Theory of the Effects of Population Structure and Sampling on Patterns of Linkage Disequilibrium Applied to Genomic Data From Humans

Corresponding author: John Wakeley, 16 Divinity Ave., Cambridge, MA 02138., wakeley{at}fas.harvard.edu (E-mail)

Communicating editor: W. STEPHAN

We develop predictions for the correlation of heterozygosity and for linkage disequilibrium between two loci using a simple model of population structure that includes migration among local populations, or demes. We compare the results for a sample of size two from the same deme (a single-deme sample) to those for a sample of size two from two different demes (a scattered sample). The correlation in heterozygosity for a scattered sample is surprisingly insensitive to both the migration rate and the number of demes. In contrast, the correlation in heterozygosity for a single-deme sample is sensitive to both, and the effect of an increase in the number of demes is qualitatively similar to that of a decrease in the migration rate: both increase the correlation in heterozygosity. These same conclusions hold for a commonly used measure of linkage disequilibrium (r²). We compare the predictions of the theory to genomic data from humans and show that subdivision might account for a substantial portion of the genetic associations observed within the human genome, even though migration rates among local populations of humans are relatively large. Because correlations due to subdivision rather than to physical linkage can be large even in a single-deme sample, then if long-term migration has been important in shaping patterns of human polymorphism, the common practice of disease mapping using linkage disequilibrium in "isolated" local populations may be subject to error.

This article has been cited by other articles:

				A. De and R. Durrett Stepping-Stone Spatial Structure Causes Slow Decay of Linkage Disequilibrium and Shifts the Site Frequency Spectrum Genetics, June 1, 2007; 176(2): 969 - 981. [Abstract] [Full Text] [PDF]

				G. McVean The Structure of Linkage Disequilibrium Around a Selective Sweep Genetics, March 1, 2007; 175(3): 1395 - 1406. [Abstract] [Full Text] [PDF]

				J. Hagenblad, J. Bechsgaard, and D. Charlesworth Linkage Disequilibrium Between Incompatibility Locus Region Genes in the Plant Arabidopsis lyrata Genetics, June 1, 2006; 173(2): 1057 - 1073. [Abstract] [Full Text] [PDF]

				A. D. Cutter Nucleotide Polymorphism and Linkage Disequilibrium in Wild Populations of the Partial Selfer Caenorhabditis elegans Genetics, January 1, 2006; 172(1): 171 - 184. [Abstract] [Full Text] [PDF]

				B. F. Voight, A. M. Adams, L. A. Frisse, Y. Qian, R. R. Hudson, and A. Di Rienzo Interrogating multiple aspects of variation in a full resequencing data set to infer human population size changes PNAS, December 20, 2005; 102(51): 18508 - 18513. [Abstract] [Full Text] [PDF]

				S. F. Schaffner, C. Foo, S. Gabriel, D. Reich, M. J. Daly, and D. Altshuler Calibrating a coalescent simulation of human genome sequence variation Genome Res., November 1, 2005; 15(11): 1576 - 1583. [Abstract] [Full Text] [PDF]

				M. T. Hamblin, M. G. Salas Fernandez, A. M. Casa, S. E. Mitchell, A. H. Paterson, and S. Kresovich Equilibrium Processes Cannot Explain High Levels of Short- and Medium-Range Linkage Disequilibrium in the Domesticated Grass Sorghum bicolor Genetics, November 1, 2005; 171(3): 1247 - 1256. [Abstract] [Full Text] [PDF]

				J. Wakeley Recent Trends in Population Genetics: More Data! More Math! Simple Models? J. Hered., September 1, 2004; 95(5): 397 - 405. [Abstract] [Full Text] [PDF]