Seemanova, Eva, Varon, Raymonda, Vejvalka, Jan, Jarolim, Petr ORCID: 0000-0002-9612-8652, Seeman, Pavel, Chrzanowska, Krystyna H., Digweed, Martin, Resnick, Igor, Kremensky, Ivo, Saar, Kathrin ORCID: 0000-0002-4483-1557, Hoffmann, Katrin, Dutrannoy, Veronique, Karbasiyan, Mohsen, Ghani, Mehdi, Baric, Ivo, Tekin, Mustafa ORCID: 0000-0002-3525-7960, Kovacs, Peter, Krawczak, Michael ORCID: 0000-0003-2603-1502, Reis, Andre ORCID: 0000-0002-6301-6363, Sperling, Karl and Nothnagel, Michael ORCID: 0000-0001-8305-7114 (2016). The Slavic NBN Founder Mutation: A Role for Reproductive Fitness? PLoS One, 11 (12). SAN FRANCISCO: PUBLIC LIBRARY SCIENCE. ISSN 1932-6203

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Abstract

The vast majority of patients with Nijmegen Breakage Syndrome (NBS) are of Slavic origin and carry a deleterious deletion (c.657de15; 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.657de15 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.657de15 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.657de15 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.657de15 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.657de15 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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Seemanova, EvaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Varon, RaymondaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vejvalka, JanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jarolim, PetrUNSPECIFIEDorcid.org/0000-0002-9612-8652UNSPECIFIED
Seeman, PavelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chrzanowska, Krystyna H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Digweed, MartinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Resnick, IgorUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kremensky, IvoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Saar, KathrinUNSPECIFIEDorcid.org/0000-0002-4483-1557UNSPECIFIED
Hoffmann, KatrinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dutrannoy, VeroniqueUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Karbasiyan, MohsenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ghani, MehdiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Baric, IvoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tekin, MustafaUNSPECIFIEDorcid.org/0000-0002-3525-7960UNSPECIFIED
Kovacs, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Krawczak, MichaelUNSPECIFIEDorcid.org/0000-0003-2603-1502UNSPECIFIED
Reis, AndreUNSPECIFIEDorcid.org/0000-0002-6301-6363UNSPECIFIED
Sperling, KarlUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nothnagel, MichaelUNSPECIFIEDorcid.org/0000-0001-8305-7114UNSPECIFIED
URN: urn:nbn:de:hbz:38-252662
DOI: 10.1371/journal.pone.0167984
Journal or Publication Title: PLoS One
Volume: 11
Number: 12
Date: 2016
Publisher: PUBLIC LIBRARY SCIENCE
Place of Publication: SAN FRANCISCO
ISSN: 1932-6203
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
NIJMEGEN BREAKAGE SYNDROME; DOUBLE-STRAND BREAKS; MAP-O-MAT; 657DEL5 MUTATION; CANCER-RISK; NBS1 GENE; HUMAN GENOME; CLINICAL-MANIFESTATION; DEFECTIVE RESPONSE; FEMALE FERTILITYMultiple languages
Multidisciplinary SciencesMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/25266

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