Complex patterns of linkage disequilibrium in the Huntington disease region.
The genetic defect causing Huntington disease (HD) has been mapped to 4p16.3 by linkage analysis using DNA markers. Two apparently contradictory classes of recombination events in HD kindreds preclude precise targeting of efforts to clone the disease gene. Here, we report a new recombination event that increases support for an internal candidate region of 2.5 Mb between D4S10 and D4S168. Analysis of 23 DNA polymorphisms in 4p16.3 revealed a complex pattern of association with the disease gene that failed to narrow the size of the candidate region. The degree of linkage disequilibrium did not show a continuous increase across the physical map, nor was a region of extreme disequilibrium identified. Markers displaying no association with the disorder were interspersed with and, in many cases, close to markers displaying significant disequilibrium. Comparison of closely spaced marker pairs on normal and HD chromosomes, as well as analysis of haplotypes across the HD region, suggest that simple recombination subsequent to a single original HD mutation cannot easily explain the pool of HD chromosomes seen today. A number of different mechanisms could contribute to the diversity of haplotypes observed on HD chromosomes, but it is likely that there has been more than one and possibly several independent origins of the HD mutation.
Neurogenetics Laboratory, Massachusetts General Hospital, Charlestown 02129.
M E
ME
MacDonald
C
C
Lin
L
L
Srinidhi
G
G
Bates
M
M
Altherr
W L
WL
Whaley
H
H
Lehrach
J
J
Wasmuth
J F
JF
Gusella
D000483:Alleles; D002874:Chromosome Mapping; D002894:Chromosomes, Human, Pair 4; D005260:Female; D005819:Genetic Markers / Q000235:genetics; D006239:Haplotypes; D006801:Humans; D006816:Huntington Disease / Q000235:genetics*; D015810:Linkage Disequilibrium / Q000235:genetics*; D008297:Male; D010375:Pedigree; D012150:Polymorphism, Restriction Fragment Length; D011995:Recombination, Genetic / Q000235:genetics
D005819:Genetic Markers