Sequence-based linkage analysis.
The rapid decrease in the cost of DNA sequencing will enable its use for novel applications. Here, we investigate the use of DNA sequencing for simultaneous discovery and genotyping of polymorphisms in family linkage studies. In the proposed approach, short contiguous segments of genomic DNA, regularly spaced across the genome, are resequenced in each pedigree member, and all sequence polymorphisms discovered within a pedigree are used as genetic markers. We use computer simulations consistent with observed human sequence diversity to show that segments of 500-1,000 base pairs, spaced at intervals of 1-2 Mb across the genome, provide linkage information that equals or exceeds that of traditional marker-based approaches. We validate these results experimentally by implementing the sequence-based linkage approach for chromosome 19 in CEPH pedigrees.
Division of Human Biology, Fred Hutchinson Cancer Research Center, University of Washington, Seattle, WA 98109-1024, USA.
Itay
I
Furman
Mark J
MJ
Rieder
Suzanne
S
Da Ponte
Dana P
DP
Carrington
Deborah A
DA
Nickerson
Leonid
L
Kruglyak
Kyriacos
K
Markianos
D002874:Chromosome Mapping / Q000379:methods*; D002888:Chromosomes, Human, Pair 19 / Q000235:genetics*; D003198:Computer Simulation; D005787:Gene Frequency; D008040:Genetic Linkage; D005819:Genetic Markers / Q000235:genetics; D005838:Genotype; D006801:Humans; D010375:Pedigree; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA / Q000379:methods*
D005819:Genetic Markers