The Met 470 Allele Is Associated with Lower Birth Rates in Fertile Men from a Population Isolate

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Although little is known about the role of the cystic fibrosis transmembrane regulator (CFTR) gene in reproductive physiology, numerous variants in this gene have been implicated in etiology of male infertility due to congenital bilateral absence of the vas deferens (CBAVD). Here, we studied the fertility effects of three CBAVD–associated CFTR polymorphisms, the (TG)m and polyT repeat polymorphisms in intron 8 and Met470Val in exon 10, in healthy men of European descent. Homozygosity for the Met470 allele was associated with lower birth rates, defined as the number of births per year of marriage (P = 0.0029). The Met470Val locus explained 4.36% of the phenotypic variance in birth rate, and men homozygous for the Met470 allele had 0.56 fewer children on average compared to Val470 carrier men. The derived Val470 allele occurs at high frequencies in non-African populations (allele frequency = 0.51 in HapMap CEU), whereas it is very rare in African population (Fst = 0.43 between HapMap CEU and YRI). In addition, haplotypes bearing Val470 show a lack of genetic diversity and are thus longer than haplotypes bearing Met470 (measured by an integrated haplotype score [iHS] of −1.93 in HapMap CEU). The fraction of SNPs in the HapMap Phase2 data set with more extreme Fst and iHS measures is 0.003, consistent with a selective sweep outside of Africa. The fertility advantage conferred by Val470 relative to Met470 may provide a selective mechanism for these population genetic observations.

Vyšlo v časopise: The Met 470 Allele Is Associated with Lower Birth Rates in Fertile Men from a Population Isolate. PLoS Genet 6(6): e32767. doi:10.1371/journal.pgen.1000974
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1000974

Souhrn

Zdroje

1. MoskowitzSM

ChmielJF

SternenDL

ChengE

GibsonRL

2008 Clinical practice and genetic counseling for cystic fibrosis and CFTR-related disorders. Genet Med 10 851 868

2. LarribaS

BassasL

GimenezJ

RamosMD

SeguraA

1998 Testicular CFTR splice variants in patients with congenital absence of the vas deferens. Hum Mol Genet 7 1739 1743

3. ClaustresM

2005 Molecular pathology of the CFTR locus in male infertility. Reprod Biomed Online 10 14 41

4. ChuCS

TrapnellBC

CurristinS

CuttingGR

CrystalRG

1993 Genetic basis of variable exon 9 skipping in cystic fibrosis transmembrane conductance regulator mRNA. Nat Genet 3 151 156

5. de MeeusA

GuittardC

DesgeorgesM

CarlesS

DemailleJ

1998 Linkage disequilibrium between the M470V variant and the IVS8 polyT alleles of the CFTR gene in CBAVD. J Med Genet 35 594 596

6. GromanJD

HefferonTW

CasalsT

BassasL

EstivillX

2004 Variation in a repeat sequence determines whether a common variant of the cystic fibrosis transmembrane conductance regulator gene is pathogenic or benign. Am J Hum Genet 74 176 179

7. HefferonTW

GromanJD

YurkCE

CuttingGR

2004 A variable dinucleotide repeat in the CFTR gene contributes to phenotype diversity by forming RNA secondary structures that alter splicing. Proc Natl Acad Sci U S A 101 3504 3509

8. CuppensH

LinW

JaspersM

CostesB

TengH

1998 Polyvariant mutant cystic fibrosis transmembrane conductance regulator genes. The polymorphic (Tg)m locus explains the partial penetrance of the T5 polymorphism as a disease mutation. J Clin Invest 101 487 496

9. HostetlerJ

1974 Hutterite Society: John Hopkins University Press, Baltimore, MD

10. SteinbergAG

BleibtreuHK

KurczynskiTW

MartinAO

KurczynskiEM

1967 Genetic studies in an inbred human isolate.

CrowJF

NeelJV

Proceedings of the Third International Congress of Human Genetics. Johns Hopkins University Press 267 290

11. MangeAP

1964 Growth and Inbreeding of a Human Isolate. Hum Biol 36 104 133

12. OberC

HyslopT

HauckWW

1999 Inbreeding effects on fertility in humans: evidence for reproductive compensation. Am J Hum Genet 64 225 231

13. ShepsMC

1965 An analysis of reproductive patterns in an American isolate. Popul Stud 19 65 80

14. NewmanDL

HoffjanS

BourgainC

AbneyM

NicolaeRI

2004 Are common disease susceptibility alleles the same in outbred and founder populations? Eur J Hum Genet 12 584 590

15. ThompsonEE

SunY

NicolaeD

OberC

2010 Shades of gray: a comparison of linkage disequilibrium between Hutterites and Europeans. Genet Epidemiol 34 133 139

16. Gallego RomeroI

OberC

2008 CFTR mutations and reproductive outcomes in a population isolate. Hum Genet 122 583 588

17. AbneyM

OberC

McPeekMS

2002 Quantitative-trait homozygosity and association mapping and empirical genomewide significance in large, complex pedigrees: fasting serum-insulin level in the Hutterites. Am J Hum Genet 70 920 934

18. McArdlePF

PollinTI

O'ConnellJR

SorkinJD

AgarwalaR

2006 Does having children extend life span? A genealogical study of parity and longevity in the Amish. J Gerontol A Biol Sci Med Sci 61 190 195

19. SabetiPC

SchaffnerSF

FryB

LohmuellerJ

VarillyP

2006 Positive natural selection in the human lineage. Science 312 1614 1620

20. A haplotype map of the human genome 2005 Nature 437 1299 1320

21. CannHM

de TomaC

CazesL

LegrandMF

MorelV

2002 A human genome diversity cell line panel. Science 296 261 262

22. ModianoG

BombieriC

CiminelliBM

BelpinatiF

GiorgiS

2005 A large-scale study of the random variability of a coding sequence: a study on the CFTR gene. Eur J Hum Genet 13 184 192

23. VoightBF

KudaravalliS

WenX

PritchardJK

2006 A map of recent positive selection in the human genome. PLoS Biol 4 e72 doi:10.1371/journal.pbio.0040072

24. PompeiF

CiminelliBM

BombieriC

CiccacciC

KoudovaM

2006 Haplotype block structure study of the CFTR gene. Most variants are associated with the M470 allele in several European populations. Eur J Hum Genet 14 85 93

25. van der VenK

MesserL

van der VenH

JeyendranRS

OberC

1996 Cystic fibrosis mutation screening in healthy men with reduced sperm quality. Hum Reprod 11 513 517

26. XuWM

ShiQX

ChenWY

ZhouCX

NiY

2007 Cystic fibrosis transmembrane conductance regulator is vital to sperm fertilizing capacity and male fertility. Proc Natl Acad Sci U S A 104 9816 9821

27. ChanHC

RuanYC

HeQ

ChenMH

ChenH

2008 CFTR in reproductive health and disease. J Physiol

28. DanksDM

AllanJ

AndersonCM

1965 A genetic study of fibrocystic disease of the pancreas. Annals of Human Genetics 28 323 356

29. CiminelliBM

BonizzatoA

BombieriC

PompeiF

GabaldoM

2007 Highly preferential association of NonF508del CF mutations with the M470 allele. J Cyst Fibros 6 15 22

30. AbneyM

McPeekMS

OberC

2000 Estimation of variance components of quantitative traits in inbred populations. Am J Hum Genet 66 629 650

31. McKusickVA

1978 Medical Genetic Studies of the Amish. John Hopkins University Press, Baltimore, MD

32. KosovaG

AbneyM

OberC

2010 Heritability of reproductive fitness traits in a human population. Proc Natl Acad Sci U S A 107 Suppl 1 1772 1778

33. AndersonS

AuquierA

HauckWW

OakesD

VandaeleW

1980 Statistical methods for comparative studies: techniques in bias reduction: John Wiley & Sons, New York

34. PetoR

PikeMC

ArmitageP

BreslowNE

CoxDR

1977 Design and analysis of randomized clinical trials requiring prolonged observation of each patient. II. analysis and examples. Br J Cancer 35 1 39

35. WeirBS

CockerhamCC

1984 Estimating F-statistics for the analysis of population structure Evolution 38 1358 70

36. PickrellJK

CoopG

NovembreJ

KudaravalliS

LiJZ

2009 Signals of recent positive selection in a worldwide sample of human populations. Genome Res

37. SabetiPC

ReichDE

HigginsJM