Linkage disequilibrium and inference of ancestral recombination in 538 single-nucleotide polymorphism clusters across the human genome

Andrew G. Clark, Rasmus Nielsen, James Signorovitch, Tara C. Matise, Stephen Glanowski, Jeremy Heil, Emily S. Winn-Deen, Arthur L. Holden, Eric Lai

Research output: Contribution to journalArticlepeer-review

65 Scopus citations


The prospect of using linkage disequilibrium (LD) for fine-scale mapping in humans has attracted considerable attention, and, during the validation of a set of single-nucleotide polymorphisms (SNPs) for linkage analysis, a set of data for 4,833 8NPs in 538 clusters was produced that provides a rich picture of local attributes of LD across the genome. LD estimates may be biased depending on the means by which 8NPs are first identified, and a particular problem of ascertainment bias arises when SNPs identified in small heterogeneous panels are subsequently typed in larger population samples. Understanding and correcting ascertainment bias is essential for a useful quantitative assessment of the landscape of LD across the human genome. Heterogeneity in the population recombination rate, ρ = 4Nr, along the genome reflects how variable the density of markers will have to be for optimal coverage. We find that ascertainment-corrected ρ varies along the genome by more than two orders of magnitude, implying great differences in the recombinational history of different portions of our genome. The distribution of ρ̂ is unimodal, and we show that this is compatible with a wide range of mixtures of hotspots in a background of variable recombination rate. Although ρ̂ is significantly correlated across the three population samples, some regions of the genome exhibit population-specific spikes or troughs in ρ that are too large to be explained by sampling. This result is consistent with differences in the genealogical depth of local genomic regions, a finding that has direct bearing on the design and utility of LD mapping and on the National Institutes of Health HapMap project.

Original languageEnglish (US)
Pages (from-to)285-300
Number of pages16
JournalAmerican Journal of Human Genetics
Issue number2
StatePublished - Aug 1 2003

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

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