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PubMed1995

Gene conversion vs point mutation in generating variability at the antigen recognition site of major histocompatibility complex loci.

In order to assess the roles of gene conversion followed by natural selection and balancing selection for point mutations in polymorphisms at major histocompatibility complex (MHC) loci, DNA sequences of several mammalian taxa were analyzed. Synonymous and nonsynonymous diversities were estimated separately for the antigen recognition site (ARS) and the remaining region of class I and class II genes. In some sequence pairs, the number of nonsynonymous substitutions exceeds that of synonymous substitutions at the ARS. This result indicates that some kind of balancing selection for point mutation is operating. In other sequence pairs (particularly of bovine and of rabbit), the number of synonymous substitutions at the ARS exceeds the same number at the remaining region. This result indicates that gene conversion involving a short region followed by natural selection is important. In general, a combination of gene conversion, point mutation, natural selection and random drift is thought to have contributed to polymorphisms.

Animals↗
PubMed1991

Sequence identity in an early chorion multigene family is the result of localized gene conversion.

The multigene families that encode the chorion (eggshell) of the silk moth, Bombyx mori, are closely linked on one chromosome. We report here the isolation and characterization of two segments, totaling 102 kb of genomic DNA, containing the genes expressed during the early period of choriogenesis. Most of these early genes can be divided into two multigene families, ErA and ErB, organized into five divergently transcribed ErA/ErB gene pairs. Nucleotide sequence identity in the major coding regions of the ErA genes was 96%, while nucleotide sequence identity for the ErB major coding regions was only 63%. Selection pressure on the encoded proteins cannot explain this difference in the level of sequence conservation between the ErA and ErB gene families, since when only fourfold redundant codon positions are considered, the divergence within the ErA genes is 8%, while the divergence within the ErB genes (corrected for multiple substitutions at the same site) is 110%. The high sequence identity of the ErA major exons can be explained by sequence exchange events similar to gene conversion localized to the major exon of the ErA genes. These gene conversions are correlated with the presence of clustered copies of the nucleotide sequence GGXGGX, encoding paired glycine residues. This sequence has previously been correlated with gradients of gene conversion that extend throughout the coding and noncoding regions of the High-cysteine (Hc) chorion genes of B. mori. We suggest that the difference in the extent of the conversion tracts in these gene families reflects a tendency for these recombination events to become localized over time to the protein encoding regions of the major exons.

Animals↗
PubMed1984

Evolution of multigene families under interchromosomal gene conversion.

A model for the evolution of the probabilities of genetic identity within and between loci of a multigene family in a finite population is formulated and investigated. Unbiased interchromosomal gene conversion, equal crossing-over between tandemly repeated genes, random genetic drift, and mutation to new alleles are incorporated. Generations are discrete and nonoverlapping; the diploid, monoecious population mates at random. Formulae for the equilibrium values of the probabilities of identity and for the rate of convergence are deduced. At equilibrium, the amount of intralocus homology, f, always exceeds the amount of interlocus homology, ĝ. The equilibrium homologies f and ĝ and the characteristic convergence time T are independent of the crossover rate. As the population size and the number of repeats increase, f and ĝ decrease and T increases; as the rate of gene conversion increases, f and T decrease whereas ĝ increases. The time T can be sufficiently short to imply that interchromosomal gene conversion may be an important mechanism for maintaining sequence homogeneity among repeated genes.

Biological Evolution↗
PubMed1997

Hyperthermic modification of radiation induced gene conversion in Saccharomyces cerevisiae.

Effect of pre- and post-irradiation hyperthermia on the induction of gene conversion (non-reciprocal recombination) in diploid yeast cells was investigated. Post irradiation heat treatment does not significantly modify the frequency of gene conversion. Both low-level (51 degrees C-10 min) and lethal (51 degrees C, 40 min) pre irradiation heat treatments enhanced the gene conversion frequency by 17-49%. There was no quantitative correlation between the observed enhancement and the radiation dose. These results suggest that hyperthermia given prior to radiation not only sensitizes the cells to killing but also increases their convertogenic response. It has been suggested that recombination may be involved in carcinogenesis and tumour promotion. Based on these observations along with other reports, wherein hyperthermia was shown to modify the carcinogenic effects in animals as well as the genetic effects of radiation in vitro, it is possible to suggest that hyperthermia may have a potential to increase the second primary cancers, especially in long term survivors. Certain differences in the mechanism of interaction between radiation and heat in the pre- irradiation and post irradiation modalities appear likely.

Gamma Rays↗
PubMed1989

Tarsius delta- and beta-globin genes: conversions, evolution, and systematic implications.

Comparisons between duplicated genes have shown that gene conversions play an important role in the evolution of multigene families. Previous comparisons have documented in the recently duplicated gamma-fetal globin genes of catarrhine primates, over 15 separate conversions affecting extensive stretches of coding and noncoding sequences. In the present study, delta- and beta- globin genes from a lower primate Tarsius syrichta, and the delta-globin gene of the Asian great ape, Pongo pygmaeus, have been isolated and sequenced. Comparisons of these sequences with other primate delta and beta sequences confirmed a previously reported conversion in an anthropoid ancestor and revealed additional conversions in basal primate, stem haplorhine, tarsier, and early lemur lineages. Conversions found between primate delta- and beta-globin genes contrast with those found in the gamma-genes in that delta-beta conversions appear much less frequently and are more restricted to regions conserved by selection (i.e. coding and 5'-regulatory sequences). These differences indicate that soon after a duplication occurs, conversions can be quite frequent and encompass extensive portions of the duplicated region. With time, sequence differences accumulate, particularly in noncoding regions, and limit both the frequency and size of the conversions. Sequences conserved by selection accumulate differences more slowly and are therefore subject to gene conversions for a longer period of time. Both unconverted and converted sequences were consistent in supporting the placement of tarsier with anthropoids.

Animals↗
PubMed1994

[The effect of sodium butyrate and luminol on reciprocal exchanges and gene conversion during extrachromosomal DNA recombination in cultured animal cells].

For determination of the extrachromosomal homologous DNA recombination efficiency, somatic cells of various lines have been transformed with plasmid DNAs which contain copies of neo-gene with non-overlapping deletions. Reconstruction of the neo-gene functional activity, which imparts a geneticin-resistant phenotype to cells, indicates that recombination has occurred. If dP1 and dR copies of the neo-gene are used, a single (reciprocal) exchange is necessary for reconstruction of the neo-gene by homologous DNA recombination, but a double exchange (gene conversion) is needed in the case of dP1 and dS copies. It is shown that in human cells of line HeLa and in mouse cells of line LMtk-, in contrast to the Chinese hamster cells of line A238, the frequency of double exchanges is comparable to that of the single DNA exchanges which is an evidence of participation in DNA recombination of gene conversion in addition to a single exchange mechanism. The treatment of cells with sodium butyrate and luminol exerts different influences on the rate of the single DNA exchanges and on that of gene conversion (double exchanges) in cells of lines LMtk- and HeLa, respectively. Essential distinctions in correlation of the single DNA exchange frequency and the gene conversion frequency in cells of the studied lines, and the possibility to distinguish between these mechanisms of recombination, under the treatment by sodium butyrate and luminol, may suggest the existence of two mechanisms of homologous DNA recombination in cultured animal cells, which function independently of one another, to a considerable extent.

Animals↗
PubMed1989

Mitotic and meiotic gene conversion of Ty elements and other insertions in Saccharomyces cerevisiae.

We examined meiotic and mitotic gene conversion events involved in deletion of Ty elements and other insertions from the genome of the yeast Saccharomyces cerevisiae. We found that Ty elements and one other insertion were deleted by mitotic gene conversion less frequently than point mutations at the same loci. One non-Ty insertion similar in size to Ty, however, did not show this bias. Mitotic conversion events deleting insertions were more frequently associated with crossing over than those deleting point mutations. In meiosis, conversion events duplicating the element were more common than those that deleted the element for one of the loci (HIS4) examined.

Blotting, Southern↗
PubMed2006

Conservative inheritance of newly synthesized DNA in double-strand break-induced gene conversion.

To distinguish among possible mechanisms of repair of a double-strand break (DSB) by gene conversion in budding yeast, Saccharomyces cerevisiae, we employed isotope density transfer to analyze budding yeast mating type (MAT) gene switching in G2/M-arrested cells. Both of the newly synthesized DNA strands created during gene conversion are found at the repaired locus, leaving the donor unchanged. These results support suggestions that mitotic DSBs are primarily repaired by a synthesis-dependent strand-annealing mechanism. We also show that the proportion of crossing-over associated with DSB-induced ectopic recombination is not affected by the presence of nonhomologous sequences at one or both ends of the DSB or the presence of additional sequences that must be copied from the donor.

Conserved Sequence↗
PubMed1985

A model of duplicative transposition and gene conversion for repetitive DNA families.

A model of duplicative transposition and gene conversion for the evolution of repetitive DNA families was studied. In this model, transposition and conversion (both unbiased) are assumed to occur both within and between the genomes in a diploid cell, and any degree of linkage intensity is incorporated. The transition equations for allelic and nonallelic identity coefficients have been formulated by using the previous results. The results are widely applicable to many repetitive sequences, from dispersed families like transposons to tightly linked multigene families. It has been shown through extensive numerical studies on equilibrium properties that duplicative transposition and gene conversion have very similar effects on nonallelic identity coefficients, but that allelism and allelic identity are greatly influenced by the relative rates of occurrence of the two processes.

Chromosomes↗
PubMed1992

New equations and a method for finding nine parameter values for two alleles at one locus to study gene conversion using Ascobolus immersus.

A quantitative treatment is given for meiotic gene conversion with its parameters and equations for their interactions to determine allele segregation class frequencies from heterozygotes. The possible pairing of both pairs of nonsister chromatids in a bivalent at exactly the same point is included. Using sets of data from Ascobolus immersus, it is shown that values for all nine parameters for hybrid DNA models of recombination can be obtained using an iterative computer program. The accuracy of the values is estimated and the double-strand gap repair model is considered. The parameter values obtained invalidate most of the simplifications used in previous quantitative analyses of gene conversion data. They showed total bias in strand preference in asymmetric hybrid DNA formation and some bias in which type of chromatid is the invading one. There were slight differences in repair frequency between the two types of mispair and very large differences in the direction of repair. Conversion control factors had major effects on hybrid DNA formation and repair of mispairs.

Alleles↗
PubMedDate not supplied

Polymorphism of human Ia antigens: gene conversion between two DR beta loci results in a new HLA-D/DR specificity.

The polymorphic HLA-DR beta-chains are encoded within the human major histocompatibility complex (MHC) by multiple loci resulting from gene duplications. Certain DR haplotypes can be grouped into families based on shared structural factors. We have studied the molecular basis of HLA-DR polymorphism within such a group which includes the haplotypes DR3, DR5 and DRw6. Molecular mapping of the DR beta-chain region allows true allelic comparisons of the two expressed DR beta-chain loci, DR beta I and DR beta III. At the more polymorphic locus, DR beta I, the allelic differences are clustered and may result from gene conversion events over very short distances. The gene encoding the HLA-DR3/Dw3 specificity has been generated by a gene conversion involving the DR beta I and the DR beta III loci of the HLA-DRw6/Dw18 haplotype, as recipient and donor gene, respectively. Based on which allele is found at DR beta III, the less polymorphic locus, two groups of haplotypes can be defined: DRw52a and DRw52b. The generation of HLA-DR polymorphism within the DRw52 supertypic group can thus be accounted for by a succession of gene duplication, divergence and gene conversion.

Alleles↗
PubMed1983

Gene conversion as a mechanism for antigenic variation in trypanosomes.

Expression of the gene coding for the trypanosome AnTat 1.1 surface antigen is linked to the duplicative transposition of a basic copy (BC) of this gene to an expression site. In two trypanosome clones successively derived from AnTat 1.1 (AnTat 1.10 and AnTat 1.1B) we found evidence that gene conversions are involved in the transformation of the AnTat 1.1 transposed element into the two new surface antigen coding sequences. Although the three resultant mRNAs--AnTat 1.1, 1.10, and 1.1B--are different, they still share large homologies. Two of them, AnTat 1.1 and 1.1B, code for surface coats that are indistinguishable by conventional serological techniques, whereas AnTat 1.10 has been found different by the same methods. The three genomic rearrangements involve two of the five members of the AnTat 1.1 gene family. These two members are both located in unstable telomeric regions similar to the expression site, each in a different orientation with respect to the DNA terminus. We have concluded that the duplicative transposition is achieved by a gene conversion that may affect variable lengths of the same silent genes, and that different members of the same surface antigen gene family can contribute to the diversification of the antigen repertoire.

Amino Acid Sequence↗
PubMed1986

Two mechanisms for directional gene conversion.

G234 is a large silent deletion located in the middle of gene b2, which controls spore pigmentation in Ascobolus immersus. Its gene conversion directionality was studied in asci, which show evidence of heteroduplex DNA at flanking markers, and was compared to the behavior of closely linked single-base-pair insertions or deletions. We found that with the G234 deletion, the genotype of the donor strand in the heteroduplex is preferentially recovered, irrespective of its G234 or wild-type nature, whereas with single-base-pair insertions or deletions, the direction of conversion favors one genotype, whether it was the donor or the recipient strand. We conclude that there exists two mechanisms for directional gene conversion, the "donor-directed" conversion mechanism being epistatic to the "genotype-directed" one. We discuss these data with regard to models for mismatch repair.

Ascomycota↗
PubMed1998

Extrachromosomal unequal homologous recombination and gene conversion in simian kidney cells: effects of UV damage.

Shuttle plasmid vectors containing the SV40 origin of replication and tandem neo genes with distally placed non-overlapping deletions were used to study the effects of DNA damage on extrachromosomal homologous recombination in simian kidney cells. DNA was introduced into COS7 cells by a lipofectin-mediated transfection procedure and recombination was assessed by analyzing the structure of plasmids. Recombinational events observed included unequal homologous recombination (triplication), gene conversion, double reciprocal recombination, deletion (pop-outs), gene amplification (4-6 copies), and multimerization. Triplication, an event that previously had not been reported in association with extrachromosomal recombination, predominated in experiments with undamaged vectors. The recombination frequency (NeoR/AmpR) of vectors randomly damaged by UV irradiation was essentially unchanged; however, the relative number of triplication events decreased significantly. Selective damage in one of the two neo genes increased the relative frequency of gene conversion. The experimental system developed for use in this study detects all major homologous recombination events observed in chromosomal direct repeat sequences in mammalian cells and yeast and should prove valuable for future studies of homologous recombination in mammalian cells.

Animals↗
PubMed2003

Gene conversion tracts in Saccharomyces cerevisiae can be extremely short and highly directional.

Gene conversion is a common outcome of double-strand break (DSB) repair in yeast. Prior studies revealed that DSB-induced gene conversion tracts are often short (<53 bp), unidirectional, and biased toward promoter-proximal (5') markers. In those studies, broken ends had short, non-homologous termini. For the present study we created plasmid x chromosome, chromosomal direct repeat and allelic recombination substrates in which donor alleles carried mutant HO sites (HOinc--not cleaved) at the same position as cleavable HO sites in recipient alleles. In these substrates, broken ends are almost completely homologous to donor alleles, differing only at the three HOinc mutations. These mutations serve as markers very close to, or within, the four-base overhang produced by HO nuclease. We identified extremely short tracts (<12 bp) and many tracts were highly directional, extending <2 bp on one side of the DSB. We thought that terminal homology would promote bidirectional tracts, but found instead that unidirectional tracts were more frequent. Interestingly, substrates with terminal homology displayed enhanced 3' conversion, and in several cases conversion bias was reversed toward 3' markers. These results are discussed in relation to factors that may influence tract length and directionality, including heteroduplex DNA formation, transcription, replication and mismatch repair.

Base Sequence↗
PubMed1987

Homology requirement for efficient gene conversion between duplicated chromosomal sequences in mammalian cells.

We report experiments designed to test homology dependence for gene conversion between duplicated chromosomal sequences in cultured mammalian cells. The experimental system is such that gene conversion events not associated with reciprocal exchange are recoverable. For this study four plasmids were constructed. Each contains a different duplication of the herpes simplex virus thymidine kinase (HSV tk) gene sequence. In particular, the interacting sequences share different lengths of homology. Our results indicate that for shared homologies between 295 base pairs (bp) and 1.8 kilobase pairs (kbp) in length, conversion is efficient with the rate being directly proportional to the extent of homology. In contrast, conversion with either 200 bp or 95 bp of homology is inefficient, and the rate is reduced at least seven- or 100-fold, respectively, relative to that observed with 295 bp of homology. These results are consistent with the notion that greater than 200 bp of homology are required for efficient gene conversion between repeated chromosomal sequences in mammalian cells.

Animals↗
PubMed1998

Diversification of rabbit VH genes by gene-conversion-like and hypermutation mechanisms.

Where, when and how does VH diversification occur in the rabbit? Early diversification by gene-conversion and somatic hypermutation in rabbit appendix and chicken bursa of Fabricius are similar processes; the chicken bursa and the rabbit appendix have homologous functions. However, diversification in bursa starts during embryonic development whereas it starts in rabbit appendix about 2 weeks after birth in the presence of antigens and superantigens that may contribute to positive and negative selection, affect B-cell expansion and mold the repertoire. The biochemical steps leading to diversification by gene conversion are unknown. However elevated levels of RAD51 mRNA in both chicken bursa and young rabbit appendix suggest that repair of double strand breaks may be involved. The base changes found in expressed rabbit VH sequences derived from rearrangement of known germline VH genes followed by one or more gene conversions occur with frequencies similar to those found in analyses of somatic hypermutation. The Ser codons in CDR1 and CDR2 of rabbit VH1 genes are all AGY rather than TCN, suggesting that they may represent intrinsic hotspots for hypermutation comparable to those described in human and mouse VH. Somatic hypermutation may further refine antibody affinities in rabbit germinal centers.

Animals↗
PubMed2001

Expansions and contractions in 36-bp minisatellites by gene conversion in yeast.

The instability of simple tandem repeats, such as human minisatellite loci, has been suggested to arise by gene conversions. In Saccharomyces cerevisiae, a double-strand break (DSB) was created by the HO endonuclease so that DNA polymerases associated with gap repair must traverse an artificial minisatellite of perfect 36-bp repeats or a yeast Y' minisatellite containing diverged 36-bp repeats. Gene conversions are frequently accompanied by changes in repeat number when the template contains perfect repeats. When the ends of the DSB have nonhomologous tails of 47 and 70 nucleotides that must be removed before repair DNA synthesis can begin, 16% of gene conversions had rearrangements, most of which were contractions, almost always in the recipient locus. When efficient removal of nonhomologous tails was prevented in rad1 and msh2 strains, repair was reduced 10-fold, but among survivors there was a 10-fold reduction in contractions. Half the remaining events were expansions. A similar decrease in the contraction rate was observed when the template was modified so that DSB ends were homologous to the template; and here, too, half of the remaining rearrangements were expansions. In this case, efficient repair does not require RAD1 and MSH2, consistent with our previous observations. In addition, without nonhomologous DSB ends, msh2 and rad1 mutations did not affect the frequency or the distribution of rearrangements. We conclude that the presence of nonhomologous ends alters the mechanism of DSB repair, likely through early recruitment of repair proteins including Msh2p and Rad1p, resulting in more frequent contractions of repeated sequences.

Base Sequence↗