High-frequency germ line gene conversion in transgenic mice.

Murti, J R; Bumbulis, M; Schimenti, John C.

doi:10.1128/mcb.12.6.2545

Cited by 52 publications

(39 citation statements)

References 40 publications

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“…Gene conversion events also appeared to occur at multiple developmental stages, in both mitotic and meiotic cells, with the overall contribution to variation in sperm genotypes being potentially much greater for mitotic events. Notably, one other study of gene conversion in the mouse germ line has been undertaken, and it was reported that as many as 2% of spermatids were recombinant (34). Comparable substrates in our study, the stabilized transgenes with interrupted palindromes, undergo recombination at least at a 20-fold-reduced rate.…”

Section: Discussionmentioning

confidence: 87%

“…In each case, one or more copies had apparently undergone recombination within the lacZ repeats prior to integration (data not shown). In this, our experience was not unusual; we and others have previously detected recombination of DNA injected into fertilized eggs (33,34). Because the transgenic sequences in these other founders were already recombinant, the mice were not further analyzed for gene conversion.…”

Section: Resultsmentioning

confidence: 99%

“…In the case of the line 78 transgene palindrome, the presence or absence of the central PstI site is diagnostic for one-sided or twosided palindrome deletions, respectively. sion in transgenic mice (34). Models for homologous recombination generally involve a double-strand break at the recipient of genetic information (44), which in our design is the lacZ4⌬ gene.…”

Section: Discussionmentioning

confidence: 99%

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Palindrome Resolution and Recombination in the Mammalian Germ Line

Akgün

Zahn

Baumes

et al. 1997

Molecular and Cellular Biology

157

162

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Genetic instability is promoted by unusual sequence arrangements and DNA structures. Hairpin DNA structures can form from palindromes and from triplet repeats, and they are also intermediates in V(D)J recombination. We have measured the genetic stability of a large palindrome which has the potential to form a one-stranded hairpin or a two-stranded cruciform structure and have analyzed recombinants at the molecular level. A palindrome of 15.3 kb introduced as a transgene was found to be transmitted at a normal Mendelian ratio in mice, in striking contrast to the profound instability of large palindromes in prokaryotic systems. In a significant number of progeny mice, however, the palindromic transgene is rearranged; between 15 and 56% of progeny contain rearrangements. Rearrangements within the palindromic repeat occur both by illegitimate and homologous, reciprocal recombination. Gene conversion within the transgene locus, as quantitated by a novel sperm fluorescence assay, is also elevated. Illegitimate events often take the form of an asymmetric deletion that eliminates the central symmetry of the palindrome. Such asymmetric transgene deletions, including those that maintain one complete half of the palindromic repeat, are stabilized so that they cannot undergo further illegitimate rearrangements, and they also exhibit reduced levels of gene conversion. By contrast, transgene rearrangements that maintain the central symmetry continue to be unstable. Based on the observed events, we propose that one mechanism promoting the instability of the palindrome may involve breaks generated at the hairpin structure by a hairpin-nicking activity, as previously detected in somatic cells. Because mammalian cells are capable of efficiently repairing chromosome breaks through nonhomologous processes, the resealing of such breaks introduces a stabilizing asymmetry at the center of the palindrome. We propose that the ability of mammalian cells to eliminate the perfect symmetry in a palindromic sequence may be an important DNA repair pathway, with implications regarding the metabolism of palindromic repeats, the mutability of quasipalindromic triplet repeats, and the early steps in gene amplification events.Recombination rates are known to vary along chromosomes. A fixed genetic distance can correspond to widely different physical lengths depending on the location on the chromosome. Although certain sequences such as the site in phage and Escherichia coli are recognized by enzymes that promote recombination (43), growing evidence suggests that DNA structure and accessibility, rather than sequence per se, have a profound impact on recombination. During meiosis in mammals, for example, very different recombination rates can be observed at identical chromosomal regions in males and females (11; for a review, see reference 45). In Saccharomyces cerevisiae, where most, if not all, meiotic recombination is initiated by double-strand breaks (48), DNA sequence is not the primary determinant of the position of breaks; rather, breaks map ...

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Section: Discussionmentioning

confidence: 87%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Palindrome Resolution and Recombination in the Mammalian Germ Line

Akgün

Zahn

Baumes

et al. 1997

Molecular and Cellular Biology

157

162

View full text Add to dashboard Cite

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“…MHC class I genes may simply provide a unique opportunity to visualize these recombination events, because they result in functional changes in the antigen-presenting properties of the encoded molecules, which can be selected by an immunological reaction. Visualization of variants in other gene families would require molecular assays capable of screening thousands of individuals or an analysis that can take advantage of the individual nature of germ-line cells such as spermatozoa (23). Approaches of this kind also would permit similar analyses to be conducted in other species, such as humans, where screening large numbers of genetically typed animals is not possible.…”

Section: Discussionmentioning

confidence: 99%

A complex major histocompatibility complexDlocus variant generated by an unusual recombination mechanism in mice

Yun

Melvold

Pease

1997

Proc. Natl. Acad. Sci. U.S.A.

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A spontaneous variant of the mouse class I major histocompatibility complex D b gene, designated D bm28 , is characterized. This mutation consists of a cluster of nucleotide substitutions in exon 3 that resembles the product of a classical gene conversion event in that the substituted nucleotides appear to be templated. However, D bm28 is distinctive, because no single donor gene containing the nucleotide sequence of the mutation exists in the genome of the parent strain. The mutation is consistent with the expected result of an interaction of two donor genes at the target locus during a single recombination event. While no known genetic mechanism gives rise to this class of mutation, we have established that 10 percent of spontaneous class I mutations in the mouse major histocompatibility complex have this complex phenotype. This process occurs at the D locus and the K locus. The significance of this kind of genetic interaction may extend beyond the major histocompatibility complex and have importance in shaping other multigene families.

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“…Aspects of the relationship between meiotic recombination and homolog pairing are revealed by studies of ectopic recombination (20)(21)(22)(23)(24). Ectopic recombination occurs during S. cerevisiae meiosis but is limited by chromosomal context.…”

mentioning

confidence: 99%

Restriction of ectopic recombination by interhomolog interactions during Saccharomyces cerevisiae meiosis

Goldman

Lichten

2000

Proc. Natl. Acad. Sci. U.S.A.

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In Saccharomyces cerevisiae meiosis, recombination occurs frequently between sequences at the same location on homologs (allelic recombination) and can take place between dispersed homologous sequences (ectopic recombination). Ectopic recombination occurs less often than does allelic, especially when homologous sequences are on heterologous chromosomes. To account for this, it has been suggested that homolog pairing (homolog colocalization and alignment) either promotes allelic recombination or restricts ectopic recombination. The latter suggestion was tested by examining ectopic recombination in two cases where normal interhomolog relationships are disrupted. In the first case, one member of a homolog pair was replaced by a homoeologous (related but not identical) chromosome that has diverged sufficiently to prevent allelic recombination. In the second case, ndj1 mutants were used to delay homolog pairing and synapsis. Both circumstances resulted in a substantial increase in the frequency of ectopic recombination between arg4-containing plasmid inserts located on heterologous chromosomes. These findings suggest that, during normal yeast meiosis, progressive homolog colocalization, alignment, synapsis, and allelic recombination restrict the ability of ectopically located sequences to find each other and recombine. In the absence of such restrictions, the meiotic homology search may encompass the entire genome.homolog pairing ͉ sequence divergence ͉ NDJ1

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High-frequency germ line gene conversion in transgenic mice.

Cited by 52 publications

References 40 publications

Palindrome Resolution and Recombination in the Mammalian Germ Line

Palindrome Resolution and Recombination in the Mammalian Germ Line

A complex major histocompatibility complexDlocus variant generated by an unusual recombination mechanism in mice

Restriction of ectopic recombination by interhomolog interactions during Saccharomyces cerevisiae meiosis

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