Selection on cis-regulatory variation at B4galnt2 and its influence on von Willebrand factor in house mice.
The RIIIS/J inbred mouse strain is a model for type 1 von Willebrand disease (VWD), a common human bleeding disorder. Low von Willebrand factor (VWF) levels in RIIIS/J are due to a regulatory mutation, Mvwf1, which directs a tissue-specific switch in expression of a glycosyltransferase, B4GALNT2, from intestine to blood vessel. We recently found that Mvwf1 lies on a founder allele common among laboratory mouse strains. To investigate the evolutionary forces operating at B4galnt2, we conducted a survey of DNA sequence polymorphism and microsatellite variation spanning the B4galnt2 gene region in natural Mus musculus domesticus populations. Two divergent haplotypes segregate in these natural populations, one of which corresponds to the RIIIS/J sequence. Different local populations display dramatic differences in the frequency of these haplotypes, and reduced microsatellite variability near B4galnt2 within the RIIIS/J haplotype is consistent with the recent action of natural selection. The level and pattern of DNA sequence polymorphism in the 5' flanking region of the gene significantly deviates from the neutral expectation and suggests that variation in B4galnt2 expression may be under balancing selection and/or arose from a recently introgressed allele that subsequently increased in frequency due to natural selection. However, coalescent simulations indicate that the heterogeneity in divergence between haplotypes is greater than expected under an introgression model. Analysis of a population where the RIIIS/J haplotype is in high frequency reveals an association between this haplotype, the B4galnt2 tissue-specific switch, and a significant decrease in plasma VWF levels. Given these observations, we propose that low VWF levels may represent a fitness cost that is offset by a yet unknown benefit of the B4galnt2 tissue-specific switch. Similar mechanisms may account for the variability in VWF levels and high prevalence of VWD in other mammals, including humans.
Johnsen
Jill M
JM
Department of Internal Medicine, University of Michigan, USA.
Teschke
Meike
M
Pavlidis
Pavlos
P
McGee
Beth M
BM
Tautz
Diethard
D
Ginsburg
David
D
Baines
John F
JF
D024506:5' Flanking Region; D000818:Animals; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D014644:Genetic Variation; D006239:Haplotypes; D051379:Mice; D017350:N-Acetylgalactosaminyltransferases / Q000235:genetics*; D011110:Polymorphism, Genetic; D012641:Selection, Genetic; D014018:Tissue Distribution; D014841:von Willebrand Factor / Q000235:genetics*
D014841:von Willebrand Factor; D017350:N-Acetylgalactosaminyltransferases; C071413:beta-1,4-N-acetyl-galactosaminyl transferase 2