Variation in crossover interference levels on individual chromosomes from human males.

Crossovers (COs) generated by homologous recombination ensure the proper segregation of chromosomes during meiosis. COs exhibit interference, which leads to widely spaced COs along chromosomes. Strong positive CO interference has been found in humans. However, little is known about the extent of human CO interference. In this study, variations in CO interference over the entire human genome and among individuals were analyzed by immunofluorescence combined with fluorescence in situ hybridization of testicular biopsies from 10 control men. These methods allow for direct identification of the frequency and location of COs in specific chromosomes of pachytene cells. The strength of CO interference was estimated by fitting the frequency distribution of inter-CO distances to the gamma model. Positive interference among CO on chromosomes was observed in these men, and the strength of inter-arm interference was significantly stronger than that for intra-arm CO. In addition, interference was observed to act across the centromere. Significant inter-individual and inter-chromosomal variations in the levels of interference were found, with smaller chromosomes exhibiting stronger interference. Discontinuous chromosome regions (gaps) and unsynapsed chromosome regions (splits) in chromosome 9 had both cis and trans effects on CO interference levels. This is the first report that the interference level varies significantly across the whole genome and that, at least in the human male, anomalies in chromosome synapsis play an important role in altering CO interference levels.

[1]  S. Keeney,et al.  Crossover Homeostasis in Yeast Meiosis , 2006, Cell.

[2]  Roeder Gs.  Meiotic chromosomes: it takes two to tango , 1997 .

[3]  N. Dillon.  Heterochromatin structure and function , 2004, Biology of the cell.

[4]  N E Morton,et al.  Integration of gene maps: updating chromosome 1 , 1995, Annals of human genetics.

[5]  B. Daneholt,et al.  The central region of the synaptonemal complex revealed in three dimensions. , 1995, Trends in cell biology.

[6]  A. Rademaker,et al.  Variation in MLH1 distribution in recombination maps for individual chromosomes from human males. , 2006, Human molecular genetics.

[7]  R. Hawley,et al.  Chromosome Choreography: The Meiotic Ballet , 2003, Science.

[8]  G. Roeder.  Meiotic chromosomes: it takes two to tango. , 1997, Genes & development.

[9]  D. Kaback,et al.  Chromosome size-dependent control of meiotic reciprocal recombination in Saccharomyces cerevisiae: the role of crossover interference. , 1999, Genetics.

[10]  H. Muller.  The Mechanism of Crossing-Over , 1916, The American Naturalist.

[11]  Hadi Quesneville,et al.  Variation in crossing-over rates across chromosome 4 of Arabidopsis thaliana reveals the presence of meiotic recombination "hot spots". , 2005, Genome research.

[12]  Thomas Liehr,et al.  Human male recombination maps for individual chromosomes. , 2004, American journal of human genetics.

[13]  C. Heyting,et al.  Meiotic interference among MLH1 foci requires neither an intact axial element structure nor full synapsis , 2007, Journal of Cell Science.

[14]  G. Coop,et al.  An evolutionary view of human recombination , 2007, Nature Reviews Genetics.

[15]  G. Copenhaver,et al.  Does Crossover Interference Count in Saccharomyces cerevisiae? , 2004, Genetics.

[16]  A. Rademaker,et al.  The effect of cold storage on recombination frequencies in human male testicular cells , 2004, Cytogenetic and Genome Research.

[17]  A. Reeves.  MicroMeasure: a new computer program for the collection and analysis of cytogenetic data. , 2001, Genome.

[18]  C. Heyting,et al.  Two levels of interference in mouse meiotic recombination. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[19]  N. Morton,et al.  An integrated map of chromosome 9 , 1995, Annals of human genetics.

[20]  L. Anderson,et al.  Distribution of crossing over on mouse synaptonemal complexes using immunofluorescent localization of MLH1 protein. , 1999, Genetics.

[21]  N. Kleckner,et al.  Crossover/Noncrossover Differentiation, Synaptonemal Complex Formation, and Regulatory Surveillance at the Leptotene/Zygotene Transition of Meiosis , 2004, Cell.

[22]  P. Colombo,et al.  Chiasma interference is blind to centromeres1 , 1997, Heredity.

[23]  O. Martin,et al.  Sex-Specific Crossover Distributions and Variations in Interference Level along Arabidopsis thaliana Chromosome 4 , 2007, PLoS genetics.

[24]  R. Chiu,et al.  Innovations: Prenatal diagnosis: progress through plasma nucleic acids , 2007, Nature Reviews Genetics.

[25]  F. Wright,et al.  Genetic crossover interference in the human genome , 2001, Annals of human genetics.

[26]  M. Rocchi,et al.  A new multicolor-FISH approach for the characterization of marker chromosomes: centromere-specific multicolor-FISH (cenM-FISH) , 2001, Human Genetics.

[27]  T P Speed,et al.  Modeling interference in genetic recombination. , 1995, Genetics.

[28]  V. Guacci,et al.  Chromosome size-dependent control of meiotic recombination. , 1992, Science.

[29]  E. Foss,et al.  Chiasma interference as a function of genetic distance. , 1993, Genetics.

[30]  C. Heyting,et al.  The Mismatch Repair Protein MLH1 Marks a Subset of Strongly Interfering Crossovers in Tomato[W][OA] , 2007, The Plant Cell Online.

[31]  A. Rademaker,et al.  Microwave decondensation and codenaturation: a new methodology to maximize FISH data from donors with very low concentrations of sperm , 2002, Cytogenetic and Genome Research.

[32]  J. Egozcue,et al.  Synapsis and meiotic recombination analyses: MLH1 focus in the XY pair as an indicator. , 2005, Human reproduction.

[33]  J. Weber,et al.  Characterization of human crossover interference. , 2000, American journal of human genetics.

[34]  K. Hillers,et al.  Crossover interference , 2004, Current Biology.

[35]  Nancy Kleckner,et al.  A mechanical basis for chromosome function. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[36]  A. Rademaker,et al.  Variation in meiotic recombination frequencies among human males , 2005, Human Genetics.

[37]  N. Kleckner,et al.  Coordinate variation in meiotic pachytene SC length and total crossover/chiasma frequency under conditions of constant DNA length. , 2003, Trends in genetics : TIG.

[38]  M. Speicher,et al.  Crossover frequency and synaptonemal complex length: their variability and effects on human male meiosis. , 2006, Molecular human reproduction.

[39]  G. Roeder,et al.  Tam1, a telomere-associated meiotic protein, functions in chromosome synapsis and crossover interference. , 1997, Genes & development.

[40]  Thomas Liehr,et al.  Discontinuities and unsynapsed regions in meiotic chromosomes have a cis effect on meiotic recombination patterns in normal human males. , 2005, Human molecular genetics.

[41]  K. Lange,et al.  Multipoint linkage map of the human pseudoautosomal region, based on single-sperm typing: do double crossovers occur during male meiosis? , 1994, American journal of human genetics.

[42]  G. Roeder,et al.  Crossover interference is abolished in the absence of a synaptonemal complex protein , 1994, Cell.

[43]  T. Liehr,et al.  Karyotyping of human synaptonemal complexes by cenM-FISH , 2003, European Journal of Human Genetics.

[44]  T. Prolla,et al.  Involvement of mouse Mlh1 in DNA mismatch repair and meiotic crossing over , 1996, Nature Genetics.