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Ancient History Drives the New Genetics



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Original Paper Hum Hered 2005 59 118 124 DOI 10 1159 000085226 Received January 25 2005 Accepted after revision February 22 2005 Published online April 18 2005 Linkage Disequilibrium Ancient History Drives the New Genetics Gon alo R Abecasis Debashis Ghosh Thomas E Nichols Department of Biostatistics School of Public Health University of Michigan Ann Arbor Mich USA Key Words Linkage disequilibrium Natural selection Association mapping Recombination rate Abstract This brief review provides a summary of the biological causes of genetic association between tightly linked markers termed linkage disequilibrium and unlinked markers termed population structure We also review the utility of linkage disequilibrium data in gene mapping in isolated populations in the estimation of recombination rates and in studying the history of particular alleles including the detection of natural selection We discuss current understanding of the extent and patterns of linkage disequilibrium in the genome and its promise for genetic association studies in complex disease Finally we highlight the importance of using appropriate statistical procedures such as the false discovery rate to maximize the chances of success in large scale association studies Copyright 2005 S Karger AG Basel freys et al 2001 Recently studies of genetic variation have focused on single nucleotide polymorphisms SNPs an abundant class of DNA variants that can be cheaply genotyped in very large numbers the most recent version of dbSNP Sachidanandam et al 2001 includes about 10 million such polymorphisms and it is likely that many more exist Carlson et al 2003 Like other genetic polymorphisms these SNPs are not independent but exhibit complex relationships For most of them a single mutation event in the distant past resulted in the two alleles that exist today The original copy of the mutant allele was con ned to a speci c haplotype belonging to a speci c individual in a speci c population Over time this allele may have



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