• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of geneticsGeneticsCurrent IssueInformation for AuthorsEditorial BoardSubscribeSubmit a Manuscript
Genetics. Aug 1999; 152(4): 1711–1722.
PMCID: PMC1460700

A scan for linkage disequilibrium across the human genome.

Abstract

Linkage disequilibrium (LD), the tendency for alleles of linked loci to co-occur nonrandomly on chromosomal haplotypes, is an increasingly useful phenomenon for (1) revealing historic perturbation of populations including founder effects, admixture, or incomplete selective sweeps; (2) estimating elapsed time since such events based on time-dependent decay of LD; and (3) disease and phenotype mapping, particularly for traits not amenable to traditional pedigree analysis. Because few descriptions of LD for most regions of the human genome exist, we searched the human genome for the amount and extent of LD among 5048 autosomal short tandem repeat polymorphism (STRP) loci ascertained as specific haplotypes in the European CEPH mapping families. Evidence is presented indicating that approximately 4% of STRP loci separated by <4.0 cM are in LD. The fraction of locus pairs within these intervals that display small Fisher's exact test (FET) probabilities is directly proportional to the inverse of recombination distance between them (1/cM). The distribution of LD is nonuniform on a chromosomal scale and in a marker density-independent fashion, with chromosomes 2, 15, and 18 being significantly different from the genome average. Furthermore, a stepwise (locus-by-locus) 5-cM sliding-window analysis across 22 autosomes revealed nine genomic regions (2.2-6.4 cM), where the frequency of small FET probabilities among loci was greater than or equal to that presented by the HLA on chromosome 6, a region known to have extensive LD. Although the spatial heterogeneity of LD we detect in Europeans is consistent with the operation of natural selection, absence of a formal test for such genomic scale data prevents eliminating neutral processes as the evolutionary origin of the LD.

Full Text

The Full Text of this article is available as a PDF (324K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Hästbacka J, de la Chapelle A, Kaitila I, Sistonen P, Weaver A, Lander E. Linkage disequilibrium mapping in isolated founder populations: diastrophic dysplasia in Finland. Nat Genet. 1992 Nov;2(3):204–211. [PubMed]
  • Hedrick PW. Gametic disequilibrium measures: proceed with caution. Genetics. 1987 Oct;117(2):331–341. [PMC free article] [PubMed]
  • Hudson TJ, Stein LD, Gerety SS, Ma J, Castle AB, Silva J, Slonim DK, Baptista R, Kruglyak L, Xu SH, et al. An STS-based map of the human genome. Science. 1995 Dec 22;270(5244):1945–1954. [PubMed]
  • Jorde LB. Linkage disequilibrium as a gene-mapping tool. Am J Hum Genet. 1995 Jan;56(1):11–14. [PMC free article] [PubMed]
  • Kaplan NL, Lewis PO, Weir BS. Age of the delta F508 cystic fibrosis mutation. Nat Genet. 1994 Nov;8(3):216–218. [PubMed]
  • Kaplan NL, Hill WG, Weir BS. Likelihood methods for locating disease genes in nonequilibrium populations. Am J Hum Genet. 1995 Jan;56(1):18–32. [PMC free article] [PubMed]
  • Ayala FJ, Escalante AA. The evolution of human populations: a molecular perspective. Mol Phylogenet Evol. 1996 Feb;5(1):188–201. [PubMed]
  • Begovich AB, McClure GR, Suraj VC, Helmuth RC, Fildes N, Bugawan TL, Erlich HA, Klitz W. Polymorphism, recombination, and linkage disequilibrium within the HLA class II region. J Immunol. 1992 Jan 1;148(1):249–258. [PubMed]
  • Laan M, Päbo S. Demographic history and linkage disequilibrium in human populations. Nat Genet. 1997 Dec;17(4):435–438. [PubMed]
  • Lewontin RC. The Interaction of Selection and Linkage. I. General Considerations; Heterotic Models. Genetics. 1964 Jan;49(1):49–67. [PMC free article] [PubMed]
  • Briscoe D, Stephens JC, O'Brien SJ. Linkage disequilibrium in admixed populations: applications in gene mapping. J Hered. 1994 Jan-Feb;85(1):59–63. [PubMed]
  • Mantel N. The detection of disease clustering and a generalized regression approach. Cancer Res. 1967 Feb;27(2):209–220. [PubMed]
  • Broman KW, Murray JC, Sheffield VC, White RL, Weber JL. Comprehensive human genetic maps: individual and sex-specific variation in recombination. Am J Hum Genet. 1998 Sep;63(3):861–869. [PMC free article] [PubMed]
  • Martin MP, Harding A, Chadwwick R, Kronick M, Cullen M, Lin L, Mignot E, Carrington M. Characterization of 12 microsatellite loci of the human MHC in a panel of reference cell lines . Immunogenetics. 1998 May;47(6):503–503. [PubMed]
  • Brzustowicz LM, Mérette C, Xie X, Townsend L, Gilliam TC, Ott J. Molecular and statistical approaches to the detection and correction of errors in genotype databases. Am J Hum Genet. 1993 Nov;53(5):1137–1145. [PMC free article] [PubMed]
  • Moonsamy PV, Klitz W, Tilanus MG, Begovich AB. Genetic variability and linkage disequilibrium within the DP region in the CEPH families. Hum Immunol. 1997 Dec;58(2):112–121. [PubMed]
  • Ohta T, Kimura M. Linkage disequilibrium at steady state determined by random genetic drift and recurrent mutation. Genetics. 1969 Sep;63(1):229–238. [PMC free article] [PubMed]
  • Chakraborty R, Weiss KM. Admixture as a tool for finding linked genes and detecting that difference from allelic association between loci. Proc Natl Acad Sci U S A. 1988 Dec;85(23):9119–9123. [PMC free article] [PubMed]
  • Peterson AC, Di Rienzo A, Lehesjoki AE, de la Chapelle A, Slatkin M, Freimer NB. The distribution of linkage disequilibrium over anonymous genome regions. Hum Mol Genet. 1995 May;4(5):887–894. [PubMed]
  • Deloukas P, Schuler GD, Gyapay G, Beasley EM, Soderlund C, Rodriguez-Tomé P, Hui L, Matise TC, McKusick KB, Beckmann JS, et al. A physical map of 30,000 human genes. Science. 1998 Oct 23;282(5389):744–746. [PubMed]
  • Dib C, Fauré S, Fizames C, Samson D, Drouot N, Vignal A, Millasseau P, Marc S, Hazan J, Seboun E, et al. A comprehensive genetic map of the human genome based on 5,264 microsatellites. Nature. 1996 Mar 14;380(6570):152–154. [PubMed]
  • Ewens WJ, Spielman RS. The transmission/disequilibrium test: history, subdivision, and admixture. Am J Hum Genet. 1995 Aug;57(2):455–464. [PMC free article] [PubMed]
  • Rothman KJ. No adjustments are needed for multiple comparisons. Epidemiology. 1990 Jan;1(1):43–46. [PubMed]
  • Foissac A, Crouau-Roy B, Fauré S, Thomsen M, Cambon-Thomsen A. Microsatellites in the HLA region: on overview. Tissue Antigens. 1997 Mar;49(3 Pt 1):197–214. [PubMed]
  • Guo SW, Thompson EA. Performing the exact test of Hardy-Weinberg proportion for multiple alleles. Biometrics. 1992 Jun;48(2):361–372. [PubMed]
  • Stephens JC, Briscoe D, O'Brien SJ. Mapping by admixture linkage disequilibrium in human populations: limits and guidelines. Am J Hum Genet. 1994 Oct;55(4):809–824. [PMC free article] [PubMed]
  • Stephens JC, Reich DE, Goldstein DB, Shin HD, Smith MW, Carrington M, Winkler C, Huttley GA, Allikmets R, Schriml L, et al. Dating the origin of the CCR5-Delta32 AIDS-resistance allele by the coalescence of haplotypes. Am J Hum Genet. 1998 Jun;62(6):1507–1515. [PMC free article] [PubMed]
  • von Haeseler A, Sajantila A, Päbo S. The genetical archaeology of the human genome. Nat Genet. 1996 Oct;14(2):135–140. [PubMed]
  • Stewart EA, McKusick KB, Aggarwal A, Bajorek E, Brady S, Chu A, Fang N, Hadley D, Harris M, Hussain S, et al. An STS-based radiation hybrid map of the human genome. Genome Res. 1997 May;7(5):422–433. [PubMed]
  • Wiehe T, Slatkin M. Epistatic selection in a multi-locus Levene model and implications for linkage disequilibrium. Theor Popul Biol. 1998 Feb;53(1):75–84. [PubMed]
  • Takahata N, Satta Y, Klein J. Polymorphism and balancing selection at major histocompatibility complex loci. Genetics. 1992 Apr;130(4):925–938. [PMC free article] [PubMed]
  • Tishkoff SA, Dietzsch E, Speed W, Pakstis AJ, Kidd JR, Cheung K, Bonné-Tamir B, Santachiara-Benerecetti AS, Moral P, Krings M. Global patterns of linkage disequilibrium at the CD4 locus and modern human origins. Science. 1996 Mar 8;271(5254):1380–1387. [PubMed]

Articles from Genetics are provided here courtesy of Genetics Society of America

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

  • MedGen
    MedGen
    Related information in MedGen
  • PubMed
    PubMed
    PubMed citations for these articles

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...