The use of linkage disequilibrium to map quantitative trait loci
M. E. Goddard A B D and T. H. E. Meuwissen CA Land and Food Resources, University of Melbourne, Royal Parade, Parkville, Vic. 3010, Australia.
B Department of Primary Industries Victoria, 475 Mickelham Road, Attwood, Vic. 3049, Australia.
C Norwegian University of Life Sciences, As, Norway.
D Corresponding author. Email: Mike.Goddard@dpi.vic.gov.au
Australian Journal of Experimental Agriculture 45(8) 837-845 https://doi.org/10.1071/EA05066
Submitted: 28 February 2005 Accepted: 23 June 2005 Published: 26 August 2005
Abstract
This paper reviews the causes of linkage disequilibrium and its use in mapping quantitative trait loci. The many causes of linkage disequilibrium can be understood as due to similarity in the coalescence tree of different loci. Consideration of the way this comes about allows us to divide linkage disequilibrium into 2 types: linkage disequilibrium between any 2 loci, even if they are unlinked, caused by variation in the relatedness of pairs of animals; and linkage disequilibrium due to the inheritance of chromosome segments that are identical by descent from a common ancestor. The extent of linkage disequilibrium due to the latter cause can be logically measured by the chromosome segment homozygosity which is the probability that chromosome segments taken at random from the population are identical by descent. This latter cause of linkage disequilibrium allows us to map quantitative trait loci to chromosome regions. The former cause of linkage disequilibrium can cause artefactual quantitative trait loci at any position in the genome. These artefacts can be avoided by fitting the relatedness of animals in the statistical model used to map quantitative trait loci. In the future it may be convenient to estimate this degree of relatedness between individuals from markers covering the whole genome. The statistical model for mapping quantitative trait loci also requires us to estimate the probability that 2 animals share quantitative trait loci alleles at a particular position because they have inherited a chromosome segment containing the quantitative trait loci identical by descent. Current methods to do this all involve approximations. Methods based on concepts of coalescence and chromosome segment homozygosity are useful, but improvements are needed for practical analysis of large datasets. Once these probabilities are estimated they can be used in flexible linear models that conveniently combine linkage and linkage disequilibrium information.
Andersson L, Georges M
(2004) Domestic animal genomics: deciphering the genetics of complex traits. Nature Genetics Reviews 5, 202–212.
| Crossref | GoogleScholarGoogle Scholar |
Chapman NH, Thompson EA
(2003) A model for the length of the tracts of identity by descent in finite random mating populations. Theoretical Population Biology 64, 141–150.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Cockerham CC
(1954) An extension of the concept of partitioning hereditary variance for analysis of covariances among relatives when epistasis is present. Genetics 39, 859–882.
Devlin B,
Roeder K, Wasserman L
(2001) Genomic control, a new approach to genetic-based association studies. Theoretical Population Biology 60, 155–160.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Farnir F,
Coppieters W,
Arranz JJ,
Berzi P, Cambisano N , et al.
(2000) Extensive genome wide linkage disequilibrium in cattle. Genome Research 10, 220–227.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Fernando RL, Grossman M
(1989) Marker assisted selection using best linear unbiased prediction. Genetics, Selection, Evolution 21, 467–477.
Gabriel SB,
Schaffner SF,
Nguyen H,
Moore JM, Roy J , et al.
(2002) The structure of haplotype blocks in the human genome. Science 296, 2225–2229.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Goddard ME
(1991) Mapping genes for quantitative traits using linkage disequilibrium. Genetics, Selection, Evolution suppl. 1 23, 1315–1345.
Green ED, Chakravarti A
(2001) The human genome sequence expedition: views from the base camp. Genome Research 11, 645–651.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Grignola FE,
Hoeschele I,
Zhang Q, Thaller G
(1996) Mapping linked quantitative trait loci in outcross populations via residual maximum likelihood. 2. A simulation study. Genetics, Selection, Evolution 28, 491–504.
Harding RM, McVean G
(2004) A structured ancestral population for the evolution of modern humans. Current Opinion in Genetics & Development 14, 667–674.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Hayes BJ,
Visscher PE,
McPartlan H, Goddard ME
(2003) A novel multi-locus measure of linkage disequilibrium and it use to estimate past effective population size. Genome Research 13, 635–643.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Hernández-Sánchez J,
Visscher P,
Plastow G, Haley C
(2003) Candidate gene analysis for quantitative traits using the transmission disequilibrium test: the example of the melanocortin 4-receptor in pigs. Genetics 164, 637–644.
| PubMed |
Hill WG
(1975) Linkage disequilibrium among multiple neutral alleles produced by mutation in finite population. Theoretical Population Biolology 8, 117–126.
| Crossref | GoogleScholarGoogle Scholar |
Hill WG, Weir BS
(1994) Maximum likelihood estimation of gene location with linkage disequilibrium. American Journal of Human Genetics 54, 705–714.
| PubMed |
Hudson RR
(2001) Two-locus sampling distributions and their application. Genetics 159, 1805–1817.
| PubMed |
Jeffreys AJ,
Kauppi L, Neuman R
(2001) Intensely punctate meiotic recombination in the class II region of the major histocompatibility complex. Nature Genetics 29, 217–222.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Knott SA, Haley CS
(1992) Maximum-likelihood mapping of quantitative trait loci using full-sib families. Genetics 132, 1211–1222.
| PubMed |
Leutenegger A-L,
Prum B,
Genin E,
Verny C,
Lemainque A,
Clerget-Darpoux F, Thompson EA
(2003) Estimation of inbreeding coefficient through the use of genomic data. American Journal of Human Genetics 73, 5516–5523.
McVean GAT
(2002) A genealogical interpretation of linkage disequilibrium. Genetics 162, 987–991.
| PubMed |
McVean G,
Awadalla P, Fearnhead P
(2002) A coalescent based method for detecting and estimating recombination from gene sequences. Genetics 160, 1231–1241.
| PubMed |
Meuwissen THE, Goddard ME
(2001) Prediction of identity by descent probabilities from marker-haplotypes. Genetics, Selection, Evolution 33, 605–634.
| Crossref | GoogleScholarGoogle Scholar |
Meuwissen THE,
Karlsen A,
Lien S,
Olsaker I, Goddard ME
(2002) Fine mapping of a quantitative trait locus for twinning rate using combined linkage and linkage disequilibrium mapping. Genetics 161, 373–379.
| PubMed |
Ohta T, Kimura M
(1971) Linkage disequilibrium between two segregating nucleotide sites under the steady flux of mutations in a finite population. Genetics 68, 571–580.
| PubMed |
Perez-Enciso M
(2003) Fine mapping of complex trait genes combining pedigree and linkage disequilibrium: a bayesian unified framework. Genetics 163, 1497–1510.
| PubMed |
Ptak SE,
Voelpel K, Przeworski M
(2004) Insights into recombination from patterns of linkage disequilibrium in humans. Genetics 167, 387–397.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Rafalski A, Morgante M
(2004) Corn and humans: recombination and linkage disequilibrium in two genomes of similar size. Trends in Genetics 20, 103–111.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Reich DE,
Schaffner SF,
Daly MJ,
McVean G,
Mullikin JC,
Higgins JM,
Richter DJ,
Lander ES, Altshuler D
(2002) Human genome sequence variation and the influence of gene history, mutation and recombination. Nature Genetics 32, 135–142.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Risch N, Merikangus K
(1996) The future of genetic studies of complex human diseases. Science 272, 1516–1517.
Saez AG,
Tatarenkov A,
Barrio E,
Beterra NH, Ayala FJ
(2003) Patterns of DNA sequence polymorphism at Sod vicinities in Drosophila melanogaster: unravelling the footprint of a recent selective sweep. Proceedings of the National Academy of Sciences of the United States of America 100, 1793.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Seldin MF,
Morii T,
Collins-schramm HE,
Chima B,
Kittles R,
Criswell LA, Li H
(2004) Putative ancestral origins of chromosome segments in individual african americans: implications for admixture mapping. Genome Research 14, 1076–1084.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Slatkin M, Bertorelle G
(2001) The use of intraallelic variability for testing neutrality and estimating population growth. Genetics 158, 865–874.
| PubMed |
Spielman RS,
McGinnis RE, Ewens WJ
(1993) Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM). American Journal of Human Genetics 52, 506–516.
| PubMed |
Stam P
(1980) The distribution of the fraction of the genome identical by descent in finite random mating populations. Genetical Research 35, 131–155.
Sved JA
(1971) Linkage disequilibrium and homozygosity of chromosome segments in finite populations. Theoretical Population Biology 2, 125–141.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Thompson JR,
Everett RW, Hammerschmidt NL
(2000a) Effects of inbreeding on production and survival in Holsteins. Journal of Dairy Science 83, 1856–1864.
| PubMed |
Thompson JR,
Everett RW, Wolfe CW
(2000b) Effects of inbreeding on production and survival in Jerseys. Journal of Dairy Science 83, 2131–2138.
| PubMed |
Van Laere AS,
Nguyen M,
Braunschweig M,
Nezer C, Collette C , et al.
(2003) A regulatory mutation in IGF2 causes a major QTL effect on muscle growth in the pig. Nature 425, 832–836.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Visscher PM, Goddard ME
(2004) Prediction of the confidence interval of QTL location. Behavior Genetics 34, 477–482.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
Wall JD, Pritchard JK
(2003) Assessing the performance of the haplotype block model of linkage disequilibrium. American Journal of Human Genetics 73, 502–515.
| Crossref | GoogleScholarGoogle Scholar | PubMed |
