Skip to main content
SpringerLink
Log in

Factors affecting ectopic gene conversion in mice

  • Original Contributions
  • Published:
Mammalian Genome Aims and scope Submit manuscript

Abstract

Duplicated genes and repetitive sequences are distributed throughout the genomes of complex organisms. The homology between related sequences can promote nonallelic (ectopic) recombination, including gene conversion and reciprocal exchange. Resolution of these events can result in translocations, deletions, or other harmful rearrangements. In yeast, ectopic recombination between sequences on nonhomologous chromosomes occurs at high frequency. Because the mammalian genome is replete with duplicated sequences and repetitive elements, high levels of ectopic exchange would cause aneuploidy and genome instability. To understand the factors regulating ectopic recombination in mice, we evaluated the effects of homology length on gene conversion between unlinked sequences in the male germline. Previously, we found high levels of gene conversion between lacZ transgenes containing 2557 bp of homology. We report here that genetic background can play a major role in ectopic recombination; frequency of gene conversion was reduced by more than an order of magnitude by transferring the transgenes from a CF1 strain background to C57BL/6J. Additionally, conversion rates decreased as the homology length decreased. Sequences sharing 1214 bp of sequence identity underwent ectopic conversion less frequently than a pair sharing 2557 bp of identity, while 624 bp was insufficient to catalyze gene conversion at significant levels. These results suggest that the germline recombination machinery in mammals has evolved in a way that prevents high levels of ectopic recombination between smaller classes of repetitive sequences, such as the Alu family. Additionally, genomic location appeared to influence the availability of sequences for ectopic recombination.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Alani E, Padmore R, Kleckner N (1990) Analysis of wild-type and rad50 mutants of yeast suggests an intimate relationship between meiotic chromosome synapsis and recombination. Cell 61, 419–436

    Article  PubMed  CAS  Google Scholar 

  • Baker MD, Read LR, Beatty BG, Ng P (1996) Requirements for ectopic homologous recombination in mammalian somatic cells. Mol Cell Biol 16, 7122–7132

    PubMed  CAS  Google Scholar 

  • Carpenter A (1987) Gene conversion, recombination nodules, and the initiation of meiotic synapsis. Bio Essays 6, 232–236

    CAS  Google Scholar 

  • Casavant NC, Hardies SC (1994a) The dynamics of murine LINE-1 subfamily amplification. J Mol Biol 241, 390–397

    Article  PubMed  CAS  Google Scholar 

  • Casavant NC, Hardies SC (1994b) Shared sequence variants of Mus spretus LINE-1 elements tracing dispersal to within the last 1 million years. Genetics 137, 565–572

    PubMed  CAS  Google Scholar 

  • de Wind N, Dekker M, Berns A, Radman M, te Riele H (1995) Inactivation of the mouse Msh2 gene results in mismatch repair deficiency, methylation tolerance, hyperrecombination, and predisposition to cancer. Cell 82, 321–330

    Article  PubMed  Google Scholar 

  • Deininger P, Batzer M, Hutchinson C, Edgell M (1992) Master genes in mammalian repetitive DNA amplification. Trends Genet 8, 307–311

    PubMed  CAS  Google Scholar 

  • Eikenboom J, Vink T, Briet E, Sixma J, Reitsma P (1994) Multiple substitutions in the von Willebrand factor gene that mimic the pseudogene sequence. Proc Natl Acad Sci USA 91, 2221–2224

    Article  PubMed  CAS  Google Scholar 

  • Engebrecht J, Hirsh J, Roeder G (1990) Meiotic gene conversion and crossing over: their relationship to each other and to chromosome synapsis and segregation. Cell 62, 927–937

    Article  PubMed  CAS  Google Scholar 

  • Engels W, Preston C, Johnson-Schlitz D (1994) Long-range preference in DNA homology search over the length of a Drosophila chromosome. Science 263, 1623–1625

    Article  PubMed  CAS  Google Scholar 

  • Gilman J (1987) The 12.6 kilobase deletion in Dutch beta-thallassemia. Br J Haematol 67, 369–372

    Article  PubMed  CAS  Google Scholar 

  • Haber J, Leung W-Y, Borts R, Lichten M (1991) The frequency of meiotic recombination in yeast is independent of the number and position of homologous donor sequences: Implications for chromosome pairing. Proc Natl Acad Sci USA 88, 1120–1124

    Article  PubMed  CAS  Google Scholar 

  • Hanneman WH, Schimenti KJ, Schimenti JC (1997) Molecular analysis of gene conversion in spermatids from transgenic mice. Gene 200, 185–192

    Article  PubMed  CAS  Google Scholar 

  • Hogstrand K, Bohme J (1994) A determination of the frequency of gene conversion in unmanipulated mouse sperm. Proc Natl Acad Sci USA 91, 9921–9925

    Article  PubMed  CAS  Google Scholar 

  • Jinks-Robertson S, Petes TD (1985) High-frequency meiotic gene conversion between repeated genes on non-homologous chromosomes in yeast. Proc Natl Acad Sci USA 82, 3350–3354

    Article  PubMed  CAS  Google Scholar 

  • Jinks-Robertson S, Petes TD (1986) Chromosomal translocations generated by high-frequency meiotic recombination between repeated yeast genes. Genetics 114, 731–752

    PubMed  CAS  Google Scholar 

  • Jurka J, Milosavljevic A (1991) Reconstruction and analysis of human Alu genes. J Mol Evol 32, 105–121

    Article  PubMed  CAS  Google Scholar 

  • Kass D, Batzer M, Deininger P (1995) Gene conversion as a secondary mechanism of short interspersed element (SINE) evolution. Mol Cell Biol 15, 19–25

    PubMed  CAS  Google Scholar 

  • Klein HL, Petes TD (1981) Intrachromosomal gene conversion in yeast. Nature 289, 144–148

    Article  PubMed  CAS  Google Scholar 

  • Kricker MC, Drake JW, Radman M (1992) Duplication-targeted DNA methylation and mutagenesis in the evolution of eukaryotic chromosomes. Proc Natl Acad Sci USA 89, 1075–1079

    Article  PubMed  CAS  Google Scholar 

  • Kvaloy K, Galvagni F, Brown WR (1994) The sequence organization of the long arm pseudoautosomal region of the human sex chromosomes. Hum Mol Genet 3, 771–778

    Article  PubMed  CAS  Google Scholar 

  • Lehrman MA, Schneider WJ, Sudhof TC, Brown MS, Goldstein JL, Russell DW (1985) Mutation in LDL receptor: Alu-Alu recombination deletes exons encoding transmembrane and cytoplasmic domains. Science 227, 140–146

    Article  PubMed  CAS  Google Scholar 

  • Lichten M, Borts RH, Haber JE (1987) Meiotic gene conversion and crossing-over between dispersed homologous sequences in Saccharomyces cerevisiae. Genetics 115, 233–246

    PubMed  CAS  Google Scholar 

  • Liskay RM, Letsou A, Stachelek JL (1987) Homology requirement for efficient gene conversion between duplicated chromosomal sequences in mammalian cells. Genetics 115, 161–167

    PubMed  CAS  Google Scholar 

  • Marcus S, Hellgren D, Lambert B, Fallstrom S, Wahlstrom J (1993) Duplication in the hypoxanthine phosphoribosyl-transferase gene caused by Alu-Alu recombination in a patient with Lesch-Nyhan syndrome. Hum Genet 90, 477–482

    Article  PubMed  CAS  Google Scholar 

  • McKee BD, Handel MA (1993) Sex chromosomes, recombination, and chromatin conformation. Chromosoma 102, 71–80

    Article  PubMed  CAS  Google Scholar 

  • Murti JR, Schimenti JC (1991) Microwave-accelerated fixation and lacZ activity staining of testicular cells in transgenic mice. Anal Biochem 198, 92–96

    Article  PubMed  CAS  Google Scholar 

  • Murti JR, Bumbulis M, Schimenti J (1992) High frequency germline gene conversion in transgenic mice. Mol Cell Biol 12, 2545–2552

    PubMed  CAS  Google Scholar 

  • Murti JR, Bumbulis M, Schimenti JC (1994a) Gene conversion between unlinked sequences in the germline of mice. Genetics 137, 837–843

    PubMed  CAS  Google Scholar 

  • Murti JR, Schimenti KJ, Schimenti JC (1994b) A recombination-based transgenic mouse system for genotoxicity testing. Mutat Res 307, 583–595

    PubMed  CAS  Google Scholar 

  • Myerowitz R, Hogikyan N (1987) A deletion involving Alu sequences in the β-hexaminase alpha-chain gene of French Canadians with Tay-Sachs disease. J Biol Chem 262, 15396–15399

    PubMed  CAS  Google Scholar 

  • Petes TD, Hill CW (1988) Recombination between repeated genes in microorganisms. Annu Rev Genet 22, 147–168

    Article  PubMed  CAS  Google Scholar 

  • Reinhart F, Ritch T, Deininger P, Schmid C (1981) Renaturation rate studies of a single family of interspersed repeated DNA sequences in human deoxyribonucleic acid. Biochemistry 20, 3003–3010

    Article  Google Scholar 

  • Rouyer F, Simmler M, Page D, Weissenbach J (1987) A sex chromosome rearrangement in a human XX male caused by Alu-Alu recombination. Cell 51, 417–425

    Article  PubMed  CAS  Google Scholar 

  • Rubnitz J, Subramani S (1984) The minimum amount of homology required for homologous recombination in mammalian cells. Mol Cell Biol 4, 2253–2258

    PubMed  CAS  Google Scholar 

  • Rubnitz J, Subramani S (1986) Extrachromosomal and chromosomal gene conversion in mammalian cells. Mol Cell Biol 6, 1608–1614

    PubMed  CAS  Google Scholar 

  • Slagel V, Flemington V, Traina-Dorge H, Bradshaw H, Deininger P (1987) Clustering and subfamily relationships of the Alu family in the human genome. Mol Biol Evol, 4, 19–29

    PubMed  CAS  Google Scholar 

  • Smithies O, Powers PA (1986) Gene conversions and their relation to homologous chromosome pairing. Philos Trans R Soc Lond B Biol Sci 312, 291–302

    Article  PubMed  CAS  Google Scholar 

  • Stallings R, Doggett N, Okumura K, Matera A, Ward D, 1993 Are repetitive DNA sequences involved with leukemia chromosome breakpoints? In Genome Rearrangement and Stability, K. Davies, S. Warren, eds. (Cold Spring Harbor, N. Y.: Cold Spring Harbor Laboratory Press) pp 59–78

    Google Scholar 

  • Sugawara N, Szostak JW (1983) Recombination between sequences in nonhomologous positions. Proc Natl Acad Sci USA 80, 5675–5679

    Article  PubMed  CAS  Google Scholar 

  • teRiele H, Maandag E, Berns A (1992) Highly efficient gene targeting in embryonic stem cells through homologous recombination with isogenic DNA constructs. Proc Natl Acad Sci USA 89, 5128–5132

    Article  Google Scholar 

  • Vnencak Jones CL, Phillips JAd, Chen EY, Seeburg PH (1988) Molecular basis of human growth hormone gene deletions. Proc Natl Acad Sci USA 85, 5615–5619

    Article  Google Scholar 

  • Waldman AS, Liskay RM (1988) Dependence of intrachromosomal gene conversion in mammalian cells on uninterrupted homology. Mol Cell Biol 8, 5350–5357

    PubMed  CAS  Google Scholar 

  • Zangenberg G, Huang MM, Arnheim N, Erlich H (1995) New HLA-DPB1 alleles generated by interallelic gene conversion detected by analysis of sperm. Nat Genet 10, 407–414

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. The Jackson Laboratory, Bar Harbor, 04609, Maine, USA

    Deoborah M. Cooper, Kerry J. Schimenti & John C. Schimenti

Authors
  1. Deoborah M. Cooper
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kerry J. Schimenti
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. John C. Schimenti
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cooper, D.M., Schimenti, K.J. & Schimenti, J.C. Factors affecting ectopic gene conversion in mice. Mammalian Genome 9, 355–360 (1998). https://doi.org/10.1007/s003359900769

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s003359900769

Keywords

Search

Navigation