Cytogenetically visible inversions are formed by multiple molecular mechanisms
Maria Pettersson1,2, Christopher M Grochowski3, Josephine Wincent1,2
1Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
Human Mutation
|September 9, 2020
Summary
Chromosomal inversions, once thought neutral, can cause copy-number gains and complex genomic rearrangements. Replication-based mechanisms contribute to these events, impacting patient phenotypes.
Area of Science:
- Genetics
- Genomics
- Molecular Biology
Background:
- Chromosomal inversions are typically considered neutral genetic events.
- Nonallelic homologous recombination was the presumed mechanism for inversion formation.
Purpose of the Study:
- To investigate the genomic structure of chromosomal inversions at nucleotide resolution.
- To identify molecular mechanisms and associated copy-number variations in inversions.
Main Methods:
- Utilized short-read whole-genome sequencing (WGS), 10X Genomics Chromium WGS, droplet digital PCR, and array CGH.
- Analyzed 18 large, unique chromosomal inversions.
- Achieved nucleotide resolution for inversion junctions in 72% of cases.
Main Results:
- Identified copy-number gains (up to 350 kb) and local genomic complexities in some inversions.
- Determined mutational signatures consistent with nonhomologous end-joining (62%) or microhomology-mediated break-induced replication (38%).
- Short-read WGS effectively detects chromosomal inversions.
Conclusions:
- Chromosomal inversions are not always copy-neutral and can harbor additional genomic alterations.
- Replication-based mechanisms play a significant role in inversion formation.
- Inversions with copy-number variation may contribute to patient phenotypes.
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