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Grant support

D.M-P. was funded by a Severo Ochoa FPI fellowship (MCIU/Fondo Social Europeo; BES-2017-079820). Work in the lab of F.S. was supported by an European Research Council ERC StG 'HYPER-INSIGHT' (757700), European Commission Horizon2020 project 'DECIDER' (965193), Spanish government project 'REPAIRSCAPE' (PID2020-118795GB-I00), CaixaResearch project 'POTENT-IMMUNO' (HR22-00402), an ICREA professorship, EMBO YIP funding, and the SGR funding of the Catalan government (SGR 00616).

Analysis of institutional authors

Mas-Ponte, DavidAuthorSupek, FranCorresponding Author

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Early Access

Mutation rate heterogeneity at the sub-gene scale due to local DNA hypomethylation

Publicated to:Nucleic Acids Research. 52 (8): 4393-4408 - 2024-04-08 52(8), DOI: 10.1093/nar/gkae252

Authors: Mas-Ponte, D; Supek, F

Affiliations

Barcelona Inst Sci & Technol BIST, Inst Res Biomed IRB Barcelona, Barcelona 08028, Spain - Author
Catalan Inst Res & Adv Studies ICREA, Barcelona 08010, Spain - Author
Genome Data Science. Institute for Research in Biomedicine - Author
Institute for Research in Biomedicine - Author
Univ Copenhagen, Fac Hlth & Med Sci, Biotech Res & Innovat Ctr BR, DK-2200 Copenhagen, Denmark - Author
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Abstract

Local mutation rates in human are highly heterogeneous, with known variability at the scale of megabase-sized chromosomal domains, and, on the other extreme, at the scale of oligonucleotides. The intermediate, kilobase-scale heterogeneity in mutation risk is less well characterized. Here, by analyzing thousands of somatic genomes, we studied mutation risk gradients along gene bodies, representing a genomic scale spanning roughly 1-10 kb, hypothesizing that different mutational mechanisms are differently distributed across gene segments. The main heterogeneity concerns several kilobases at the transcription start site and further downstream into 5 ' ends of gene bodies; these are commonly hypomutated with several mutational signatures, most prominently the ubiquitous C > T changes at CpG dinucleotides. The width and shape of this mutational coldspot at 5 ' gene ends is variable across genes, and corresponds to variable interval of lowered DNA methylation depending on gene activity level and regulation. Such hypomutated loci, at 5 ' gene ends or elsewhere, correspond to DNA hypomethylation that can associate with various landmarks, including intragenic enhancers, Polycomb-marked regions, or chromatin loop anchor points. Tissue-specific DNA hypomethylation begets tissue-specific local hypomutation. Of note, direction of mutation risk is inverted for AID/APOBEC3 cytosine deaminase activity, whose signatures are enriched in hypomethylated regions. [GRAPHICS] .

Keywords

5-hydroxymethylcytosineBinding-sitesCancerExpressioHypermutationMethylationMismatch repairNucleotide excision-repairSignaturesSomatic mutations

Quality index

Bibliometric impact. Analysis of the contribution and dissemination channel

The work has been published in the journal Nucleic Acids Research due to its progression and the good impact it has achieved in recent years, according to the agency WoS (JCR), it has become a reference in its field. In the year of publication of the work, 2024 there are still no calculated indicators, but in 2023, it was in position 6/313, thus managing to position itself as a Q1 (Primer Cuartil), in the category Biochemistry & Molecular Biology. Notably, the journal is positioned above the 90th percentile.

Independientemente del impacto esperado determinado por el canal de difusión, es importante destacar el impacto real observado de la propia aportación.

Según las diferentes agencias de indexación, el número de citas acumuladas por esta publicación hasta la fecha 2025-06-16:

  • WoS: 1
  • Scopus: 3
  • Europe PMC: 1

Impact and social visibility

From the perspective of influence or social adoption, and based on metrics associated with mentions and interactions provided by agencies specializing in calculating the so-called "Alternative or Social Metrics," we can highlight as of 2025-06-16:

  • The use, from an academic perspective evidenced by the Altmetric agency indicator referring to aggregations made by the personal bibliographic manager Mendeley, gives us a total of: 4.
  • The use of this contribution in bookmarks, code forks, additions to favorite lists for recurrent reading, as well as general views, indicates that someone is using the publication as a basis for their current work. This may be a notable indicator of future more formal and academic citations. This claim is supported by the result of the "Capture" indicator, which yields a total of: 6 (PlumX).

With a more dissemination-oriented intent and targeting more general audiences, we can observe other more global scores such as:

  • The Total Score from Altmetric: 57.6.
  • The number of mentions on the social network X (formerly Twitter): 16 (Altmetric).
  • The number of mentions in news outlets: 7 (Altmetric).

It is essential to present evidence supporting full alignment with institutional principles and guidelines on Open Science and the Conservation and Dissemination of Intellectual Heritage. A clear example of this is:

  • The work has been submitted to a journal whose editorial policy allows open Open Access publication.

Leadership analysis of institutional authors

This work has been carried out with international collaboration, specifically with researchers from: Denmark.

There is a significant leadership presence as some of the institution’s authors appear as the first or last signer, detailed as follows: First Author (Mas Ponte, David) and Last Author (Supek, Fran).

the author responsible for correspondence tasks has been Supek, Fran.