Life without mismatch repair
Mathijs A Sanders,
Harald S. Vohringer,
Victoria J. Forster,
Brittany B. Campbell,
Timothy M Butler,
Philip S Robinson,
Rebecca A. Bilardi,
Ian J Majewski,
Posted 15 Apr 2021
bioRxiv DOI: 10.1101/2021.04.14.437578
Posted 15 Apr 2021
Mismatch repair (MMR) is a critical defence against mutation, but we lack quantification of its activity on different DNA lesions during human life. We performed whole-genome sequencing of normal and neoplastic tissues from individuals with constitutional MMR deficiency to establish the roles of MMR components, tissue type and disease state in somatic mutation rates. Mutational signatures varied extensively across genotypes, some coupled to leading-strand replication, some to lagging-strand replication and some independent of replication, implying that the various MMR components engage different forms of DNA damage. Loss of MSH2 or MSH6 (MutS), but not MLH1 or PMS2 (MutL), caused 5-methylcytosine-dependent hypermutation, indicating that MutS is the pivotal complex for repairing spontaneous deamination of methylated cytosines in humans. Neoplastic change altered the distribution of mutational signatures, particularly accelerating replication-coupled indel signatures. Each component of MMR repairs 1-10 lesions/day per normal human cell, and many thousands of additional events during neoplastic transformation.
- Downloaded 1,288 times
- Download rankings, all-time:
- Site-wide: 15,729
- In genomics: 1,591
- Year to date:
- Site-wide: 1,521
- Since beginning of last month:
- Site-wide: 1,457
Downloads over time
Distribution of downloads per paper, site-wide
- 27 Nov 2020: The website and API now include results pulled from medRxiv as well as bioRxiv.
- 18 Dec 2019: We're pleased to announce PanLingua, a new tool that enables you to search for machine-translated bioRxiv preprints using more than 100 different languages.
- 21 May 2019: PLOS Biology has published a community page about Rxivist.org and its design.
- 10 May 2019: The paper analyzing the Rxivist dataset has been published at eLife.
- 1 Mar 2019: We now have summary statistics about bioRxiv downloads and submissions.
- 8 Feb 2019: Data from Altmetric is now available on the Rxivist details page for every preprint. Look for the "donut" under the download metrics.
- 30 Jan 2019: preLights has featured the Rxivist preprint and written about our findings.
- 22 Jan 2019: Nature just published an article about Rxivist and our data.
- 13 Jan 2019: The Rxivist preprint is live!