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MBE Advance Access published online on February 4, 2003
Molecular Biology and Evolution, doi:10.1093/molbev/msg032
Molecular Biology and Evolution © Society for Molecular Biology and Evolution 2003; all rights reserved
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Accepted October 7, 2002
© 2003 Society for Molecular Biology and Evolution

Original Articles

The Effect of Single Nucleotide Polymorphism Identification Strategies on Estimates of Linkage Disequilibrium

Joshua M. Akey 1*, Kun Zhang 2, Momiao Xiong 2, Li Jin 1

1 Center for Genome Information, University of Cincinnati, Cincinnati, Ohio
2 Human Genetics Center, University of Texas-Houston, Houston, Texas

* To whom correspondence should be addressed. E-mail: Joshua.Akey{at}uc.edu.


  Abstract

Currently, there is tremendous interest in characterizing the magnitude and distribution of linkage disequilibrium (LD) throughout the human genome, which will provide the necessary foundation for genome-wide LD analyses and facilitate detailed evolutionary studies. To this end, a human high-density single nucleotide polymorphism (SNP) marker map has been constructed. However, many of these SNPs were identified by sampling a small number of chromosomes from a single population, and inferences drawn from studies using such SNPs may be influenced by ascertainment bias (AB). Through extensive simulations, we have found that AB is a potentially significant problem in estimating and comparing LD within and between populations. Specifically, the magnitude of AB is a function of the SNP discovery strategy, number of chromosomes used for SNP discovery, population genetic characteristics of the particular genomic region considered, amount of gene flow between populations, and the demographic history of the populations. We demonstrate that a balanced SNP discovery strategy (where an equal number of chromosomes are sampled from multiple subpopulations) is the optimal study design for generating broadly applicable SNP resources. Finally, we validate our theoretical predictions by comparing our results to publicly available data from 10 genes sequenced in 24 African American and 23 European American individuals.

Key Words: key words: Ascertainment bias, Linkage Disequilibrium, SNPs, coalescent


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