A Metric Linkage Disequilibrium Map of a Human Chromosome

Tapper, William; Maniatis, Nikolas; Morton, N. E.; Collins, Andrew

doi:10.1046/j.1469-1809.2003.00050.x

Cited by 43 publications

(29 citation statements)

References 32 publications

(46 reference statements)

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“…However, additivity must be lost locally below critical SNP densities that depend to a large extent on recombination intensity. We were able to reproduce the two large recombination cold spans observed in the data of Dawson et al (2001) (Tapper et al 2003) (Fig. 1).…”

Section: Discussionsupporting

confidence: 53%

“…It will be of interest to examine other populations with partial or complete African ancestry to determine the impact of recent admixture on the EBT. Tapper et al (2003) have constructed LD maps of chromosome 22 for the data of Dawson et al (2002). LDU map lengths in UK-unrelated and CEPH samples are very similar, being in the range 818 LDUs to 841 LDUs over 62.8 cM, implying a genome of approximately 48,000 LDUs in these populations.…”

Section: Discussionmentioning

confidence: 99%

“…The close correspondence between long-range LD patterns in these populations, as is evident from the many shared plateau and step regions, presumably reflects the common distribution of underlying recombination hot spots across populations (Kauppi et al 2003). In finer scale, chromosomal segments with extensive LD and low haplotype diversity (i.e., haplotype "blocks"; Gabriel et al 2002) can be identified as plateaus in the LD map where the increase in LDUs Cold Spring Harbor Laboratory Press on April 27, 2019 -Published by genome.cshlp.org Downloaded from is very small or zero (Tapper et al 2003). The latter block definition, although arbitrary, is more robust than those based on heuristics that typically yield ambiguous boundaries (Gabriel et al 2002;compare with Schwartz et al 2003).…”

Section: Construction and Analysis Of Metric Ld Mapsmentioning

confidence: 99%

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The linkage disequilibrium maps of three human chromosomes across four populations reflect their demographic history and a common underlying recombination pattern

Vega¹,

Isaac²,

Collins

et al. 2005

Genome Res.

110

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The extent and patterns of linkage disequilibrium (LD) determine the feasibility of association studies to map genes that underlie complex traits. Here we present a comparison of the patterns of LD across four major human populations (African-American, Caucasian, Chinese, and Japanese) with a high-resolution single-nucleotide polymorphism (SNP) map covering almost the entire length of chromosomes 6, 21, and 22. We constructed metric LD maps formulated such that the units measure the extent of useful LD for association mapping. LD reaches almost twice as far in chromosome 6 as in chromosomes 21 or 22, in agreement with their differences in recombination rates. By all measures used, out-of-Africa populations showed over a third more LD than African-Americans, highlighting the role of the population's demography in shaping the patterns of LD. Despite those differences, the long-range contour of the LD maps is remarkably similar across the four populations, presumably reflecting common localization of recombination hot spots. Our results have practical implications for the rational design and selection of SNPs for disease association studies.

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Section: Discussionsupporting

confidence: 53%

Section: Discussionmentioning

confidence: 99%

Section: Construction and Analysis Of Metric Ld Mapsmentioning

confidence: 99%

See 1 more Smart Citation

The linkage disequilibrium maps of three human chromosomes across four populations reflect their demographic history and a common underlying recombination pattern

Vega¹,

Isaac²,

Collins

et al. 2005

Genome Res.

110

View full text Add to dashboard Cite

show abstract

“…Identification of LD blocks: We used the LDU scale to identify LD blocks as suggested by Tapper et al (2003). Initially, we used the most stringent definition of blocks; i.e., blocks were formed by combining adjacent intervals with LDU widths of 0.…”

Section: Methodsmentioning

confidence: 99%

A First-Generation Metric Linkage Disequilibrium Map of Bovine Chromosome 6

et al. 2006

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We constructed a metric linkage disequilibrium (LD) map of bovine chromosome 6 (BTA6) on the basis of data from 220 SNPs genotyped on 433 Australian dairy bulls. This metric LD map has distances in LD units (LDUs) that are analogous to centimorgans in linkage maps. The LD map of BTA6 has a total length of 8.9 LDUs. Within the LD map, regions of high LD (represented as blocks) and regions of low LD (steps) are observed, when plotted against the integrated map in kilobases. At the most stringent block definition, namely a set of loci with zero LDU increase over the span of these markers, BTA6 comprises 40 blocks, accounting for 41% of the chromosome. At a slightly lower stringency of block definition (a set of loci covering a maximum of 0.2 LDUs on the LD map), up to 81% of BTA6 is spanned by 46 blocks and with 13 steps that are likely to reflect recombination hot spots. The mean swept radius (the distance over which LD is likely to be useful for mapping) is 13.3 Mb, confirming extensive LD in Holstein-Friesian dairy cattle, which makes such populations ideal for whole-genome association studies.

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“…Each SNP has an LD location, and distance between adjacent SNPs in the LD map was constrained to a maximum of 3 LDU. Such intervals are called holes (12), constituting 0.6% of the total map intervals, 17.8% of the total LDU length, and 2.2% of the total physical length. Ignoring stochastic variation and selection in the LD map and errors in estimating the linkage map in morgans (w), the Malecot model predicts that the ratio of corresponding distances in LD and linkage maps estimates t, the number of generations over which recombination has accumulated after one or more population bottlenecks (8).…”

mentioning

confidence: 99%

A map of the human genome in linkage disequilibrium units

Tapper

Collins²,

Gibson³

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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Two genetic maps with additive distances contribute information about recombination patterns, recombinogenic sequences, and discovery of genes affecting a particular phenotype. Recombination is measured in morgans (w) over a single generation in a linkage map but may cover thousands of generations in a linkage disequilibrium (LD) map measured in LD units (LDU). We used a subset of single nucleotide polymorphisms from the HapMap Project to create a genome-wide map in LDU. Recombination accounts for 96.8% of the LDU variance in chromosome arms and 92.4% in their deciles. However, deeper analysis shows that LDU͞w, an estimate of the effective bottleneck time (t), is significantly variable among chromosome arms because (i) the linkage map is approximated from the Haldane function, then adjusted toward the Kosambi function that is more accurate but still exaggerates w for all chromosomes, especially shorter ones; (ii) the nonpseudoautosomal region of the X chromosome is subject to hemizygous selection; and (iii) at resolution less than Ϸ40,000 markers per w, there are indeterminacies (holes) in the LD map reflecting intervals of very high recombination. Selection and stochastic variation in small regions must have effects, which remain to be investigated by comparisons among populations. These considerations suggest an optimal strategy to eliminate holes quickly, greatly enhance the resolution of sex-specific linkage maps, and maximize the gain in association mapping by using LD maps.effective bottleneck time ͉ HapMap ͉ recombination ͉ interference ͉ selection A linkage map with 14,759 polymorphic markers has recently been published, far exceeding the density and coverage of earlier maps (1). Although the human genome sequence facilitated construction of this genetic map by determining the physical order of its markers, 56% of its intervals have recombination rates of zero. This observation demonstrates the relatively low resolution of the linkage map, for which a costly solution would be the analysis of many more pedigrees and markers. Alternatively, sperm typing offers recombination data of the highest resolution currently available (2) but is feasible only for very small regions in male chromosomes and does not reflect historical recombination events. Using the HapMap data (3) to construct linkage disequilibrium (LD) maps measured in LD units (LDU) (4) and interpolating them into the sex-specific linkage map enhances the resolution of the linkage map as a by-product of our main objective, which is to construct genomewide LD maps with additive LDU distances. Such maps are applicable to association mapping (5, 6), population comparisons (7-9), and identification of genomic regions that are influenced by selection (10). LD mapping has begun the task of explaining and exploiting complexities (8) that do not affect application of the Malecot model (4) to create an LD map but determine how the map should be used to increase resolution of the linkage map. LD Map Construction. LD maps were constructed by the methods in th...

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A Metric Linkage Disequilibrium Map of a Human Chromosome

Cited by 43 publications

References 32 publications

The linkage disequilibrium maps of three human chromosomes across four populations reflect their demographic history and a common underlying recombination pattern

The linkage disequilibrium maps of three human chromosomes across four populations reflect their demographic history and a common underlying recombination pattern

A First-Generation Metric Linkage Disequilibrium Map of Bovine Chromosome 6

A map of the human genome in linkage disequilibrium units

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