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

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00064203%3A_____%2F16%3A10332863" target="_blank" >RIV/00064203:_____/16:10332863 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/00216208:11130/16:10332863

Výsledek na webu

<a href="http://dx.doi.org/10.1371/journal.pone.0167984" target="_blank" >http://dx.doi.org/10.1371/journal.pone.0167984</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1371/journal.pone.0167984" target="_blank" >10.1371/journal.pone.0167984</a>

Jazyk výsledku

angličtina

Název v původním jazyce

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

Popis výsledku v původním jazyce

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.

Název v anglickém jazyce

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

Popis výsledku anglicky

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.

Druh

J_x - Nezařazeno - Článek v odborném periodiku (Jimp, Jsc a Jost)

CEP obor

EB - Genetika a molekulární biologie

OECD FORD obor

—

Projekt

<a href="/cs/project/NV15-31899A" target="_blank" >NV15-31899A: Dědičná recesivní onemocnění u českých Romů – zefektivnění a rozšíření diagnostiky s využitím homozygotního mapování a celoexomového sekvenování.</a><br>

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)<br>I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2016

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

PLoS ONE

ISSN

1932-6203

e-ISSN

—

Svazek periodika

11

Číslo periodika v rámci svazku

12

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

18

Strana od-do

—

Kód UT WoS článku

000389587100245

EID výsledku v databázi Scopus

2-s2.0-85005943170