Description
This track shows the location of recombination hotspots detected from
patterns of genetic variation. It is based on the HapMap ENCODE data,
in the ten ENCODE regions that have been resequenced:
- ENr112 (chr2)
- ENr131 (chr2)
- ENr113 (chr4)
- ENm010 (chr7)
- ENm013 (chr7)
- ENm014 (chr7)
- ENr321 (chr8)
- ENr232 (chr9)
- ENr123 (chr12)
- ENr213 (chr18)
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
disequlibrium (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 10 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: by extensive
simulation studies and by comparisons with independent estimates of
recombination rates, both over large scales from the genetic map 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 data are based on HapMap
release 16a. 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).
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).
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