratory pays non établi dans la noticeUniversité ou école supérieure
-
The University of Western Australia pays non établi dans la noticeUniversité ou école supérieure
-
Pathwest Laboratory Medicine Present address: Diagnostic Genomics pays non établi dans la noticeÉtablissement de santé
-
Thomas Jefferson University pays non établi dans la noticeUniversité ou école supérieure
The University of Texas MD Anderson Cancer Center, Department of Molecular and Human Genetics — Baylor College of Medicine et DuPont (United States), avec 9 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.