KEY POINTS * One effect of recombination is to determine the extent of linkage disequilibrium in population DNA samples. * Direct measurement of the recombination rate is difficult and often

impractical. For this reason, population-genetic methods are often used to infer recombination rates from patterns of variation among DNA sequences. * Population-genetic methods can detect

variation in the recombination rate at the level of single genes. * Although simple parsimony methods allow the number of recombination events to be counted, most recombination events are

missed using this approach. * Sophisticated statistical approaches use population-genetic models to estimate recombination rates. * Several statistical methods that estimate the population

biological processes. * Estimated recombination rates enable the detailed interpretation of linkage disequilibrium and haplotype data. ABSTRACT Obtaining an accurate measure of how

recombination rates vary across the genome has implications for understanding the molecular basis of recombination, its evolutionary significance and the distribution of linkage

disequilibrium in natural populations. Although measuring the recombination rate is experimentally challenging, good estimates can be obtained by applying population-genetic methods to DNA

sequences taken from natural populations. Statistical methods are now providing insights into the nature and scale of variation in the recombination rate, particularly in humans. Such

knowledge will become increasingly important owing to the growing use of population-genetic methods in biomedical research. Access through your institution Buy or subscribe This is a preview

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POPULATIONS: APPRECIATING AND ESTIMATING RECOMBINATION RATE VARIATION Article 29 May 2020 INFERENCE AND APPLICATIONS OF ANCESTRAL RECOMBINATION GRAPHS Article 30 September 2024

RANK-INVARIANT ESTIMATION OF INBREEDING COEFFICIENTS Article Open access 25 November 2021 REFERENCES * Hartl, D. L. & Clark, A. G. _Principles of Population Genetics_ (Sinauer,

Sunderland, 1998). Google Scholar  * Weiss, K. M. & Clark, A. G. Linkage disequilibrium and the mapping of complex human traits. _Trends Genet._ 18, 19–24 (2002). THIS WORK HIGHLIGHTS

ISSUES THAT ARE RELATED TO THE APPLICATION OF LD DATA TO ASSOCIATION STUDIES. CAS  PubMed  Google Scholar  * Kaplan, N. & Morris, R. Prospects for association-based fine mapping of a

susceptibility gene for a complex disease. _Theor. Popul. Biol._ 60, 181–191 (2001). CAS  PubMed  Google Scholar  * Jeffreys, A. J., Ritchie, A. & Neumann, R. High resolution analysis of

haplotype diversity and meiotic crossover in the human _TAP2_ recombination hotspot. _Hum. Mol. Genet._ 9, 725–733 (2000). CAS  PubMed  Google Scholar  * Badge, R. M., Yardley, J.,

Jeffreys, A. J. & Armour, J. A. Crossover breakpoint mapping identifies a subtelomeric hotspot for male meiotic recombination. _Hum. Mol. Genet._ 9, 1239–1244 (2000). CAS  PubMed  Google

Scholar  * Cullen, M., Erlich, H., Klitz, W. & Carrington, M. Molecular mapping of a recombination hotspot located in the second intron of the human _TAP2_ locus. _Am. J. Hum. Genet._

56, 1350–1358 (1995). CAS  PubMed  PubMed Central  Google Scholar  * Zhao, H. Family-based association studies. _Stat. Methods Med. Res._ 9, 563–87 (2000). CAS  PubMed  Google Scholar  *

Cardon, L. R. & Bell, J. I. Association study designs for complex diseases. _Nature Rev. Genet._ 2, 91–99 (2001). CAS  PubMed  Google Scholar  * Jeffreys, A. J., Murray, J. &

Neumann, R. High-resolution mapping of crossovers in human sperm defines a minisatellite-associated recombination hotspot. _Mol. Cell_ 2, 267–273 (1998). CAS  PubMed  Google Scholar  *

Fearnhead, P. & Donnelly, P. Estimating recombination rates from population genetic data. _Genetics_ 159, 1299–1318 (2001). CAS  PubMed  PubMed Central  Google Scholar  * Fearnhead, P.

& Donnelly, P. Approximate likelihood methods for estimating local recombination rates. _J. R. Stat. Soc. Ser. B Stat. Methodol._ 64, 657–680 (2002). Google Scholar  * Kuhner, M. K.,

Yamato, J. & Felsenstein, J. Maximum likelihood estimation of recombination rates from population data. _Genetics_ 156, 1393–1401 (2000). CAS  PubMed  PubMed Central  Google Scholar  *

Stephens, M. & Donnelly, P. Inference in molecular population genetics. _J. R. Stat. Soc. Ser. B Stat. Methodol._ 62, 605–635 (2000). Google Scholar  * Pritchard, J. K. & Przeworski,

M. Linkage disequilibrium in humans: models and data. _Am. J. Hum. Genet._ 69, 1–14 (2001). A COMPREHENSIVE REVIEW OF LD AND ITS DEPENDENCE ON DEMOGRAPHY; THE PAPER ALSO EXAMINES THE

CONNECTION BETWEEN THEORETICAL MODELS AND EXPERIMENTAL DATA. CAS  PubMed  PubMed Central  Google Scholar  * Golding, G. B. The sampling distribution of linkage disequilibrium. _Genetics_

108, 257–274 (1984). CAS  PubMed  PubMed Central  Google Scholar  * Kruglyak, L. Prospects for whole-genome linkage disequilibrium mapping of common disease genes. _Nature Genet._ 22,

139–144 (1999). CAS  PubMed  Google Scholar  * Calafell, F., Grigorenko, E. L., Chikanian, A. A. & Kidd, K. K. Haplotype evolution and linkage disequilibrium: a simulation study. _Hum.

Hered._ 51, 85–96 (2000). Google Scholar  * Wang, N., Akey, J. M., Zhang, K., Chakraborty, R. & Jin, L. Distribution of recombination crossovers and the origin of haplotype blocks: the

interplay of population history, recombination, and mutation. _Am. J. Hum. Genet._ 71, 1227–1234 (2002). CAS  PubMed  PubMed Central  Google Scholar  * Barton, N. H. Genetic hitchhiking.

_Philos. Trans. R. Soc. Lond., B, Biol. Sci._ 355, 1553–1562 (2000). CAS  Google Scholar  * Charlesworth, B., Nordborg, M. & Charlesworth, D. The effects of local selection, balanced

polymorphism and background selection on equilibrium patterns of genetic diversity in subdivided populations. _Genet. Res._ 70, 155–174 (1997). CAS  PubMed  Google Scholar  * Chapman, N. H.

& Thompson, E. A. Linkage disequilibrium mapping: the role of population history, size, and structure. _Adv. Genet._ 42, 413–437 (2001). CAS  PubMed  Google Scholar  * Freimer, N. B.,

Service, S. K. & Slatkin, M. Expanding on population studies. _Nature Genet._ 17, 371–373 (1997). CAS  PubMed  Google Scholar  * Hudson, R. R. The sampling distribution of linkage

disequilibrium under an infinite allele model without selection. _Genetics_ 109, 611–631 (1985). CAS  PubMed  PubMed Central  Google Scholar  * Garner, C. & Slatkin, M. On selecting

markers for association studies: patterns of linkage disequilibrium between two and three diallelic loci. _Genet. Epidemiol_ 24, 57–67 (2003). PubMed  Google Scholar  * Phillips, M. S. et

al. Chromosome-wide distribution of haplotype blocks and the role of recombination hot spots. _Nature Genet._ 33, 382–387 (2003). A STUDY OF A DENSE MARKER MAP ON CHROMOSOME 19 THAT,

TOGETHER WITH A DETAILED THEORETICAL ANALYSIS, HIGHLIGHTS PROBLEMS IN DEFINING HAPLOTYPE BLOCKS. CAS  PubMed  Google Scholar  * Cardon, L. R. & Abecasis, G. R. Using haplotype blocks to

map human complex trait loci. _Trends Genet._ 19, 135–140 (2003). CAS  PubMed  Google Scholar  * Akey, J. M., Zhang, K., Xiong, M. M. & Jin, L. The effect of single nucleotide

polymorphism identification strategies on estimates of linkage disequilibrium. _Mol. Biol. Evol._ 20, 232–242 (2003). CAS  PubMed  Google Scholar  * Nielsen, R. & Signorovitch, J.

Correcting for ascertainment bias when analyzing SNP data: applications to the estimation of linkage disequilibrium. _Theor. Popul. Biol._ 63, 245–255 (2003). PubMed  Google Scholar  *

Rannala, B. & Slatkin, M. Likelihood analysis of disequilibrium mapping, and related problems. _Am. J. Hum. Genet._ 62, 459–473 (1998). CAS  PubMed  PubMed Central  Google Scholar  *

Zollner, S. & von Haeseler, A. A coalescent approach to study linkage disequilibrium between single-nucleotide polymorphisms. _Am. J. Hum. Genet._ 66, 615–628 (2000). CAS  PubMed  PubMed

Central  Google Scholar  * Nordborg, M. & Tavare, S. Linkage disequilibrium: what history has to tell us. _Trends Genet._ 18, 83–90 (2002). A CAREFUL ATTEMPT AT DISCUSSING THE EFFECTS

OF POPULATION HISTORY ON LD IN A GENEALOGICAL FRAMEWORK. CAS  PubMed  Google Scholar  * Stumpf, M. P. H. & Goldstein, D. B. Genealogical and evolutionary inference with the human Y

chromosome. _Science_ 291, 1738–1742 (2001). CAS  PubMed  Google Scholar  * Donnelly, P. & Tavare, S. Coalescents and genealogical structure under neutrality. _Annu. Rev. Genet._ 29,

401–421 (1995). CAS  PubMed  Google Scholar  * Nordborg, M. in _Handbook of Statistical Genetics_ (eds Balding, D. J. M. B. & Cannings, C.) 179–212 (Wiley, Chichester, 2000). A MODERN

EXPOSITION OF THE COALESCENT AND ITS APPLICATION IN MODERN POPULATION GENETICS. Google Scholar  * Hudson, R. R. in _Oxford Surveys in Evolutionary Biology_ (ed. Futuyama, D. J. A.) 1–43

(Oxford University Press, Oxford, 1990). Google Scholar  * Tavare, S. A genealogical view of some stochastic-models in population-genetics. _Stochastic Processes and their Applications

Abstr._ 19, 10 (1985). Google Scholar  * Tavare, S., Balding, D. J., Griffiths, R. C. & Donnelly, P. Inferring coalescence times from DNA sequence data. _Genetics_ 145, 505–518 (1997).

CAS  PubMed  PubMed Central  Google Scholar  * Stephens, M. in _Handbook of Statistical Genetics_ (eds Balding, D. J. M. B. & Cannings, C.) 213–238 (Wiley, Chichester, 2001). A DETAILED

AND HIGHLY ACCESSIBLE ACCOUNT OF STATISTICAL INFERENCE IN POPULATION GENETICS USING THE COALESCENT. Google Scholar  * Griffiths, R. C. & Marjoram, P. Ancestral inference from samples of

DNA sequences with recombination. _J. Comput. Biol._ 3, 479–502 (1996). CAS  PubMed  Google Scholar  * Hudson, R. R. & Kaplan, N. L. The coalescent process in models with selection and

recombination. _Genetics_ 120, 831–840 (1988). CAS  PubMed  PubMed Central  Google Scholar  * Wiuf, C. & Hein, J. The ancestry of a sample of sequences subject to recombination.

_Genetics_ 151, 1217–1228 (1999). CAS  PubMed  PubMed Central  Google Scholar  * Wiuf, C. & Hein, J. Recombination as a point process along sequences. _Theor. Popul. Biol._ 55, 248–259

(1999). CAS  PubMed  Google Scholar  * Kuhner, M. K., Beerli, P., Yamato, J. & Felsenstein, J. Usefulness of single nucleotide polymorphism data for estimating population parameters.

_Genetics_ 156, 439–447 (2000). CAS  PubMed  PubMed Central  Google Scholar  * Weir, B. S. Inferences about linkage disequilibrium. _Biometrics_ 35, 235–254 (1979). CAS  PubMed  Google

Scholar  * Myers, S. R. & Griffiths, R. C. Bounds on the minimum number of recombination events in a sample history. _Genetics_ 163, 375–394 (2003). CAS  PubMed  PubMed Central  Google

Scholar  * Wiuf, C. On the minimum number of topologies explaining a sample of DNA sequences. _Theor. Popul. Biol._ 62, 357–363 (2002). PubMed  Google Scholar  * Posada, D. & Crandall,

K. A. Evaluation of methods for detecting recombination from DNA sequences: computer simulations. _Proc. Natl Acad. Sci. USA_ 98, 13757–13762 (2001). CAS  PubMed  PubMed Central  Google

Scholar  * Wiuf, C., Christensen, T. & Hein, J. A simulation study of the reliability of recombination detection methods. _Mol. Biol. Evol._ 18, 1929–1939 (2001). CAS  PubMed  Google

Scholar  * McVean, G. A. A genealogical interpretation of linkage disequilibrium. _Genetics_ 162, 987–991 (2002). THIS PAPER DISCUSSES LD IN A GENEALOGICAL FRAMEWORK AND SHOWS HOW FEATURES

OF THE GENEALOGY ARE CONNECTED TO LD SUMMARY STATISTICS. PubMed  PubMed Central  Google Scholar  * Myers, S. _The Detection of Recombination Events Using DNA Sequence Data_. Thesis, Univ.

Oxford (2003). Google Scholar  * Wiuf, C. & Hein, J. On the number of ancestors to a DNA sequence. _Genetics_ 147, 1459–1468 (1997). CAS  PubMed  PubMed Central  Google Scholar  *

Kingman, J. F. C. The coalescent. _Stochastic Processes and their Applications_ 13, 235–248 (1982). Google Scholar  * Rosenberg, N. A. & Nordborg, M. Genealogical trees, coalescent

theory and the analysis of genetic polymorphisms. _Nature Rev. Genet._ 3, 380–390 (2002). CAS  PubMed  Google Scholar  * Wiuf, C. & Posada, D. A coalescent model of recombination

hotspots. _Genetics_ 164, 407–417 (2003). PubMed  PubMed Central  Google Scholar  * Cavalli-Sforza, L. L., Mennazzi, P. & Piazza, A. _The History and Geography of Human Genes_ (Princeton

Univ. Press, Princeton, 1996). Google Scholar  * Rannala, B. Gene genealogy in a population of variable size. _Heredity_ 78, 417–423 (1997). PubMed  Google Scholar  * Wakeley, J. &

Lessard, S. Theory of the effects of population structure and sampling on patterns of linkage disequilibrium applied to genomic data from humans. _Genetics_ 164, 1043–1053 (2003). CAS 

PubMed  PubMed Central  Google Scholar  * Nordborg, M. Linkage disequilibrium, gene trees and selfing: an ancestral recombination graph with selfing. _Genetics_ 154, 923–929 (2000). CAS 

PubMed  PubMed Central  Google Scholar  * Hey, J. & Wakeley, J. A coalescent estimator of the population recombination rate. _Genetics_ 145, 833–846 (1997). CAS  PubMed  PubMed Central 

Google Scholar  * Wall, J. D. A comparison of estimators of the population recombination rate. _Mol. Biol. Evol._ 17, 156–163 (2000). CAS  PubMed  Google Scholar  * Cox, D. R. & Hinkley,

D. V. _Theoretical Statistics_ (Chapman and Hall, London, 1974). Google Scholar  * Casella, G. & Berger, R. L. _Statistical Inference_ (Duxbury, Pacific Grove, 2002). Google Scholar  *

Steel, M. & Penny, D. Parsimony, likelihood, and the role of models in molecular phylogenetics. _Mol. Biol. Evol._ 17, 839–850 (2000). CAS  PubMed  Google Scholar  * Reich, D. E. et al.

Linkage disequilibrium in the human genome. _Nature_ 411, 199–204 (2001). CAS  PubMed  Google Scholar  * Gabriel, S. B. et al. The structure of haplotype blocks in the human genome.

_Science_ 296, 2225–2229 (2002). AN INFLUENTIAL EXPERIMENTAL STUDY THAT INVESTIGATES THE PRESENCE OF HAPLOTYPE BLOCKS IN DIFFERENT POPULATIONS ACROSS 52 GENOMIC REGIONS. CAS  PubMed  Google

Scholar  * Jeffreys, A. J., Kauppi, L. & Neumann, R. Intensely punctate meiotic recombination in the class II region of the major histocompatibility complex. _Nature Genet._ 29, 217–222

(2001). A BEAUTIFUL EXPERIMENTAL STUDY OF RECOMBINATION HOTSPOTS AND ASSOCIATED PATTERNS OF LD IN A HUMAN POPULATION SAMPLE. CAS  PubMed  Google Scholar  * Clark, A. G. et al. Haplotype

structure and population genetic inferences from nucleotide-sequence variation in human lipoprotein lipase. _Am. J. Hum. Genet._ 63, 595–612 (1998). CAS  PubMed  PubMed Central  Google

Scholar  * Hudson, R. R. Two-locus sampling distributions and their application. _Genetics_ 159, 1805–1817 (2001). THE FIRST STUDY TO ESTIMATE RECOMBINATION RATES USING PAIRWISE

APPROXIMATION TO THE LIKELIHOOD. CAS  PubMed  PubMed Central  Google Scholar  * McVean, G., Awadalla, P. & Fearnhead, P. A coalescent-based method for detecting and estimating

recombination from gene sequences. _Genetics_ 160, 1231–1241 (2002). CAS  PubMed  PubMed Central  Google Scholar  * Li, N. & Stephens, M. A new multilocus model for linkage

disequilibrium, with application to exploring variations in recombination rate. _Genetics_ (in the press). * Fearnhead, P. Consistency of estimators of the population-scaled recombination

rate. _Theor. Popul. Biol._ 64, 67–79 (2003). PubMed  Google Scholar  * Ardlie, K. G., Kruglyak, L. & Seielstad, M. Patterns of linkage disequilibrium in the human genome. _Nature Rev.

Genet._ 3, 299–309 (2002). CAS  PubMed  Google Scholar  * Stumpf, M. P. & Goldstein, D. B. Demography, recombination hotspot intensity, and the block structure of linkage disequilibrium.

_Curr. Biol._ 13, 1–8 (2003). CAS  PubMed  Google Scholar  * Stumpf, M. P. Haplotype diversity and the block structure of linkage disequilibrium. _Trends Genet._ 18, 226–228 (2002). CAS 

PubMed  Google Scholar  * Reich, D. E. et al. Human genome sequence variation and the influence of gene history, mutation and recombination. _Nature Genet._ 32, 135–142 (2002). CAS  PubMed 

Google Scholar  * Frisse, L. et al. Gene conversion and different population histories may explain the contrast between polymorphism and linkage disequilibrium levels. _Am. J. Hum. Genet._

69, 831–843 (2001). CAS  PubMed  PubMed Central  Google Scholar  * Sabeti, P. C. et al. Detecting recent positive selection in the human genome from haplotype structure. _Nature_ 419,

832–837 (2002). CAS  PubMed  Google Scholar  * Przeworski, M. & Wall, J. D. Why is there so little intragenic linkage disequilibrium in humans? _Genet. Res._ 77, 143–151 (2001). CAS 

PubMed  Google Scholar  * Griffiths, R. C. & Tavare, S. Ancestral inference in population-genetics. _Stat. Sci._ 9, 307–319 (1994). Google Scholar  * Smith, J. M., Smith, N. H.,

O'Rourke, M. & Spratt, B. G. How clonal are bacteria? _Proc. Natl Acad. Sci. USA_ 90, 4384–4388 (1993). CAS  PubMed  PubMed Central  Google Scholar  * Smith, J. M. The detection and

measurement of recombination from sequence data. _Genetics_ 153, 1021–1027 (1999). CAS  PubMed  PubMed Central  Google Scholar  * Holmes, E. C. On the origin and evolution of the human

immunodeficiency virus (HIV). _Biol. Rev_ 76, 239–254 (2001). CAS  PubMed  Google Scholar  * Fu, Y. X. Estimating mutation rate and generation time from longitudinal samples of DNA

sequences. _Mol. Biol. Evol._ 18, 620–626 (2001). CAS  PubMed  Google Scholar  * Awadalla, P. The evolutionary genomics of pathogen recombination. _Nature Rev. Genet._ 4, 50–60 (2003). CAS 

PubMed  Google Scholar  * Drummond, A. J., Nicholls, G. K., Rodrigo, A. G. & Solomon, W. Estimating mutation parameters, population history and genealogy simultaneously from temporally

spaced sequence data. _Genetics_ 161, 1307–1320 (2002). CAS  PubMed  PubMed Central  Google Scholar  * Grassly, N. C. & Holmes, E. C. A likelihood method for the detection of selection

and recombination using nucleotide sequences. _Mol. Biol. Evol._ 14, 239–247 (1997). CAS  PubMed  Google Scholar  * Hey, J. & Harris, E. Population bottlenecks and patterns of human

polymorphism. _Mol. Biol. Evol._ 16, 1423–1426 (1999). CAS  PubMed  Google Scholar  * Nordborg, M. & Donnelly, P. The coalescent process with selfing. _Genetics_ 146, 1185–1195 (1997).

CAS  PubMed  PubMed Central  Google Scholar  * Przeworski, M. The signature of positive selection at randomly chosen loci. _Genetics_ 160, 1179–1189 (2002). PubMed  PubMed Central  Google

Scholar  * Posada, D. & Wiuf, C. Simulating haplotype blocks in the human genome. _Bioinformatics_ 19, 289–290 (2003). CAS  PubMed  Google Scholar  * Gillespie, J. H. _Population

Genetics: a Concise Guide_ (Johns Hopkins Univ. Press, Baltimore, 1998). Google Scholar  * Wall, J. D. Recombination and the power of statistical tests of neutrality. _Genet. Res._ 74, 65–79

(1999). Google Scholar  * Brown, C. J., Garner, E. C., Dunker, A. K. & Joyce, P. The power to detect recombination using the coalescent. _Mol. Biol. Evol._ 18, 1421–1424 (2001). CAS 

PubMed  Google Scholar  * Gillespie, J. H. _The Causes of Molecular Evolution_ (Oxford Univ. Press, Oxford, 1991). Google Scholar  * Przeworski, M., Charlesworth, B. & Wall, J. D.

Genealogies and weak purifying selection. _Mol. Biol. Evol._ 16, 246–252 (1999). CAS  PubMed  Google Scholar  * Johnson, G. C. et al. Haplotype tagging for the identification of common

disease genes. _Nature Genet._ 29, 233–237 (2001). THIS PAPER PIONEERED THE CONCEPT OF HAPLOTYPE TAGGING TO DESCRIBE GENETIC VARIATION. CAS  PubMed  Google Scholar  * Wall, J. D. &

Pritchard, J. K. Assessing the performance of haplotype block models of linkage disequilibrium. _Am. J. Hum. Genet._ 73, 502–515 (2003). CAS  PubMed  PubMed Central  Google Scholar  * Wall,

J. D. & Pritchard, J. K. Haplotype blocks and linkage disequilibrium in the human genome. _Nature Rev. Genet._ 4, 587–597 (2003). CAS  PubMed  Google Scholar  * Anderson, E. C. &

Novembre, J. Finding haplotype block boundaries by using the minimum-description-length principle. _Am. J. Hum. Genet._ 73, 336–354 (2003). CAS  PubMed  PubMed Central  Google Scholar  *

Koivisto, M. et al. in _Pac. Symp. Biocomput. 2003_ (eds Altman, R. B., Dukner, A. K., Hunter, L., Jung, T. A. & Klein, T. E.) 502–513 (World Scientific, Singapore, 2002). Google Scholar

  * Liu, J. S. _Monte Carlo Strategies in Scientific Computing_ (Springer, New York, 2003). Google Scholar  * Nielsen, R. Estimation of population parameters and recombination rates from

single nucleotide polymorphisms. _Genetics_ 154, 931–942 (2000). CAS  PubMed  PubMed Central  Google Scholar  * Stephens, M., Smith, N. J. & Donnelly, P. A new statistical method for

haplotype reconstruction from population data. _Am. J. Hum. Genet._ 68, 978–989 (2001). CAS  PubMed  PubMed Central  Google Scholar  * Watterson, G. A. On the number of segregating sites in

genetic models without recombination. _Theor. Popul. Biol._ 7, 256–276 (1975). CAS  PubMed  Google Scholar  Download references ACKNOWLEDGEMENTS We thank A. Jeffreys and P. Donnelly for

useful discussions, and C. Wiuf, M. Slatkin, L. Cardon, G. Coop, C. Spencer and three anonymous referees for their helpful comments on earlier drafts of this manuscript. Generous support

through research fellowships from the Wellcome Trust (to M.P.H.S) and the Royal Society (to G.A.T.M.) is gratefully acknowledged. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Department of

Biological Sciences, Imperial College of Science, Technology and Medicine, London, SW7 2AY, UK Michael P. H. Stumpf * Department of Statistics, University of Oxford, Oxford, OX1 3TG, UK

Gilean A. T. McVean Authors * Michael P. H. Stumpf View author publications You can also search for this author inPubMed Google Scholar * Gilean A. T. McVean View author publications You can

also search for this author inPubMed Google Scholar ETHICS DECLARATIONS COMPETING INTERESTS The authors declare that they have no competing financial interests. RELATED LINKS RELATED LINKS

DATABASES LOCUSLINK _LTA_ _LTB_ FURTHER INFORMATION Michael Stumpf's laboratory Gilean McVean's laboratory _LTA_ and _LTB_ genotypes SHOX genotypes Data of Gabriel _et al_. PHASE

software GLOSSARY * LINKAGE DISEQUILIBRIUM (LD). A measure of genetic associations between alleles at different loci, which indicates whether allelic or marker associations on the same

chromosome are more common than expected. * MARGINAL GENEALOGY The part of a genealogical graph that corresponds to a single locus or stretch of DNA that is inherited without recombination.

* MARKER ASCERTAINMENT The process by which new genetic markers are obtained — for example, by re-sequencing a subset of chromosomes in a population sample. If those markers are

population-specific then inferences that are based on them in other populations might be biased through so-called ascertainment bias. * HAPLOTYPE The combination of alleles or genetic

markers that is found on a single chromosome of a given individual. * INFINITE SITES MUTATION MODEL A model that assumes that there are an infinite number of nucleotide sites and

consequently that each new mutation occurs at a different locus. * FOUR-GAMETE TEST (FGT). If all four possible gametes are observed for two bi-allelic loci then this test infers that a

recombination event must have occurred between them (under an infinite sites mutation model). * PER-GENERATION RECOMBINATION RATE (_r_). The probability of a recombination event occurring

during meiosis. * EFFECTIVE POPULATION SIZE (_N_e). The size of the ideal constant-size population, in which the effects of random drift would be the same as those seen in the actual

population. * POPULATION RECOMBINATION RATE (_ρ_). Population-genetic parameters are generally proportional to the product of a molecular per-generation rate (for example, the per-generation

recombination rate, _r_) and the effective population size (_N_e). The population recombination rate has therefore often been defined as _ρ_ = 4_N_er. * CENSUS POPULATION SIZE Actual

population size (total number of individuals) as compared to the theoretical effective population size. * ESTIMATOR A statistical method that is used to obtain a numerical estimate for a

quantity of interest, such as a model parameter. * SUMMARY STATISTIC A statistical function that summarizes complex data in terms of simple numbers (examples include the mean and variance).

* VARIANCE A statistic that quantifies the dispersion of data about the mean. * LIKELIHOOD SURFACE The likelihood of a parameter is proportional to the probability of obtaining the observed

data under a parametric model given the model parameter. The likelihood surface is a function/curve that specifies how well the data agrees with the predictions made by a parametric model

for different values of the model parameter. * MARKOV CHAIN MONTE CARLO A computational technique for the efficient numerical calculation of likelihoods. * RECURSION A repeated mathematical

operation that is often used to aid numerical analysis. * GENE CONVERSION The non-reciprocal transfer of genetic information between homologous genes as a consequence of mismatch repair

after heteroduplex formation. * PHASING Determining the haplotype phase (the arrangement of alleles at two loci on homologous chromosomes) from genotype data using statistical methods. *

ASSOCIATION STUDIES A set of methods that are used to correlate polymorphisms in genotype to polymorphisms in phenotype in populations. * MODEL MIS-SPECIFICATION The consequence of using a

parametric model in the inference process that is different from the true model under which the data was generated. * CPG ISLANDS Genome sequences of >200 base pairs that have high G+C

content and CpG frequency. * TEMPLATE SWITCHING The process by which RNA templates are switched between viral genomes during reverse transcription. * BOTTLENECK A temporary marked reduction

in population size. * SELECTIVE SWEEP The process by which positive selection for a mutation eliminates neutral variation at linked sites. * HARDY–WEINBERG EQUILIBRIUM A state in which the

frequency of each diploid genotype at a locus equals that expected from the random union of alleles. * HAPLOTYPE-BASED APPROACH An approach to association studies in which the co-inheritance

of phenotypes and haplotypes — as opposed to single markers — is statistically analysed. * TAGGING APPROACH Identifying sub-sets of markers ('tags') that describe patterns of

association or haplotypes among larger marker sets. * MINIMUM-DESCRIPTION LENGTH APPROACHES A concept from information theory, in which all of the information contained in a system (for

example, a sample of DNA sequences) is described in the most compact form possible. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Stumpf, M., McVean,

G. Estimating recombination rates from population-genetic data. _Nat Rev Genet_ 4, 959–968 (2003). https://doi.org/10.1038/nrg1227 Download citation * Issue Date: 01 December 2003 * DOI:

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