Skip to main content
PMC home page
Journal of Medical Genetics logoLink to Journal of Medical Genetics
. 1989 Sep;26(9):546–552. doi: 10.1136/jmg.26.9.546

Asymmetry in chromosome pairing: a major factor in de novo mutation and the production of genetic disease in man.

A C Chandley 1
PMCID: PMC1015692  PMID: 2681783

Abstract

At the outset of the meiotic pairing process in man, trial and error mismatching and misalignment, both within homologous pairs and between heterologues, can be observed cytologically. Pairing starts at early zygotene principally within subtelomeric regions where the synaptonemal complex initiates. In the present paper, evidence for the primary role in synaptic initiation of a GC rich minisatellite in the human XY pseudoautosomal segment is presented, and circumstantial evidence is provided to support the view that GC rich sequences (minisatellites and Alu repeats) function to promote pairing within autosomes. The known sequence hypervariability of proterminal human minisatellites, it is suggested, arises as a secondary consequence of unequal exchange after misalignment between tandem repeats at the outset of the pairing process. Unequal exchange within misaligned repeat sequences at early prophase of meiosis could make a major contribution to de novo germinal mutation (conversion, duplication, deficiency, inversion, translocation), with serious consequences in man for the production of hereditary disease. For somatic tissues, rare mispairing between G rich repeats followed by unequal exchange could be a key step in cancer progression. It might also explain somatic mosaicism in some non-neoplastic clinical conditions.

Full text

PDF
546

Images in this article

547Image
on p.547
548Image
on p.548

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Armour J. A., Patel I., Thein S. L., Fey M. F., Jeffreys A. J. Analysis of somatic mutations at human minisatellite loci in tumors and cell lines. Genomics. 1989 Apr;4(3):328–334. doi: 10.1016/0888-7543(89)90338-8. [DOI] [PubMed] [Google Scholar]
  2. Bodrug S. E., Ray P. N., Gonzalez I. L., Schmickel R. D., Sylvester J. E., Worton R. G. Molecular analysis of a constitutional X-autosome translocation in a female with muscular dystrophy. Science. 1987 Sep 25;237(4822):1620–1624. doi: 10.1126/science.3629260. [DOI] [PubMed] [Google Scholar]
  3. Carpenter A. T. Electron microscopy of meiosis in Drosophila melanogaster females. I. Structure, arrangement, and temporal change of the synaptonemal complex in wild-type. Chromosoma. 1975;51(2):157–182. doi: 10.1007/BF00319833. [DOI] [PubMed] [Google Scholar]
  4. Carpenter A. T. Gene conversion, recombination nodules, and the initiation of meiotic synapsis. Bioessays. 1987 May;6(5):232–236. doi: 10.1002/bies.950060510. [DOI] [PubMed] [Google Scholar]
  5. Chandley A. C., Goetz P., Hargreave T. B., Joseph A. M., Speed R. M. On the nature and extent of XY pairing at meiotic prophase in man. Cytogenet Cell Genet. 1984;38(4):241–247. doi: 10.1159/000132070. [DOI] [PubMed] [Google Scholar]
  6. Chandley A. C., Speed R. M., McBeath S., Hargreave T. B. A human 9;20 reciprocal translocation associated with male infertility analyzed at prophase and metaphase I of meiosis. Cytogenet Cell Genet. 1986;41(3):145–153. doi: 10.1159/000132219. [DOI] [PubMed] [Google Scholar]
  7. Cooke H. J., Brown W. R., Rappold G. A. Hypervariable telomeric sequences from the human sex chromosomes are pseudoautosomal. Nature. 1985 Oct 24;317(6039):687–692. doi: 10.1038/317687a0. [DOI] [PubMed] [Google Scholar]
  8. Cooke H. J., Smith B. A. Variability at the telomeres of the human X/Y pseudoautosomal region. Cold Spring Harb Symp Quant Biol. 1986;51(Pt 1):213–219. doi: 10.1101/sqb.1986.051.01.026. [DOI] [PubMed] [Google Scholar]
  9. Doolittle W. F., Sapienza C. Selfish genes, the phenotype paradigm and genome evolution. Nature. 1980 Apr 17;284(5757):601–603. doi: 10.1038/284601a0. [DOI] [PubMed] [Google Scholar]
  10. Gabriel-Robez O., Jaafar H., Ratomponirina C., Boscher J., Bonneau J., Popescu C. P., Rumpler Y. Heterosynapsis in a heterozygous fertile boar carrier of a 3;7 translocation. Chromosoma. 1988;97(1):26–32. doi: 10.1007/BF00331792. [DOI] [PubMed] [Google Scholar]
  11. Gerondakis S., Cory S., Adams J. M. Translocation of the myc cellular oncogene to the immunoglobulin heavy chain locus in murine plasmacytomas is an imprecise reciprocal exchange. Cell. 1984 Apr;36(4):973–982. doi: 10.1016/0092-8674(84)90047-3. [DOI] [PubMed] [Google Scholar]
  12. Goldberg M. L., Sheen J. Y., Gehring W. J., Green M. M. Unequal crossing-over associated with asymmetrical synapsis between nomadic elements in the Drosophila melanogaster genome. Proc Natl Acad Sci U S A. 1983 Aug;80(16):5017–5021. doi: 10.1073/pnas.80.16.5017. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Hall J. G. Review and hypotheses: somatic mosaicism: observations related to clinical genetics. Am J Hum Genet. 1988 Oct;43(4):355–363. [PMC free article] [PubMed] [Google Scholar]
  14. Holliday R. Recombination and meiosis. Philos Trans R Soc Lond B Biol Sci. 1977 Mar 21;277(955):359–370. doi: 10.1098/rstb.1977.0024. [DOI] [PubMed] [Google Scholar]
  15. Holmquist G. P. Role of replication time in the control of tissue-specific gene expression. Am J Hum Genet. 1987 Feb;40(2):151–173. [PMC free article] [PubMed] [Google Scholar]
  16. Hultén M. Chiasma distribution at diakinesis in the normal human male. Hereditas. 1974;76(1):55–78. doi: 10.1111/j.1601-5223.1974.tb01177.x. [DOI] [PubMed] [Google Scholar]
  17. Jacobs P. A. Correlation between euploid structural chromosome rearrangements and mental subnormality in humans. Nature. 1974 May 10;249(453):164–165. doi: 10.1038/249164a0. [DOI] [PubMed] [Google Scholar]
  18. Jarman A. P., Higgs D. R. A new hypervariable marker for the human alpha-globin gene cluster. Am J Hum Genet. 1988 Sep;43(3):249–256. [PMC free article] [PubMed] [Google Scholar]
  19. Jeffreys A. J., Morton D. B. DNA fingerprints of dogs and cats. Anim Genet. 1987;18(1):1–15. doi: 10.1111/j.1365-2052.1987.tb00739.x. [DOI] [PubMed] [Google Scholar]
  20. Jeffreys A. J., Royle N. J., Wilson V., Wong Z. Spontaneous mutation rates to new length alleles at tandem-repetitive hypervariable loci in human DNA. Nature. 1988 Mar 17;332(6161):278–281. doi: 10.1038/332278a0. [DOI] [PubMed] [Google Scholar]
  21. Jeffreys A. J., Wilson V., Thein S. L. Hypervariable 'minisatellite' regions in human DNA. Nature. 1985 Mar 7;314(6006):67–73. doi: 10.1038/314067a0. [DOI] [PubMed] [Google Scholar]
  22. Knudson A. G., Jr Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci U S A. 1971 Apr;68(4):820–823. doi: 10.1073/pnas.68.4.820. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Korenberg J. R., Rykowski M. C. Human genome organization: Alu, lines, and the molecular structure of metaphase chromosome bands. Cell. 1988 May 6;53(3):391–400. doi: 10.1016/0092-8674(88)90159-6. [DOI] [PubMed] [Google Scholar]
  24. Lehrman M. A., Goldstein J. L., Russell D. W., Brown M. S. Duplication of seven exons in LDL receptor gene caused by Alu-Alu recombination in a subject with familial hypercholesterolemia. Cell. 1987 Mar 13;48(5):827–835. doi: 10.1016/0092-8674(87)90079-1. [DOI] [PubMed] [Google Scholar]
  25. Luciani J. M., Guichaoua M. R., Cau P., Devictor B., Salagnon N. Differential elongation of autosomal pachytene bivalents related to their DNA content in human spermatocytes. Chromosoma. 1988;97(1):19–25. doi: 10.1007/BF00331791. [DOI] [PubMed] [Google Scholar]
  26. Maizels N. Might gene conversion be the mechanism of somatic hypermutation of mammalian immunoglobulin genes? Trends Genet. 1989 Jan;5(1):4–8. doi: 10.1016/0168-9525(89)90004-8. [DOI] [PubMed] [Google Scholar]
  27. Nakamura Y., Leppert M., O'Connell P., Wolff R., Holm T., Culver M., Martin C., Fujimoto E., Hoff M., Kumlin E. Variable number of tandem repeat (VNTR) markers for human gene mapping. Science. 1987 Mar 27;235(4796):1616–1622. doi: 10.1126/science.3029872. [DOI] [PubMed] [Google Scholar]
  28. Nicholls R. D., Fischel-Ghodsian N., Higgs D. R. Recombination at the human alpha-globin gene cluster: sequence features and topological constraints. Cell. 1987 May 8;49(3):369–378. doi: 10.1016/0092-8674(87)90289-3. [DOI] [PubMed] [Google Scholar]
  29. Nussbaum R. L., Ledbetter D. H. Fragile X syndrome: a unique mutation in man. Annu Rev Genet. 1986;20:109–145. doi: 10.1146/annurev.ge.20.120186.000545. [DOI] [PubMed] [Google Scholar]
  30. Oberlé I., Drayna D., Camerino G., White R., Mandel J. L. The telomeric region of the human X chromosome long arm: presence of a highly polymorphic DNA marker and analysis of recombination frequency. Proc Natl Acad Sci U S A. 1985 May;82(9):2824–2828. doi: 10.1073/pnas.82.9.2824. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Pembrey M. E., Winter R. M., Davies K. E. A premutation that generates a defect at crossing over explains the inheritance of fragile X mental retardation. Am J Med Genet. 1985 Aug;21(4):709–717. doi: 10.1002/ajmg.1320210413. [DOI] [PubMed] [Google Scholar]
  32. Roberts P. A. Screening for x-ray-induced crossover suppressors in Drosophila melanogaster: prevalence and effectiveness of translocations. Genetics. 1970 Jul;65(3):429–448. doi: 10.1093/genetics/65.3.429. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Rogstad S. H., Patton J. C., 2nd, Schaal B. A. M13 repeat probe detects DNA minisatellite-like sequences in gymnosperms and angiosperms. Proc Natl Acad Sci U S A. 1988 Dec;85(23):9176–9178. doi: 10.1073/pnas.85.23.9176. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Rouyer F., Simmler M. C., Johnsson C., Vergnaud G., Cooke H. J., Weissenbach J. A gradient of sex linkage in the pseudoautosomal region of the human sex chromosomes. Nature. 1986 Jan 23;319(6051):291–295. doi: 10.1038/319291a0. [DOI] [PubMed] [Google Scholar]
  35. Rouyer F., Simmler M. C., Page D. C., Weissenbach J. A sex chromosome rearrangement in a human XX male caused by Alu-Alu recombination. Cell. 1987 Nov 6;51(3):417–425. doi: 10.1016/0092-8674(87)90637-4. [DOI] [PubMed] [Google Scholar]
  36. Royle N. J., Clarkson R. E., Wong Z., Jeffreys A. J. Clustering of hypervariable minisatellites in the proterminal regions of human autosomes. Genomics. 1988 Nov;3(4):352–360. doi: 10.1016/0888-7543(88)90127-9. [DOI] [PubMed] [Google Scholar]
  37. Sen D., Gilbert W. Formation of parallel four-stranded complexes by guanine-rich motifs in DNA and its implications for meiosis. Nature. 1988 Jul 28;334(6180):364–366. doi: 10.1038/334364a0. [DOI] [PubMed] [Google Scholar]
  38. Simmler M. C., Johnsson C., Petit C., Rouyer F., Vergnaud G., Weissenbach J. Two highly polymorphic minisatellites from the pseudoautosomal region of the human sex chromosomes. EMBO J. 1987 Apr;6(4):963–969. doi: 10.1002/j.1460-2075.1987.tb04846.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Singer M. F. Highly repeated sequences in mammalian genomes. Int Rev Cytol. 1982;76:67–112. doi: 10.1016/s0074-7696(08)61789-1. [DOI] [PubMed] [Google Scholar]
  40. Siniscalco M. Genetic recombination and disease. Cold Spring Harb Symp Quant Biol. 1986;51(Pt 1):191–194. doi: 10.1101/sqb.1986.051.01.023. [DOI] [PubMed] [Google Scholar]
  41. Smith G. P. Evolution of repeated DNA sequences by unequal crossover. Science. 1976 Feb 13;191(4227):528–535. doi: 10.1126/science.1251186. [DOI] [PubMed] [Google Scholar]
  42. Smithies O., Powers P. A. Gene conversions and their relation to homologous chromosome pairing. Philos Trans R Soc Lond B Biol Sci. 1986 Jan 29;312(1154):291–302. doi: 10.1098/rstb.1986.0008. [DOI] [PubMed] [Google Scholar]
  43. Speed R. M. The possible role of meiotic pairing anomalies in the atresia of human fetal oocytes. Hum Genet. 1988 Mar;78(3):260–266. doi: 10.1007/BF00291673. [DOI] [PubMed] [Google Scholar]
  44. Stern H., Hotta Y. Biochemistry of meiosis. Philos Trans R Soc Lond B Biol Sci. 1977 Mar 21;277(955):277–294. doi: 10.1098/rstb.1977.0018. [DOI] [PubMed] [Google Scholar]
  45. Sturtevant A H. The Effects of Unequal Crossing over at the Bar Locus in Drosophila. Genetics. 1925 Mar;10(2):117–147. doi: 10.1093/genetics/10.2.117. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Tartof K. D. Unequal crossing over then and now. Genetics. 1988 Sep;120(1):1–6. doi: 10.1093/genetics/120.1.1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Yunis J. J. The chromosomal basis of human neoplasia. Science. 1983 Jul 15;221(4607):227–236. doi: 10.1126/science.6336310. [DOI] [PubMed] [Google Scholar]
  48. de Klein A., van Agthoven T., Groffen C., Heisterkamp N., Groffen J., Grosveld G. Molecular analysis of both translocation products of a Philadelphia-positive CML patient. Nucleic Acids Res. 1986 Sep 11;14(17):7071–7082. doi: 10.1093/nar/14.17.7071. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. von Wettstein D., Rasmussen S. W., Holm P. B. The synaptonemal complex in genetic segregation. Annu Rev Genet. 1984;18:331–413. doi: 10.1146/annurev.ge.18.120184.001555. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Medical Genetics are provided here courtesy of BMJ Publishing Group

RESOURCES