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Tuesday, December 13, 2016

Genetic reproductive edge may have boosted Slavic expansions

Open access at PLoS ONE:

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.


Of the 92 haplotypes that carried NBN c.657del5 and that could be deduced without ambiguity (S1 File), 22 (23.9%) carried identical alleles at all markers between the two most distant microsatellites D8S271 (allele 257) and D8S270 (allele 200). This haplotype (Table 8) was found in individuals from Poland, Germany, CS [Czech Republic/Slovakia] and Lusatia (Sorbs) and most likely represents the ancestral haplotype. The remaining 95 haplotypes from 40 homozygous and 15 heterozygous c.657del5 carriers (out of a total of 187 chromosomes) could not be resolved without ambiguity and are best guesses (S1 File). Among these haplotypes, we observed the putative ancestral haplotype not only in individuals from the countries mentioned above, but also from Bulgaria, Russia, and the Ukraine. Some 30% of chromosomes carrying the founder mutation showed the deduced founder haplotype (Table 8). Moreover, all 187 chromosomes carrying c.657del5 showed the same SNP alleles (Table 3). Therefore, the deletion is not only confined to individuals of Slavic origin but is most likely due to a single mutational event. All differences observed for individual microsatellite alleles are explicable by past recombination or mutation owing to the non-negligible recombination rate between the STR markers (Table 2) and the high mutation rates of microsatellites of 10−4 to 10−2 per generation.

Seemanova E, Varon R, Vejvalka J, Jarolim P, Seeman P, Chrzanowska KH, et al. (2016) The Slavic NBN Founder Mutation: A Role for Reproductive Fitness? PLoS ONE 11(12): e0167984. doi:10.1371/journal.pone.0167984


EastPole said...

Table 9 shows 0.05% for Slovaks and 0.05% for Belarusians.

Such a low presence of mutation NBN c. 657del5 among Slovaks and Belarusians, Slavic population and genetically very similar to the Poles, indicates the possibility of formation of a Slavs even before the proposed 266-300 generation or 5300-7100 years ago.

The dating 6200 ± 900 years ago suggests that the Slavs existed in the time of the Corded Ware culture, and possibly even earlier, in the late Sredny Stog culture.

This dating agree with the findings of some linguists like Oleg Trubachyov, who estimated the time of formation of proto-Slavic language at about 3000 BC.

MOCKBA said...

It sounds like a ethno-social origin confound rather than a true association. The population used to consist of Slavic serfs and Austrian, Hungarian and Jewish urbanites and landowners. Indeed, the authors imply non-Hardy-Weinberg locality patchwork distribution of the variant, at least in Slovakia.
Former rural underclass origins would nicely correspond to slightly larger contemporary family sizes?
Interestingly, the same variant was linked with a sight increase in cancer risk in Czech Republic but not in the US. One possible explanation may also be the same ethnic and class confounding effect? The rural origin, more traditional, less well off families would be less likely to enroll in clinical genetics projects, and their participation may depend on a chance clustering of cancer cases.

Matt said...

Kinda seems like it would be unimportant in driving a population wave due to fitness, because of the frequency of like 0.5-1.0%. It's not like the IGFBP3 (Insulin-like growth factor-binding protein 3) and IGH (Immunoglobulin heavy locus ) locii which actually seem to produce a big West-East European FST difference But it sounds like the kind of mutation that could certainly happen.

Btw, for anyone who is still following the Native American adna work, there's a new paper by Willerslev's group on biorxiv - I'm not terribly interested myself, as it all seems very microstructural, but for anyone who is really into what they're doing there.

FrankN said...

Quite a nice, regionally focused medical study, but hardly suitable for more general conclusions:

1. Frequencies of 657del5 between 0.5 and 1% hardly suggest a substantial demographic impact, especially when considering that above frequencies cover both homozygous (= infertile) and heterozygous (= reproductive advantage) carriers.

2. Sampling has focused on (Post-)Slavic countries/ regions (ca. 4,000 samples). Acc. to Table 1, in addition, 3 Turkish, 1 Belgian and 1 Italian sample were considered. Essentially, this means we have no idea yet to which extent the phenomenon is really "Slavic", or more widespread across W. Eurasia.

3. The age estimation for the 657del5 mutation is naive at best (assumed 1% constant population growth since the Neolithic). "Larger estimates of 343 to 369 and 509 to 698 generations were obtained for growth rates of 0.5% and 0.1%, respectively." An applied generation time of 15 years is completely unrealistic, even 20 years seems too low.
Realistically, we have to anticipate at least 3-4% stillborn rate, and ~50% infant mortality, as reported in Austro-Hungarian statistics for the 1880s, and also apparent in MN/CA burial age analyses. This implies ~ 5 births/ female to achieve population growth. Isotope analyses point at prolonged breast-feeding, up to three years, during the Neolithic, implying a pregnancy every 3-4 years. Thus, 25 years per female generation is a realistic assumption, and the standard commonly applied in demographic modelling.
Using the crude modelling applied in the study, dependent on the assumed population growth rate, the mutation may have arisen any time between 37 and 4 kya (Table 7).

4. The study points at a spread of the mutation out of Lusatia/ Bohemia/ Silesia into Bulgaria, Russia and Ukraine. When this spread happened is left open. Moreover, as long as the presence of the 657del5 mutation hasn't been checked for in aDNA, we can't say anything about its geographic origin. Hypothetically, it may, e.g., have arrived with the Magyars (Hungary hasn't been sampled for the study).

Romulus said...

It seems like a strange conclusion that something as debilitating and fatal as NBS could be linked to a reproductive advantage.

capra internetensis said...


The new Alaskan genome might have big picture implications actually - in ADMIXTURE he comes out as about half Mal'ta, despite having umpteen Amerindian components to choose from, while Anzick-1 and Kennewick do not (the latter does have a bit of it though). And in TreeMix he is basal to all Amerindians without an edge, or groups with North Amerindians but with an edge from Europe. It might be due to contamination, but if not it looks like some kind of very old population structure. The supplementary information is not out yet though so hard to judge any of this.

FrankN said...

Yep, capra, noted that as well. I would have wished them to investigate both possibilities - European admix, or contamination, in more detail. Instead, "Given the TreeMix admixture results between Shuká Káa and European populations we performed a contamination correction to the D statistic as described in Raghavan et al. (22) utilizing observed D statistics with European populations (SI Appendix)". They did the same for 939. This makes their D-stats quite worthless.

This is a follow-up paper to a recent analysis that focused more on the Tsimshian's population history. There already, affinity of some "ancients" to Europeans, especially Finns, was indicated.
Dave's Admix.13.Q has Kennewick as only 75% Amerindian, with the remainder being Beringian (12%), Siberian (5%), Steppe_EMBA (4%), and EastAsian (4%). I'd be curious what his analysis of Shuká Káa would yield ..

Otherwise, the mtDNA shift from D4h3a in older to A2 in more recent samples is interesting. They couldn't prove a statistically significant genetic break, but that may be due to poor sample quality and a lack of data.

Shaikorth said...


Here are the Treemix residuals for Tsimshian paper, from the positive ones it's easy to figure out what migration edges would improve the fit.

Shuká Káa's f3 stats in figure 3 look typical Amerindian (supplements can't be viewed for whatever reason) and its PCA position, though projected, looks like that as well. A very slight tilt towards Europe compared to Anzick-302 cline, but hard to say if it means anything.