Universität zu Köln

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:	Creators Email ORCID ORCID Put Code Seemanova, Eva UNSPECIFIED UNSPECIFIED UNSPECIFIED Varon, Raymonda UNSPECIFIED UNSPECIFIED UNSPECIFIED Vejvalka, Jan UNSPECIFIED UNSPECIFIED UNSPECIFIED Jarolim, Petr UNSPECIFIED orcid.org/0000-0002-9612-8652 UNSPECIFIED Seeman, Pavel UNSPECIFIED UNSPECIFIED UNSPECIFIED Chrzanowska, Krystyna H. UNSPECIFIED UNSPECIFIED UNSPECIFIED Digweed, Martin UNSPECIFIED UNSPECIFIED UNSPECIFIED Resnick, Igor UNSPECIFIED UNSPECIFIED UNSPECIFIED Kremensky, Ivo UNSPECIFIED UNSPECIFIED UNSPECIFIED Saar, Kathrin UNSPECIFIED orcid.org/0000-0002-4483-1557 UNSPECIFIED Hoffmann, Katrin UNSPECIFIED UNSPECIFIED UNSPECIFIED Dutrannoy, Veronique UNSPECIFIED UNSPECIFIED UNSPECIFIED Karbasiyan, Mohsen UNSPECIFIED UNSPECIFIED UNSPECIFIED Ghani, Mehdi UNSPECIFIED UNSPECIFIED UNSPECIFIED Baric, Ivo UNSPECIFIED UNSPECIFIED UNSPECIFIED Tekin, Mustafa UNSPECIFIED orcid.org/0000-0002-3525-7960 UNSPECIFIED Kovacs, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Krawczak, Michael UNSPECIFIED orcid.org/0000-0003-2603-1502 UNSPECIFIED Reis, Andre UNSPECIFIED orcid.org/0000-0002-6301-6363 UNSPECIFIED Sperling, Karl UNSPECIFIED UNSPECIFIED UNSPECIFIED Nothnagel, Michael UNSPECIFIED orcid.org/0000-0001-8305-7114 UNSPECIFIED
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:	Faculty of Mathematics and Natural Sciences
Divisions:	Faculty of Mathematics and Natural Sciences > Department of Biology > Institute for Genetics
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language NIJMEGEN BREAKAGE SYNDROME; DOUBLE-STRAND BREAKS; MAP-O-MAT; 657DEL5 MUTATION; CANCER-RISK; NBS1 GENE; HUMAN GENOME; CLINICAL-MANIFESTATION; DEFECTIVE RESPONSE; FEMALE FERTILITY Multiple languages Multidisciplinary Sciences Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/25266