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The Slavic NBN Founder Mutation: A Role for Reproductive Fitness?

Authors :
Eva Seemanova
Raymonda Varon
Jan Vejvalka
Petr Jarolim
Pavel Seeman
Krystyna H Chrzanowska
Martin Digweed
Igor Resnick
Ivo Kremensky
Kathrin Saar
Katrin Hoffmann
Véronique Dutrannoy
Mohsen Karbasiyan
Mehdi Ghani
Ivo Barić
Mustafa Tekin
Peter Kovacs
Michael Krawczak
André Reis
Karl Sperling
Michael Nothnagel
Source :
PLoS ONE, Vol 11, Iss 12, p e0167984 (2016)
Publication Year :
2016
Publisher :
Public Library of Science (PLoS), 2016.

Abstract

The vast majority of patients with Nijmegen Breakage Syndrome (NBS) are of Slavic origin and carry a deleterious deletion (c.657del5; rs587776650) in the NBN gene on chromosome 8q21. This mutation is essentially confined to Slavic populations and may thus be considered a Slavic founder mutation. Notably, not a single parenthood of a homozygous c.657del5 carrier has been reported to date, while heterozygous carriers do reproduce but have an increased cancer risk. These observations seem to conflict with the considerable carrier frequency of c.657del5 of 0.5% to 1% as observed in different Slavic populations because deleterious mutations would be eliminated quite rapidly by purifying selection. Therefore, we propose that heterozygous c.657del5 carriers have increased reproductive success, i.e., that the mutation confers heterozygote advantage. In fact, in our cohort study of the reproductive history of 24 NBS pedigrees from the Czech Republic, we observed that female carriers gave birth to more children on average than female non-carriers, while no such reproductive differences were observed for males. We also estimate that c.657del5 likely occurred less than 300 generations ago, thus supporting the view that the original mutation predated the historic split and subsequent spread of the 'Slavic people'. We surmise that the higher fertility of female c.657del5 carriers reflects a lower miscarriage rate in these women, thereby reflecting the role of the NBN gene product, nibrin, in the repair of DNA double strand breaks and their processing in immune gene rearrangements, telomere maintenance, and meiotic recombination, akin to the previously described role of the DNA repair genes BRCA1 and BRCA2.

Subjects

Subjects :
Medicine
Science

Details

Language :
English
ISSN :
19326203 and 42269296
Volume :
11
Issue :
12
Database :
Directory of Open Access Journals
Journal :
PLoS ONE
Publication Type :
Academic Journal
Accession number :
edsdoj.422692967694a85bee0fb44721c5434
Document Type :
article
Full Text :
https://doi.org/10.1371/journal.pone.0167984