## Description

This track shows the location of recombination hotspots detected from patterns of genetic variation. It is based on the HapMap Phase I data, release 16a, and Perlegen data (Hinds et al., 2005).

Observations from sperm studies (Jeffreys et al., 2001) and patterns of genetic variation (McVean et al., 2004; Crawford et al., 2004) show that recombination rates in the human genome vary extensively over kilobase scales and that much recombination occurs in recombination hotspots. This provides an explanation for the apparent block-like structure of linkage disequilibrium (Daly et al., 2001; Gabriel et al., 2002).

Recombination hotspot estimates provide a new route to understanding the molecular mechanisms underlying human recombination. A better understanding of the genomic landscape of human recombination hotspots would facilitate the efficient design and analysis of disease association studies and greatly improve inferences from polymorphism data about selection and human demographic history.

## Methods

Recombination hotspots are identified using the likelihood-ratio test described in McVean et al. (2004) and Winckler et al. (2005), referred to as LDhot. For successive intervals of 200 kb, the maximum likelihood of a model with a constant recombination rate is compared to the maximum likelihood of a model in which the central 2 kb is a recombination hotspot (likelihoods are approximated by the composite likelihood method of Hudson 2001). The observed difference in log composite likelihood is compared against the null distribution, which is obtained by simulations. Simulations are matched for sample size, SNP density, background recombination rate and an approximation to the ascertainment scheme (a panel of 12 individuals with a Poisson number of chromosomes, mean 1, sampled from this panel, using a single hit ascertainment scheme for dbSNP and resequencing of 16 individuals for the ten HapMap ENCODE regions). Evidence for a hotspot was assessed in each analysis panel separately (YRI, CEU and combined CHB+JPT), and p-values were combined such that a hotspot requires that two of the three populations show some evidence of a hotspot (p < 0.05) and at least one population showed stronger evidence for a hotspot (p < 0.01). Hotspot centers were estimated at those locations where distinct recombination rate estimate peaks occurred with at least a factor of two separation between peaks, within the low p-value intervals.

## Validation

This approach has been validated in three ways: Over large scales from the genetic map, both by extensive simulation studies and by comparisons with independent estimates of recombination rates, and over fine scales from sperm analysis. Full details of validation can be found in McVean et al. (2004) and Winckler et al. (2005).

## Credits

The HapMap data are based on HapMap release 16a; the Perlegen data are from Hinds et al. (2005). The recombination hotspots were ascertained by Simon Myers from the Mathematical Genetics Group at the University of Oxford.

## References

Crawford, D.C., Bhangale, T., Li, N., Hellenthal, G., Rieder, M.J., Nickerson, D.A. and Stephens, M. Evidence for substantial fine-scale variation in recombination rates across the human genome. Nat Genet. 36(7), 700-6 (2004).

Daly, M.J., Rioux, J.D., Schaffner, S.F., Hudson, T.J. and Lander, E.S. High-resolution haplotype structure in the human genome. Nat Genet. 29(2), 229-32 (2001).

Gabriel, S.B., Schaffner, S.F., Nguyen, H., Moore, J.M., Roy, J., Blumenstiel, B., Higgins, J., DeFelice, M., Lochner, A., Faggart, M. et al. The structure of haplotype blocks in the human genome. Science 296(5576), 2225-9 (2002).

Hudson, R. R. Two-locus sampling distributions and their application. Genetics 159(4):1805-1817 (2001).

Hinds, D.A., Stuve, L.L., Nilsen, G.B., Halperin, E., Eskin, E., Ballinger, D.G., Frazer, K.A., Cox, D.R. Whole-Genome Patterns of Common DNA Variation in Three Human Populations. Science 307(5712), 1072-1079 (2005).

Jeffreys, A.J,. Kauppi, L. and Neumann, R. Intensely punctate meiotic recombination in the class II region of the major histocompatibility complex. Nat Genet. 29(2), 217-22 (2001).

McVean, G.A., Myers, S.R., Hunt, S., Deloukas, P., Bentley, D.R. and Donnelly, P. The fine-scale structure of recombination rate variation in the human genome. Science 304(5670), 581-4 (2004).

Winckler, W., Myers, S.R., Richter, D.J., Onofrio, R.C., McDonald, G.J., Bontrop, R.E., McVean, G.A., Gabriel, S.B., Reich, D., Donnelly, P. et al. Comparison of fine-scale recombination rates in humans and chimpanzees. Science 308(5718), 107-11 (2005).