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Cytogenetically visible inversions are formed by multiple molecular mechanisms
Cytogenetically detected inversions are generally assumed to be copy number and phenotypically neutral events. While nonallelic homologous recombination is thought to play a major role, recent data suggest the involvement of other molecular mechanisms in inversion formation. Using a combination of s...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7702065/ https://www.ncbi.nlm.nih.gov/pubmed/32906200 http://dx.doi.org/10.1002/humu.24106 |
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author | Pettersson, Maria Grochowski, Christopher M. Wincent, Josephine Eisfeldt, Jesper Breman, Amy M. Cheung, Sau W. Krepischi, Ana C. V. Rosenberg, Carla Lupski, James R. Ottosson, Jesper Lovmar, Lovisa Gacic, Jelena Lundberg, Elisabeth S. Nilsson, Daniel Carvalho, Claudia M. B. Lindstrand, Anna |
author_facet | Pettersson, Maria Grochowski, Christopher M. Wincent, Josephine Eisfeldt, Jesper Breman, Amy M. Cheung, Sau W. Krepischi, Ana C. V. Rosenberg, Carla Lupski, James R. Ottosson, Jesper Lovmar, Lovisa Gacic, Jelena Lundberg, Elisabeth S. Nilsson, Daniel Carvalho, Claudia M. B. Lindstrand, Anna |
author_sort | Pettersson, Maria |
collection | PubMed |
description | Cytogenetically detected inversions are generally assumed to be copy number and phenotypically neutral events. While nonallelic homologous recombination is thought to play a major role, recent data suggest the involvement of other molecular mechanisms in inversion formation. Using a combination of short‐read whole‐genome sequencing (WGS), 10X Genomics Chromium WGS, droplet digital polymerase chain reaction and array comparative genomic hybridization we investigated the genomic structure of 18 large unique cytogenetically detected chromosomal inversions and achieved nucleotide resolution of at least one chromosomal inversion junction for 13/18 (72%). Surprisingly, we observed that seemingly copy number neutral inversions can be accompanied by a copy‐number gain of up to 350 kb and local genomic complexities (3/18, 17%). In the resolved inversions, the mutational signatures are consistent with nonhomologous end‐joining (8/13, 62%) or microhomology‐mediated break‐induced replication (5/13, 38%). Our study indicates that short‐read 30x coverage WGS can detect a substantial fraction of chromosomal inversions. Moreover, replication‐based mechanisms are responsible for approximately 38% of those events leading to a significant proportion of inversions that are actually accompanied by additional copy‐number variation potentially contributing to the overall phenotypic presentation of those patients. |
format | Online Article Text |
id | pubmed-7702065 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-77020652020-12-14 Cytogenetically visible inversions are formed by multiple molecular mechanisms Pettersson, Maria Grochowski, Christopher M. Wincent, Josephine Eisfeldt, Jesper Breman, Amy M. Cheung, Sau W. Krepischi, Ana C. V. Rosenberg, Carla Lupski, James R. Ottosson, Jesper Lovmar, Lovisa Gacic, Jelena Lundberg, Elisabeth S. Nilsson, Daniel Carvalho, Claudia M. B. Lindstrand, Anna Hum Mutat Research Articles Cytogenetically detected inversions are generally assumed to be copy number and phenotypically neutral events. While nonallelic homologous recombination is thought to play a major role, recent data suggest the involvement of other molecular mechanisms in inversion formation. Using a combination of short‐read whole‐genome sequencing (WGS), 10X Genomics Chromium WGS, droplet digital polymerase chain reaction and array comparative genomic hybridization we investigated the genomic structure of 18 large unique cytogenetically detected chromosomal inversions and achieved nucleotide resolution of at least one chromosomal inversion junction for 13/18 (72%). Surprisingly, we observed that seemingly copy number neutral inversions can be accompanied by a copy‐number gain of up to 350 kb and local genomic complexities (3/18, 17%). In the resolved inversions, the mutational signatures are consistent with nonhomologous end‐joining (8/13, 62%) or microhomology‐mediated break‐induced replication (5/13, 38%). Our study indicates that short‐read 30x coverage WGS can detect a substantial fraction of chromosomal inversions. Moreover, replication‐based mechanisms are responsible for approximately 38% of those events leading to a significant proportion of inversions that are actually accompanied by additional copy‐number variation potentially contributing to the overall phenotypic presentation of those patients. John Wiley and Sons Inc. 2020-10-01 2020-11 /pmc/articles/PMC7702065/ /pubmed/32906200 http://dx.doi.org/10.1002/humu.24106 Text en © 2020 The Authors. Human Mutation published by Wiley Periodicals LLC This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Articles Pettersson, Maria Grochowski, Christopher M. Wincent, Josephine Eisfeldt, Jesper Breman, Amy M. Cheung, Sau W. Krepischi, Ana C. V. Rosenberg, Carla Lupski, James R. Ottosson, Jesper Lovmar, Lovisa Gacic, Jelena Lundberg, Elisabeth S. Nilsson, Daniel Carvalho, Claudia M. B. Lindstrand, Anna Cytogenetically visible inversions are formed by multiple molecular mechanisms |
title | Cytogenetically visible inversions are formed by multiple molecular mechanisms |
title_full | Cytogenetically visible inversions are formed by multiple molecular mechanisms |
title_fullStr | Cytogenetically visible inversions are formed by multiple molecular mechanisms |
title_full_unstemmed | Cytogenetically visible inversions are formed by multiple molecular mechanisms |
title_short | Cytogenetically visible inversions are formed by multiple molecular mechanisms |
title_sort | cytogenetically visible inversions are formed by multiple molecular mechanisms |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7702065/ https://www.ncbi.nlm.nih.gov/pubmed/32906200 http://dx.doi.org/10.1002/humu.24106 |
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