Linkage disequilibrium patterns vary with chromosomal location: a case study from the von Willebrand factor region.
Linkage disequilibrium analysis has been used as a tool for analyzing marker order and locating disease genes. Under appropriate circumstances, disequilibrium patterns reflect recombination events that have occurred throughout a population's history. As a result, disequilibrium mapping may be useful in genomic regions of < 1 cM where the number of informative meioses needed to detect recombinant individuals within pedigrees is exceptionally high. Its utility for refining target areas for candidate disease genes before initiating chromosomal walks and cloning experiments will be enhanced as the relationship between linkage disequilibrium and physical distance is better understood. To address this issue, we have characterized linkage disequilibrium in a 144-kb region of the von Willebrand factor gene on chromosome 12. Sixty CEPH and 12 von Willebrand disease families were genotyped for five PCR-based markers, which include two microsatellite repeats and three single-base-pair substitutions. Linkage disequilibrium and physical distance between polymorphisms are highly correlated (rm = -.76; P < .05) within this region. None of the five markers showed significant disequilibrium with the von Willebrand disease phenotype. The linkage disequilibrium/physical distance relationship was also analyzed as a function of chromosomal location for this and eight previously characterized regions. This analysis revealed a general trend in which linkage disequilibrium dissipates more rapidly with physical distance in telomeric regions than in centromeric regions. This trend is consistent with higher recombination rates near telomeres.
Watkins
W S
WS
Department of Human Genetics, University of Utah School of Medicine, Salt Lake City 84112.
Zenger
R
R
O'Brien
E
E
Nyman
D
D
Eriksson
A W
AW
Renlund
M
M
Jorde
L B
LB
D000483:Alleles; D001483:Base Sequence; D002460:Cell Line; D002503:Centromere; D016009:Chi-Square Distribution; D002874:Chromosome Mapping / Q000379:methods; D002881:Chromosomes, Human, Pair 12 / Q000648:ultrastructure; D017931:DNA Primers; D006801:Humans; D016013:Likelihood Functions; D015810:Linkage Disequilibrium; D008969:Molecular Sequence Data; D012150:Polymorphism, Restriction Fragment Length; D012044:Regression Analysis; D016615:Telomere; D014842:von Willebrand Diseases / Q000235:genetics*; D014841:von Willebrand Factor / Q000235:genetics*
D017931:DNA Primers; D014841:von Willebrand Factor