Linkage disequilibrium — understanding the evolutionary past and mapping the medical future

Linkage disequilibrium — the nonrandom association of alleles at different loci — is a sensitive indicator of the population genetic forces that structure a genome. Because of the explosive growth of methods for assessing genetic variation at a fine scale, evolutionary biologists and human geneticists are increasingly exploiting linkage disequilibrium in order to understand past evolutionary and demographic events, to map genes that are associated with quantitative characters and inherited diseases, and to understand the joint evolution of linked sets of genes. This article introduces linkage disequilibrium, reviews the population genetic processes that affect it and describes some of its uses. At present, linkage disequilibrium is used much more extensively in the study of humans than in non-humans, but that is changing as technological advances make extensive genomic studies feasible in other species.

[1]  James A. Cuff,et al.  Genome sequence, comparative analysis and haplotype structure of the domestic dog , 2005, Nature.

[2]  P. Keightley,et al.  Interference among deleterious mutations favours sex and recombination in finite populations , 2006, Nature.

[3]  N. Morton,et al.  The optimal measure of linkage disequilibrium reduces error in association mapping of affection status. , 2005, Human molecular genetics.

[4]  Andrew Collins,et al.  Impact of population structure, effective bottleneck time, and allele frequency on linkage disequilibrium maps , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[5]  P. Donnelly,et al.  A Fine-Scale Map of Recombination Rates and Hotspots Across the Human Genome , 2005, Science.

[6]  T. Nagylaki.  The evolution of one- and two-locus systems. II. , 1977, Genetics.

[7]  M. Slatkin,et al.  The use of intraallelic variability for testing neutrality and estimating population growth rate. , 2001, Genetics.

[8]  R. K. Koehn,et al.  Population genetics of marine pelecypods. 3. Epistasis between functionally related isoenzymes of Mytilus edulis. , 1973, Genetics.

[9]  M. Slatkin,et al.  On treating the chromosome as the unit of selection. , 1972, Genetics.

[10]  J. Pritchard,et al.  A Map of Recent Positive Selection in the Human Genome , 2006, PLoS biology.

[11]  Christopher Gignoux,et al.  SNPSTRs: empirically derived, rapidly typed, autosomal haplotypes for inference of population history and mutational processes. , 2002, Genome research.

[12]  M. Daly,et al.  High-resolution haplotype structure in the human genome , 2001, Nature Genetics.

[13]  Lester L. Peters,et al.  Genome-wide association study identifies novel breast cancer susceptibility loci , 2007, Nature.

[14]  C. Langley,et al.  Molecular and phenotypic variation of the white locus region in Drosophila melanogaster. , 1988, Genetics.

[15]  D. Gudbjartsson,et al.  Common variants on chromosomes 2q35 and 16q12 confer susceptibility to estrogen receptor–positive breast cancer , 2007, Nature Genetics.

[16]  B. Weir.  Genetic Data Analysis II. , 1997 .

[17]  S Karlin,et al.  Linkage and selection: two locus symmetric viability model. , 1970, Theoretical population biology.

[18]  Paul Marjoram,et al.  Estimating the rate of gene conversion on human chromosome 21. , 2004, American journal of human genetics.

[19]  T. Ohta,et al.  Linkage disequilibrium with the island model. , 1982, Genetics.

[20]  J. Wall,et al.  Detecting ancient admixture in humans using sequence polymorphism data. , 2000, Genetics.

[21]  P. Donnelly,et al.  A new multipoint method for genome-wide association studies by imputation of genotypes , 2007, Nature Genetics.

[22]  P. Fearnhead,et al.  A coalescent-based method for detecting and estimating recombination from gene sequences. , 2002, Genetics.

[23]  F J Ayala,et al.  Evidence for positive selection in the superoxide dismutase (Sod) region of Drosophila melanogaster. , 1994, Genetics.

[24]  John Maynard Smith,et al.  The hitch-hiking effect of a favourable gene. , 1974, Genetical research.

[25]  R. Hudson,et al.  Evidence that the adaptive allele of the brain size gene microcephalin introgressed into Homo sapiens from an archaic Homo lineage , 2006, Proceedings of the National Academy of Sciences.

[26]  Richard M. Single,et al.  Signatures of Demographic History and Natural Selection in the Human Major Histocompatibility Complex Loci , 2006, Genetics.

[27]  P. Hedrick,et al.  Gametic disequilibrium measures: proceed with caution. , 1987, Genetics.

[28]  J. Felsenstein.  The evolutionary advantage of recombination. , 1974, Genetics.

[29]  R. Lewontin,et al.  On measures of gametic disequilibrium. , 1988, Genetics.

[30]  G. Thomson,et al.  Measuring the strength of associations between HLA antigens and diseases. , 1981, Tissue antigens.

[31]  Gonçalo R. Abecasis,et al.  GOLD-Graphical Overview of Linkage Disequilibrium , 2000, Bioinform..

[32]  H. Ostrer,et al.  Dating the origin of the CCR5-Delta32 AIDS-resistance allele by the coalescence of haplotypes. , 1998, American journal of human genetics.

[33]  Jonathan C. Cohen,et al.  A Common Allele on Chromosome 9 Associated with Coronary Heart Disease , 2007, Science.

[34]  G. McVean,et al.  Estimating Meiotic Gene Conversion Rates From Population Genetic Data , 2007, Genetics.

[35]  C. Carlson,et al.  Selecting a maximally informative set of single-nucleotide polymorphisms for association analyses using linkage disequilibrium. , 2004, American journal of human genetics.

[36]  M. Olivier.  A haplotype map of the human genome. , 2003, Nature.

[37]  L. Kruglyak.  Prospects for whole-genome linkage disequilibrium mapping of common disease genes , 1999, Nature Genetics.

[38]  J. Felsenstein,et al.  The effect of linkage on directional selection. , 1965, Genetics.

[39]  W. Stephan,et al.  Detecting a local signature of genetic hitchhiking along a recombining chromosome. , 2002, Genetics.

[40]  E. Eichler,et al.  Fine-scale structural variation of the human genome , 2005, Nature Genetics.

[41]  Eric Lander,et al.  Linkage disequilibrium mapping in isolated founder populations: diastrophic dysplasia in Finland , 1992, Nature Genetics.

[42]  M. Nei,et al.  Stable linkage disequilibrium without epistasis in subdivided populations. , 1974, Theoretical population biology.

[43]  G. Abecasis,et al.  A Genome-Wide Association Study of Type 2 Diabetes in Finns Detects Multiple Susceptibility Variants , 2007, Science.

[44]  R. Lewontin,et al.  Is the gene the unit of selection? , 1970, Genetics.

[45]  Chao Qian,et al.  Population , 1940, State Rankings 2020: A Statistical View of America.

[46]  Colin N. Dewey,et al.  Population Genomics: Whole-Genome Analysis of Polymorphism and Divergence in Drosophila simulans , 2007, PLoS biology.

[47]  Mattias Jakobsson,et al.  The Pattern of Polymorphism in Arabidopsis thaliana , 2005, PLoS biology.

[48]  F. Depaulis,et al.  Neutrality tests based on the distribution of haplotypes under an infinite-site model. , 1998, Molecular biology and evolution.

[49]  Steven Gallinger,et al.  Genome-wide association scan identifies a colorectal cancer susceptibility locus on chromosome 8q24 , 2007, Nature Genetics.

[50]  C. Schmegner,et al.  Genetic variability in a genomic region with long-range linkage disequilibrium reveals traces of a bottleneck in the history of the European population , 2005, Human Genetics.

[51]  Vaqaar-un-Nisa Dar,et al.  Effective population size and tests of neutrality at cytoplasmic genes in Arabidopsis. , 2008, Genetics research.

[52]  Detlef Weigel,et al.  Recombination and linkage disequilibrium in Arabidopsis thaliana , 2007, Nature Genetics.

[53]  T. Ohta,et al.  Linkage disequilibrium at steady state determined by random genetic drift and recurrent mutation. , 1969, Genetics.

[54]  Joanne Barker.  The human genome diversity project , 2004 .

[55]  M. Olivier.  A haplotype map of the human genome , 2003, Nature.

[56]  Vincent Plagnol,et al.  Possible Ancestral Structure in Human Populations , 2006, PLoS genetics.

[57]  R. Hudson,et al.  The sampling distribution of linkage disequilibrium under an infinite allele model without selection. , 1985, Genetics.

[58]  R. A. Fisher,et al.  The Genetical Theory of Natural Selection , 1931 .

[59]  R. Lewontin,et al.  THE EVOLUTIONARY DYNAMICS OF COMPLEX POLYMORPHISMS , , , 1960 .

[60]  M. Feldman,et al.  Multilocus Structure of Natural Populations of HORDEUM SPONTANEUM. , 1980, Genetics.

[61]  M. Przeworski.  Estimating the time since the fixation of a beneficial allele. , 2003, Genetics.

[62]  S. Gabriel,et al.  The Structure of Haplotype Blocks in the Human Genome , 2002, Science.

[63]  Kevin R. Thornton,et al.  Approximate Bayesian Inference Reveals Evidence for a Recent, Severe Bottleneck in a Netherlands Population of Drosophila melanogaster , 2006, Genetics.

[64]  J. Reardon.  The Human Genome Diversity Project , 2001 .

[65]  M. McCarthy,et al.  Replication of Genome-Wide Association Signals in UK Samples Reveals Risk Loci for Type 2 Diabetes , 2007, Science.

[66]  D. Conrad,et al.  A high-resolution survey of deletion polymorphism in the human genome , 2006, Nature Genetics.

[67]  M. Kimura.  Attainment of Quasi Linkage Equilibrium When Gene Frequencies Are Changing by Natural Selection. , 1965, Genetics.

[68]  A. Clark,et al.  Inference of haplotypes from PCR-amplified samples of diploid populations. , 1990, Molecular biology and evolution.

[69]  R. Hudson,et al.  Statistical properties of the number of recombination events in the history of a sample of DNA sequences. , 1985, Genetics.

[70]  H. Cunningham.  Colonial Encounters in Postcolonial Contexts , 1998 .

[71]  P. Donnelly,et al.  A new statistical method for haplotype reconstruction from population data. , 2001, American journal of human genetics.

[72]  H. Bickeböller,et al.  Case‐Control Association Tests Correcting for Population Stratification , 2006, Annals of human genetics.

[73]  P. Donnelly,et al.  Case-control studies of association in structured or admixed populations. , 2001, Theoretical population biology.

[74]  M. Slatkin.  Linkage disequilibrium in growing and stable populations. , 1994, Genetics.

[75]  J. Wall,et al.  Haplotype blocks and linkage disequilibrium in the human genome , 2003, Nature Reviews Genetics.

[76]  M Slatkin,et al.  Gene flow and selection in a two-locus system. , 1975, Genetics.

[77]  W. G. Hill,et al.  Genetic Data Analysis II . By Bruce S. Weir, Sunderland, Massachusetts. Sinauer Associates, Inc.445 pages. ISBN 0-87893-902-4. , 1996 .

[78]  L Kruglyak,et al.  Lower-than-expected linkage disequilibrium between tightly linked markers in humans suggests a role for gene conversion. , 2001, American journal of human genetics.

[79]  J. Wall,et al.  Gene conversion and different population histories may explain the contrast between polymorphism and linkage disequilibrium levels. , 2001, American journal of human genetics.

[80]  H. Jennings.  The Numerical Results of Diverse Systems of Breeding, with Respect to Two Pairs of Characters, Linked or Independent, with Special Relation to the Effects of Linkage. , 1917, Genetics.

[81]  Jon A Yamato,et al.  Maximum likelihood estimation of recombination rates from population data. , 2000, Genetics.

[82]  Eric E. Smith,et al.  Variants conferring risk of atrial fibrillation on chromosome 4q25 , 2007, Nature.

[83]  Feng Chen,et al.  Sequencing and Analysis of Neanderthal Genomic DNA , 2006, Science.

[84]  Oliver Sieber,et al.  A genome-wide association scan of tag SNPs identifies a susceptibility variant for colorectal cancer at 8q24.21 , 2007, Nature Genetics.

[85]  B. Weir,et al.  Group inbreeding with two linked loci. , 1969, Genetics.

[86]  W. G. Hill,et al.  Estimation of linkage disequilibrium in randomly mating populations , 1974, Heredity.

[87]  J. M. Smith,et al.  The hitch-hiking effect of a favourable gene. , 1974, Genetical research.

[88]  Zhaohui S. Qin,et al.  A second generation human haplotype map of over 3.1 million SNPs , 2007, Nature.

[89]  B. J. Carey,et al.  Chromosome-wide distribution of haplotype blocks and the role of recombination hot spots , 2003, Nature Genetics.

[90]  S. Tishkoff,et al.  Global Patterns of Linkage Disequilibrium at the CD4 Locus and Modern Human Origins , 1996, Science.

[91]  Sewall Wright,et al.  Breeding Structure of Populations in Relation to Speciation , 1940, The American Naturalist.

[92]  E. Boerwinkle,et al.  Haplotype structure and population genetic inferences from nucleotide-sequence variation in human lipoprotein lipase. , 1998, American journal of human genetics.

[93]  G. B. Golding,et al.  Linkage disequilibrium in a finite population that is partially selfing. , 1980, Genetics.

[94]  N. Barton,et al.  A general model for the evolution of recombination. , 1995, Genetical research.

[95]  Carlos Bustamante,et al.  Genomic scans for selective sweeps using SNP data. , 2005, Genome research.

[96]  T. Nagylaki.  The evolution of one- and two-locus systems. , 1976, Genetics.

[97]  M. Slatkin.  A Bayesian method for jointly estimating allele age and selection intensity. , 2008, Genetics research.

[98]  Edwin Cuppen,et al.  Haplotype Block Structure Is Conserved across Mammals , 2006, PLoS genetics.

[99]  W. Klitz,et al.  Constrained disequilibrium values and hitchhiking in a three-locus system. , 1998, Genetics.

[100]  B. Charlesworth,et al.  A study of linkage disequilibrium in populations of Drosophila melanogaster. , 1973, Genetics.

[101]  B. Weir.  Inferences about linkage disequilibrium. , 1979, Biometrics.

[102]  R. Karp,et al.  Efficient reconstruction of haplotype structure via perfect phylogeny. , 2002, Journal of bioinformatics and computational biology.

[103]  B. Charlesworth.  The evolution of sex and recombination. , 1989, Trends in ecology & evolution.

[104]  M Slatkin,et al.  Distinguishing recombination and intragenic gene conversion by linkage disequilibrium patterns. , 2000, Genetical research.

[105]  C. Langley,et al.  Linkage disequilibrium in natural populations of Drosophila melanogaster. , 1974, Genetics.

[106]  M. Nei,et al.  Linkage disequilibrium in subdivided populations. , 1973, Genetics.

[107]  Pardis C Sabeti,et al.  Detecting recent positive selection in the human genome from haplotype structure , 2002, Nature.

[108]  M W Feldman,et al.  Selection in complex genetic systems. I. The symmetric equilibria of the three-locus symmetric viability model. , 1974, Genetics.

[109]  T. Hudson,et al.  A genome-wide association study identifies novel risk loci for type 2 diabetes , 2007, Nature.

[110]  Pardis C Sabeti,et al.  Genome-wide detection and characterization of positive selection in human populations , 2007, Nature.

[111]  Marcia M. Nizzari,et al.  Genome-Wide Association Analysis Identifies Loci for Type 2 Diabetes and Triglyceride Levels , 2007, Science.

[112]  E. Boerwinkle,et al.  Evidence for Consistent Intragenic and Intergenic Interactions between SNP Effects in the APOA1/C3/A4/A5 Gene Cluster , 2006, Human Heredity.

[113]  M. Slatkin,et al.  Estimating the age of alleles by use of intraallelic variability. , 1997, American journal of human genetics.

[114]  Eric S. Lander,et al.  The diastrophic dysplasia gene encodes a novel sulfate transporter: Positional cloning by fine-structure linkage disequilibrium mapping , 1994, Cell.

[115]  W. G. Hill,et al.  The effect of linkage on limits to artificial selection. , 1966, Genetical research.

[116]  S. Guo,et al.  Estimating the age of mutant disease alleles based on linkage disequilibrium. , 1997, Human heredity.

[117]  R. Hudson.  Two-locus sampling distributions and their application. , 2001, Genetics.

[118]  Hilla Peretz,et al.  Ju n 20 03 Schrödinger ’ s Cat : The rules of engagement , 2003 .

[119]  T. Ohta,et al.  Linkage disequilibrium due to random genetic drift in finite subdivided populations. , 1982, Proceedings of the National Academy of Sciences of the United States of America.

[120]  R. Lewontin.  The Interaction of Selection and Linkage. I. General Considerations; Heterotic Models. , 1964, Genetics.

[121]  L. Excoffier,et al.  Maximum-likelihood estimation of molecular haplotype frequencies in a diploid population. , 1995, Molecular biology and evolution.

[122]  W. Weinberg.  Über Vererbungsgesetze beim Menschen , 1908, Zeitschrift für induktive Abstammungs- und Vererbungslehre.

[123]  R. Hudson.  Properties of a neutral allele model with intragenic recombination. , 1983, Theoretical population biology.

[124]  J. Dekkers,et al.  Evaluation of linkage disequilibrium measures between multi-allelic markers as predictors of linkage disequilibrium between single nucleotide polymorphisms. , 2007, Genetical research.

[125]  J. M. Smith,et al.  How clonal are bacteria? , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[126]  P. Kahn.  Genetic diversity project tries again. , 1994, Science.

[127]  G. McVean,et al.  The effects of Hill-Robertson interference between weakly selected mutations on patterns of molecular evolution and variation. , 2000, Genetics.

[128]  François Rousset,et al.  GENEPOP (version 1.2): population genetic software for exact tests and ecumenicism , 1995 .

[129]  T. Nagylaki.  Quasilinkage equilibrium and the evolution of two-locus systems. , 1974, Proceedings of the National Academy of Sciences of the United States of America.

[130]  A. Jeffreys,et al.  Intensely punctate meiotic recombination in the class II region of the major histocompatibility complex , 2001, Nature Genetics.

[131]  B. Weir,et al.  Age of the ΔF508 cystic fibrosis mutation , 1994, Nature Genetics.

[132]  W. G. Hill,et al.  Linkage disequilibrium in finite populations , 1968, Theoretical and Applied Genetics.

[133]  H. Geiringer.  On the Probability Theory of Linkage in Mendelian Heredity , 1944 .

[134]  G. Lathrop,et al.  Genetic and Haplotypic Structure in 14 European and African Cattle Breeds , 2007, Genetics.

[135]  Mary K. Kuhner,et al.  LAMARC 2.0: maximum likelihood and Bayesian estimation of population parameters , 2006, Bioinform..

[136]  R. A. Fisher,et al.  The Genetical Theory of Natural Selection , 1931 .

[137]  Jocelyn Kaiser,et al.  A Plan to Capture Human Diversity in 1000 Genomes , 2008, Science.

[138]  Zhaohui S. Qin,et al.  A comparison of phasing algorithms for trios and unrelated individuals. , 2006, American journal of human genetics.

[139]  J. Novembre,et al.  Finding haplotype block boundaries by using the minimum-description-length principle. , 2003, American journal of human genetics.