Skip Navigation



MBE Advance Access published online on December 16, 2008
Molecular Biology and Evolution, doi:10.1093/molbev/msn284
This Article
Right arrow Advance Access manuscript (PDF) Freely available
Right arrow Supplementary Data
Right arrowOA All Versions of this Article:
26/3/567    most recent
msn284v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Google Scholar
Right arrow Articles by Johnsen, J. M.
Right arrow Articles by Baines, J. F.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Johnsen, J. M.
Right arrow Articles by Baines, J. F.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Published by Oxford University Press 2008.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Research Article

Selection on cis-regulatory variation at B4galnt2 and its influence on von Willebrand Factor in house mice

Jill M. Johnsen1,*, Meike Teschke3, Pavlos Pavlidis4, Beth M. McGee2, Diethard Tautz3, David Ginsburg1,2,{dagger} and John F. Baines4

1 Department of Internal Medicine, University of Michigan, Ann Arbor, MI
2 Howard Hughes Medical Institute, Department of Human Genetics, and the Life Sciences Institute, University of Michigan, Ann Arbor, MI
3 Max-Planck Institute for Evolutionary Biology, 24306 Plön, Germany
4 Section of Evolutionary Biology, Department Biology II, University of Munich (LMU), 82152 Planegg-Martinsried, Germany

{dagger} Corresponding author: David Ginsburg, Howard Hughes Medical Institute, University of Michigan, 210 Washtenaw Avenue, Life Sciences Institute, Room 5028, Ann Arbor, MI 48109-2216; Phone: (734) 647-4808; FAX: (734) 936-2888; e-mail: ginsburg{at}umich.edu

Received for publication April 14, 2008. Revision received October 21, 2008. Accepted for publication November 17, 2008.

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.

Key Words: balancing selection • introgression cis-regulatory variation • house mouse • Mus musculus • von Willebrand disease (VWD) • von Willebrand Factor (VWF)

* Now at the Research Division, Puget Sound Blood Center and Department of Internal Medicine, University of Washington, Seattle, WA


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?




Disclaimer: Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.