Estimating Meiotic Gene Conversion Rates From Population Genetic Data

Gene conversion plays an important part in shaping genetic diversity in populations, yet estimating the rate at which it occurs is difficult because of the short lengths of DNA involved. We have developed a new statistical approach to estimating gene conversion rates from genetic variation, by extending an existing model for haplotype data in the presence of crossover events. We show, by simulation, that when the rate of gene conversion events is at least comparable to the rate of crossover events, the method provides a powerful approach to the detection of gene conversion and estimation of its rate. Application of the method to data from the telomeric X chromosome of Drosophila melanogaster, in which crossover activity is suppressed, indicates that gene conversion occurs ∼400 times more often than crossover events. We also extend the method to estimating variable crossover and gene conversion rates and estimate the rate of gene conversion to be ∼1.5 times higher than the crossover rate in a region of human chromosome 1 with known recombination hotspots.

[1]  A. Jeffreys,et al.  Intense and highly localized gene conversion activity in human meiotic crossover hot spots , 2004, Nature Genetics.

[2]  J. Pritchard,et al.  Linkage disequilibrium in humans: models and data. , 2001, American journal of human genetics.

[3]  M. Nei,et al.  Concerted and birth-and-death evolution of multigene families. , 2005, Annual review of genetics.

[4]  G Harauz,et al.  Meiotic gene conversion tract length distribution within the rosy locus of Drosophila melanogaster. , 1994, Genetics.

[5]  Paul Marjoram,et al.  Estimating Recombination Rates From Single-Nucleotide Polymorphisms Using Summary Statistics , 2006, Genetics.

[6]  G. A. Watterson.  On the number of segregating sites in genetical models without recombination. , 1975, Theoretical population biology.

[7]  Nigel French,et al.  Analysis of Recombination in Campylobacterjejuni from MLST Population Data , 2005, Journal of Molecular Evolution.

[8]  K. McKim,et al.  Meiotic recombination and chromosome segregation in Drosophila females. , 2002, Annual review of genetics.

[9]  J. Hein,et al.  Consequences of recombination on traditional phylogenetic analysis. , 2000, Genetics.

[10]  R. Fridell,et al.  Evidence for a role of the Drosophila melanogaster suppressor of sable gene in the pre-mRNA splicing pathway , 1994, Molecular and Cellular Biology.

[11]  J. Hein,et al.  The coalescent with gene conversion. , 2000, Genetics.

[12]  J. Wall,et al.  Why is there so little intragenic linkage disequilibrium in humans? , 2001, Genetical research.

[13]  B. Golding.  Non-Neutral Evolution: Theories And Molecular Data , 1994 .

[14]  J. Nickoloff,et al.  Gene conversion tracts in Saccharomyces cerevisiae can be extremely short and highly directional. , 2003, Nucleic acids research.

[15]  Robert Hooke,et al.  `` Direct Search'' Solution of Numerical and Statistical Problems , 1961, JACM.

[16]  Nicholas J Schork,et al.  Power calculations for genetic association studies using estimated probability distributions. , 2002, American journal of human genetics.

[17]  R. Hudson.  Two-locus sampling distributions and their application. , 2001, Genetics.

[18]  M. Aguadé,et al.  Polymorphism and Divergence in Regions of Low Recombination in Drosophila , 1994 .

[19]  Molly Przeworski,et al.  Insights into recombination from patterns of linkage disequilibrium in humans. , 2002, Genetics.

[20]  Garrett Hellenthal,et al.  msHOT: modifying Hudson's ms simulator to incorporate crossover and gene conversion hotspots , 2007, Bioinform..

[21]  R. Hudson.  Properties of a neutral allele model with intragenic recombination. , 1983, Theoretical population biology.

[22]  G. McVean,et al.  Estimating recombination rates from population-genetic data , 2003, Nature Reviews Genetics.

[23]  M. Stephens,et al.  Modeling linkage disequilibrium and identifying recombination hotspots using single-nucleotide polymorphism data. , 2003, Genetics.

[24]  P. Donnelly,et al.  A new statistical method for haplotype reconstruction from population data. , 2001, American journal of human genetics.

[25]  M. Nordborg,et al.  The effect of gene conversion on intralocus associations. , 1998, Genetics.

[26]  Peter Donnelly,et al.  Human recombination hot spots hidden in regions of strong marker association , 2005, Nature Genetics.

[27]  Matthew Stephens,et al.  Insights into recombination from population genetic variation. , 2006, Current opinion in genetics & development.

[28]  Jeffrey D. Wall,et al.  Estimating Recombination Rates Using Three-Site Likelihoods , 2004, Genetics.

[29]  K. T. Nishant,et al.  Characterization of a Mouse Recombination Hot Spot Locus Encoding a Novel Non-Protein-Coding RNA , 2004, Molecular and Cellular Biology.

[30]  F. Stahl,et al.  The Holliday junction on its thirtieth anniversary. , 1994, Genetics.

[31]  M Slatkin,et al.  Distinguishing recombination and intragenic gene conversion by linkage disequilibrium patterns. , 2000, Genetical research.

[32]  A. Auton,et al.  Recombination rate estimation in the presence of hotspots. , 2007, Genome research.

[33]  D. Gudbjartsson,et al.  A high-resolution recombination map of the human genome , 2002, Nature Genetics.

[34]  J. Haber,et al.  Length and distribution of meiotic gene conversion tracts and crossovers in Saccharomyces cerevisiae. , 1989, Genetics.

[35]  P. Fearnhead,et al.  A coalescent-based method for detecting and estimating recombination from gene sequences. , 2002, Genetics.

[36]  Graham Coop,et al.  SelSim: a program to simulate population genetic data with natural selection and recombination , 2004, Bioinform..

[37]  J. Wall,et al.  Gene conversion and different population histories may explain the contrast between polymorphism and linkage disequilibrium levels. , 2001, American journal of human genetics.

[38]  P. Fearnhead,et al.  A Comparison of Three Estimators of the Population-Scaled Recombination Rate: Accuracy and Robustness , 2005, Genetics.

[39]  M. Nachman,et al.  Variation in recombination rate across the genome: evidence and implications. , 2002, Current opinion in genetics & development.

[40]  Richard R. Hudson,et al.  Generating samples under a Wright-Fisher neutral model of genetic variation , 2002, Bioinform..

[41]  P. Donnelly,et al.  The Fine-Scale Structure of Recombination Rate Variation in the Human Genome , 2004, Science.

[42]  S. Elgin,et al.  The fourth chromosome of Drosophila melanogaster: interspersed euchromatic and heterochromatic domains. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[43]  J. Braverman,et al.  Linkage disequilibria and the site frequency spectra in the su(s) and su(w(a)) regions of the Drosophila melanogaster X chromosome. , 2000, Genetics.

[44]  Jack W. Szostak,et al.  The double-strand-break repair model for recombination , 1983, Cell.

[45]  M. Stephens,et al.  Accounting for Decay of Linkage Disequilibrium in Haplotype Inference and Missing-data Imputation , 2022 .