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PMID: 16251462 Published · ppublish English Comparative Study Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Sequence features in regions of weak and strong linkage disequilibrium.

Genome research ·Vol. 15 ·No. 11 ·2005-11-00 ·Pages 1519-34

Smith AV, Thomas DJ, Munro HM, Abecasis GR

Abstract

We use genotype data generated by the International HapMap Project to dissect the relationship between sequence features and the degree of linkage disequilibrium in the genome. We show that variation in linkage disequilibrium is broadly similar across populations and examine sequence landscape in regions of strong and weak disequilibrium. Linkage disequilibrium is generally low within approximately 15 Mb of the telomeres of each chromosome and noticeably elevated in large, duplicated regions of the genome as well as within approximately 5 Mb of centromeres and other heterochromatic regions. At a broad scale (100-1000 kb resolution), our results show that regions of strong linkage disequilibrium are typically GC poor and have reduced polymorphism. In addition, these regions are enriched for LINE repeats, but have fewer SINE, DNA, and simple repeats than the rest of the genome. At a fine scale, we examine the sequence composition of "hotspots" for the rapid breakdown of linkage disequilibrium and show that they are enriched in SINEs, in simple repeats, and in sequences that are conserved between species. Regions of high and low linkage disequilibrium (the top and bottom quartiles of the genome) have a higher density of genes and coding bases than the rest of the genome. Closer examination of the data shows that whereas some types of genes (including genes involved in immune response and sensory perception) are typically located in regions of low linkage disequilibrium, other genes (including those involved in DNA and RNA metabolism, response to DNA damage, and the cell cycle) are preferentially located in regions of strong linkage disequilibrium. Our results provide a detailed analysis of the relationship between sequence features and linkage disequilibrium and suggest an evolutionary justification for the heterogeneity in linkage disequilibrium in the genome.

MeSH Terms
Base Composition Chromosomes, Human/genetics Computational Biology/methods Gene Frequency Genetic Variation Genome, Human/genetics Genomics/methods Haplotypes/genetics Humans Linkage Disequilibrium/genetics Models, Genetic Multivariate Analysis Short Interspersed Nucleotide Elements/genetics Statistics, Nonparametric
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Smith Albert V
Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA.
Thomas Daryl J
Munro Heather M
Abecasis Gonçalo R
References (50)
50 references, click to expand
  1. Mammalian retroelements.
    Genome Res. 2002 Oct;12(10):1455-65 PMID: 12368238
  2. Initial sequencing and comparative analysis of the mouse genome.
    Nature. 2002 Dec 5;420(6915):520-62 PMID: 12466850
  3. Using haplotype blocks to map human complex trait loci.
    Trends Genet. 2003 Mar;19(3):135-40 PMID: 12615007
  4. Advantage of rare HLA supertype in HIV disease progression.
    Nat Med. 2003 Jul;9(7):928-35 PMID: 12819779
  5. The Gene Ontology (GO) database and informatics resource.
    Nucleic Acids Res. 2004 Jan 1;32(Database issue):D258-61 PMID: 14681407
  6. The UCSC Table Browser data retrieval tool.
    Nucleic Acids Res. 2004 Jan 1;32(Database issue):D493-6 PMID: 14681465
  7. The International HapMap Project.
    Nature. 2003 Dec 18;426(6968):789-96 PMID: 14685227
  8. Modeling linkage disequilibrium and identifying recombination hotspots using single-nucleotide polymorphism data.
    Genetics. 2003 Dec;165(4):2213-33 PMID: 14704198
  9. The X chromosome in population genetics.
    Nat Rev Genet. 2004 Jan;5(1):43-51 PMID: 14708015
  10. Genome sequence of the Brown Norway rat yields insights into mammalian evolution.
    Nature. 2004 Apr 1;428(6982):493-521 PMID: 15057822
  11. Aligning multiple genomic sequences with the threaded blockset aligner.
    Genome Res. 2004 Apr;14(4):708-15 PMID: 15060014
  12. The fine-scale structure of recombination rate variation in the human genome.
    Science. 2004 Apr 23;304(5670):581-4 PMID: 15105499
  13. Efficiency and consistency of haplotype tagging of dense SNP maps in multiple samples.
    Hum Mol Genet. 2004 Nov 1;13(21):2557-65 PMID: 15367493
  14. The effect of linkage on limits to artificial selection.
    Genet Res. 1966 Dec;8(3):269-94 PMID: 5980116
  15. Gene ontology: tool for the unification of biology. The Gene Ontology Consortium.
    Nat Genet. 2000 May;25(1):25-9 PMID: 10802651
  16. An isochore transition in the NF1 gene region coincides with a switch in the extent of linkage disequilibrium.
    Am J Hum Genet. 2000 Oct;67(4):873-80 PMID: 10978227
  17. A map of human genome sequence variation containing 1.42 million single nucleotide polymorphisms.
    Nature. 2001 Feb 15;409(6822):928-33 PMID: 11237013
  18. Comparison of human genetic and sequence-based physical maps.
    Nature. 2001 Feb 15;409(6822):951-3 PMID: 11237020
  19. Mobile elements and the human genome.
    Nat Rev Genet. 2000 Nov;1(2):134-44 PMID: 11253653
  20. Polymorphism and evolution of HLA class I and II genes and molecules.
    Rev Immunogenet. 1999;1(1):105-23 PMID: 11256568
  21. Local rates of recombination are positively correlated with GC content in the human genome.
    Mol Biol Evol. 2001 Jun;18(6):1139-42 PMID: 11371603
  22. Intensely punctate meiotic recombination in the class II region of the major histocompatibility complex.
    Nat Genet. 2001 Oct;29(2):217-22 PMID: 11586303
  23. Two-locus sampling distributions and their application.
    Genetics. 2001 Dec;159(4):1805-17 PMID: 11779816
  24. Linkage disequilibrium: what history has to tell us.
    Trends Genet. 2002 Feb;18(2):83-90 PMID: 11818140
  25. The human genome browser at UCSC.
    Genome Res. 2002 Jun;12(6):996-1006 PMID: 12045153
  26. The structure of haplotype blocks in the human genome.
    Science. 2002 Jun 21;296(5576):2225-9 PMID: 12029063
  27. A high-resolution recombination map of the human genome.
    Nat Genet. 2002 Jul;31(3):241-7 PMID: 12053178
  28. A first-generation linkage disequilibrium map of human chromosome 22.
    Nature. 2002 Aug 1;418(6897):544-8 PMID: 12110843
  29. Linkage disequilibrium in subdivided populations.
    Genetics. 1973 Sep;75(1):213-9 PMID: 4762877
  30. Levels of naturally occurring DNA polymorphism correlate with recombination rates in D. melanogaster.
    Nature. 1992 Apr 9;356(6369):519-20 PMID: 1560824
  31. A second-generation linkage map of the human genome.
    Nature. 1992 Oct 29;359(6398):794-801 PMID: 1436057
  32. Global patterns of linkage disequilibrium at the CD4 locus and modern human origins.
    Science. 1996 Mar 8;271(5254):1380-7 PMID: 8596909
  33. Mismatch repair in replication fidelity, genetic recombination, and cancer biology.
    Annu Rev Biochem. 1996;65:101-33 PMID: 8811176
  34. Evolutionary conservation of histone macroH2A subtypes and domains.
    Nucleic Acids Res. 1998 Jun 15;26(12):2837-42 PMID: 9611225
  35. Comprehensive human genetic maps: individual and sex-specific variation in recombination.
    Am J Hum Genet. 1998 Sep;63(3):861-9 PMID: 9718341
  36. DNA variability and recombination rates at X-linked loci in humans.
    Genetics. 1998 Nov;150(3):1133-41 PMID: 9799265
  37. Genomic disorders: structural features of the genome can lead to DNA rearrangements and human disease traits.
    Trends Genet. 1998 Oct;14(10):417-22 PMID: 9820031
  38. Prospects for whole-genome linkage disequilibrium mapping of common disease genes.
    Nat Genet. 1999 Jun;22(2):139-44 PMID: 10369254
  39. Haplotype block structures show significant variation among populations.
    Genet Epidemiol. 2004 Dec;27(4):385-400 PMID: 15389924
  40. How strong is the mutagenicity of recombination in mammals?
    Mol Biol Evol. 2005 Mar;22(3):426-31 PMID: 15496551
  41. Genome-wide association studies for common diseases and complex traits.
    Nat Rev Genet. 2005 Feb;6(2):95-108 PMID: 15716906
  42. Whole-genome patterns of common DNA variation in three human populations.
    Science. 2005 Feb 18;307(5712):1072-9 PMID: 15718463
  43. Complement factor H variant increases the risk of age-related macular degeneration.
    Science. 2005 Apr 15;308(5720):419-21 PMID: 15761120
  44. Complement factor H polymorphism and age-related macular degeneration.
    Science. 2005 Apr 15;308(5720):421-4 PMID: 15761121
  45. Complement factor H polymorphism in age-related macular degeneration.
    Science. 2005 Apr 15;308(5720):385-9 PMID: 15761122
  46. Linkage disequilibrium: ancient history drives the new genetics.
    Hum Hered. 2005;59(2):118-24 PMID: 15838181
  47. Strong association of the Y402H variant in complement factor H at 1q32 with susceptibility to age-related macular degeneration.
    Am J Hum Genet. 2005 Jul;77(1):149-53 PMID: 15895326
  48. Evolutionarily conserved elements in vertebrate, insect, worm, and yeast genomes.
    Genome Res. 2005 Aug;15(8):1034-50 PMID: 16024819
  49. Handling marker-marker linkage disequilibrium: pedigree analysis with clustered markers.
    Am J Hum Genet. 2005 Nov;77(5):754-67 PMID: 16252236
  50. The International HapMap Project Web site.
    Genome Res. 2005 Nov;15(11):1592-3 PMID: 16251469
Article Info
Journal
Genome research
Abbr.
Genome Res
ISSN
1088-9051
DOI
10.1101/gr.4421405
Published
2005-11-00
Pages
1519-34
Language
English
Region
United States
NLM ID
9518021
PMCID
PMC1310640
Subset
IM
Grants
NHGRI NIH HHS · HG02238 · United States
NHGRI NIH HHS · R01 HG002651 · United States
NHGRI NIH HHS · P41 HG002371 · United States
NHGRI NIH HHS · HG02651 · United States
PHPPO CDC HHS · IPH41HG02371 · United States
NHGRI NIH HHS · R01 HG002238 · United States
External Links
PubMed source DOI: 10.1101/gr.4421405 PMC Full Text View journal details
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