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PubMed1983

Gene conversion: point-mutation heterozygosities lower heteroduplex formation.

The effects of heterozygosity on meiotic gene conversion characteristics have been studied in the fungus Ascobolus immersus. The non-Mendelian segregation patterns of seven white ascospore mutants of the b2 gene were established in the presence or the absence of additional neighbouring allelic mutations. These correspond to nine different double mutants with wild-type or pseudo-wild-type phenotypes, constituted by two +1, -1 frameshift mutations of complementary phases. When heterozygous, these double point mutations decrease, by an average of one third, the gene conversion frequencies of the mutants located on their right, toward the low conversion end of the gene. The decrease corresponds either to a reduction in all classes of non-Mendelian segregation (6:2, 5:3 and aberrant 4:4 asci) or to a reduction restricted to the single class of aberrant 4:4 asci. These modifications are explained by changes in hybrid DNA parameter values: frequencies of formation and modalities of distribution (asymmetric versus symmetric ratio). Besides the nature of the non-homology, point mutation versus deletion, which leads to quantitative differential effects, the region where the non-homology is located within the gene also appears to play an important role.

Ascomycota↗
PubMed1984

A class II gene conversion event defines an antigen-specific Ir gene epitope.

To assess the role of Ia epitopes in conferring specificity for the immune response to nominal antigen, we compared the insulin response of mice with a defined mutation in the I-Ab beta gene, the B6.C-H-2bm12 (bm12), with that of wild-type H-2b C57BL/6 (B6) mice. We report that the bm 12 mutation resulted in a selective alteration of the specificity of insulin recognition, such that bm 12 mice responded upon immunization with sheep but not beef insulin, which differ by only one amino acid at position 9 of the insulin A chain. Thus, the bm12 mutation allows for the definition of the actual nucleotide sequence coding for an Ia epitope that is responsible for controlling the specificity of immune recognition of insulin. Furthermore, we show that the sheep insulin response of H-2k mice is controlled by the E molecule and that sheep insulin can be recognized by primed bm12 and H-2k T cells in the context of either bm12, B10.A, or B10.A(5R) antigen-presenting cells. Our data suggest that the mechanism for the bm12 mutation was the intergenic transfer of a hypervariable region in the first domain that is identical in the I-Abm12 beta, I-Eb beta, and I-Ek beta genes.

Animals↗
PubMed1981

Gene conversion between duplicated genetic elements in yeast.

The mitotic recombination behaviour of a duplication of the his4 region on chromosome III in the yeast Saccharomyces cerevisiae was studied. The major recombination event between the duplicated segments is gene conversion unassociated with reciprocal recombination. The rad52-1 mutation preferentially decreases mitotic gene conversion. These results suggest that mitotic gene conversion may occur by a different pathway from that occurring in meiosis. This mitotic gene conversion may be important in yeast mating type interconversion and the maintenance of sequence homogeneity in families of repeated eukaryotic genes.

Alleles↗
PubMed1987

Correction of deletions in mammalian cells by gene conversion.

We have constructed substrates to study the conversion of deletions in mammalian cells both extrachromosomally and after the stable integration of the substrates into the chromosome. These substrates were designed to study gene conversion without the complication of reciprocal recombination events. The substrates contain insertion or deletion mutations of the neomycin resistance gene (neo) and an internal, homologous fragment of the neo gene (neo-526), such that gene conversion from neo-526 to the mutated neo gene restores a functional neo gene. We have shown that extrachromosomally insertions of 10 bp or deletions of 22 or 167 bp are converted to wild-type at similar frequencies (1-6 X 10(-4)). Chromosomal gene conversion occurred at frequencies of about 10(-6)-10(-7) per cell generation. As expected from the experimental design, all recombination events analyzed in mammalian cells using these substrates appear to be due to gene conversion.

Animals↗
PubMed1991

The hyper-gene conversion hpr5-1 mutation of Saccharomyces cerevisiae is an allele of the SRS2/RADH gene.

The HPR5 gene has been defined by the mutation hpr5-1 that results in an increased rate of gene conversion. This mutation suppresses the UV sensitive phenotype of rad18 mutations in hpr5-1 rad18 double mutants by channeling the aborted repair events into a recombination repair pathway. The HPR5 gene has been cloned and is shown to be allelic to the SRS2/RADH gene, a putative DNA helicase. The HPR5 gene, which is nonessential, is tightly linked to the ARG3 locus chromosome X. The hpr5-1 allele contains missense mutation in the putative ATP binding domain. A comparison of the recombination properties of the hpr5-1 allele and the null allele suggests that recombination events in hpr5 defective strains can be generated by several mechanisms. We propose that the HPR5 gene functions in the RAD6 repair pathway.

Alleles↗
PubMed1988

Apparent gene conversion in an Escherichia coli rec+ strain is explained by multiple rounds of reciprocal crossing-over.

Gene conversion, the non-reciprocal transfer of sequence information between homologous DNA sequences, has been reported in lower eukaryotes, mammals and in Escherichia coli. In an E. coli rec+ strain, we established a plasmid carrying two different deleted neo genes (neoDL and neoDR) in an inverted orientation and then selected for homologous recombination events that had reconstructed an intact neo+ gene. We found some plasmids that had apparently experienced intramolecular gene conversion. Further evidence, however, suggests that they are products of multiple rounds of reciprocal crossing-over, apparently involving two plasmid molecules. First, most of the Neo+ clones contained multiple types of Neo+ plasmids, although the frequency of producing the neo+ clones was low. Second, all the neo+ clones also contained, as a minority, one particular form of dimer, which can be formed by reciprocal crossing-over between neoDL of one plasmid molecule and neoDR of another plasmid molecule. Third, in reconstruction experiments, we cloned and purified this dimer and transferred it back into the rec+ cells. The dimer gave rise to clones containing multiple types of neo+ recombinant monomers, including those apparent gene conversion types, and containing only few molecules of this dimer plasmid.

Clone Cells↗
PubMed2001

Gene conversion homogenizes the CMT1A paralogous repeats.

BACKGROUND: Non-allelic homologous recombination between paralogous repeats is increasingly being recognized as a major mechanism causing both pathogenic microdeletions and duplications, and structural polymorphism in the human genome. It has recently been shown empirically that gene conversion can homogenize such repeats, resulting in longer stretches of absolute identity that may increase the rate of non-allelic homologous recombination. RESULTS: Here, a statistical test to detect gene conversion between pairs of non-coding sequences is presented. It is shown that the 24 kb Charcot-Marie-Tooth type 1A paralogous repeats (CMT1A-REPs) exhibit the imprint of gene conversion processes whilst control orthologous sequences do not. In addition, Monte Carlo simulations of the evolutionary divergence of the CMT1A-REPs, incorporating two alternative models for gene conversion, generate repeats that are statistically indistinguishable from the observed repeats. Bounds are placed on the rate of these conversion processes, with central values of 1.3 x 10(-4) and 5.1 x 10(-5) per generation for the alternative models. CONCLUSIONS: This evidence presented here suggests that gene conversion may have played an important role in the evolution of the CMT1A-REP paralogous repeats. The rates of these processes are such that it is probable that homogenized CMT1A-REPs are polymorphic within modern populations. Gene conversion processes are similarly likely to play an important role in the evolution of other segmental duplications and may influence the rate of non-allelic homologous recombination between them.

Journal Article↗
PubMed1988

The behavior of insertions near a site of mitotic gene conversion in yeast.

In yeast, coincident gene conversion events involving the LEU1 and TRP5 loci (16 cM apart) occur at frequencies that are far greater than is expected for two independent acts of recombination. When a large plasmid (pJM53) is placed between these genes so that a direct repeat is produced, there is frequent loss of the insert among coincident convertants. Previous results strongly suggest that this is due to a separate, intrachromosomal exchange between the direct repeats rather than to excision from an extensive region of heteroduplex DNA. In this paper, we extend our genetic and molecular analysis to a plasmid insertion (pKSH) which replaces rather than duplicates the chromosomal material. The relative stabilities of pKSH and pJM53 are compared among coincident Leu+Trp+ convertants and convertants involving only one locus (LEU1). The pKSH insertion is significantly more stable in the latter which constitute a large majority of the selectable recombinants. In the former, both insertions are lost with high frequency. These results are used to argue that, while most mitotic conversion does not result from long intermediates, coincident convertants may arise from either multiple intermediates or extensive heteroduplex regions.

DNA Transposable Elements↗
PubMed2002

Carriership of a defective tenascin-X gene in steroid 21-hydroxylase deficiency patients: TNXB -TNXA hybrids in apparent large-scale gene conversions.

Steroid 21-hydroxylase deficiency is caused by a defect in the CYP21A2 gene. CYP21A2, the adjacent complement C4 gene and parts of the flanking genes RP1 and TNXB constitute a tandemly duplicated arrangement in the central (class III) region of the major histocompatibility complex. The typical number of repeats of the CYP21/C4 region is two, with one repeat carrying CYP21A2 and the other carrying the highly homologous pseudogene CYP21A1P. By comparison with this standard, three categories of CYP21A2 defects have traditionally been distinguished: CYP21A2 deletions, large-scale gene conversions of CYP21A2 into a structure similar to CYP21A1P, and smaller mutations in CYP21A2 (also derived from CYP21A1P, by means of small-scale gene conversions). The genetic mechanisms suggested by these designations have originally been inferred from the layout of the haplotypes involved and were later confirmed by observation of deletions and small mutations, but not large-scale conversions, as de novo events. Apparent large-scale conversions account for the defect in 9 out of 77 chromosomes in our patient group. We here demonstrate that 4 out of these 9 'conversions' extend into the flanking TNXB gene, which encodes tenascin-X. This implies that approximately 1 in every 10 steroid 21-hydroxylase deficiency patients is a carrier of tenascin-X deficiency, which is associated with a recessive form of the Ehlers-Danlos syndrome. Currently available data on the structure of 'deletion' and 'large-scale conversion' chromosomes strongly suggests that both are the result of the same mechanism, namely unequal meiotic crossover. Since it is unlikely that the term 'large-scale gene conversion' describes a mechanism that actually occurs between the CYP21A2 and CYP21A1P genes, we propose the discontinuation of that terminology.

Gene Conversion↗
PubMed1984

The properties of meiotic gene conversion important in its effects on evolution.

In order to determine how important gene conversion is as a force in populations, extensive surveys have been made to determine the limits, distributions and typical values of evolution-related conversion parameters from various fungi, Drosophila and maize. The conversion frequency, c, had an enormous range for different mutations within a species, with loci often having different means and limits for c. b, the frequency of a particular allelle in the products of meiotic tetrads or octads with aberrant segregation ratios, often showed values near the theoretical extremes; d, disparity in direction of conversion, was frequent and often extreme. b and d could only be studied in fungi, and their less extreme values in Saccharomyces than in Sordaria or Ascobolus are clearly related to the lack of frame-shift mutations in the yeast data. For different mutations at a locus, neither c nor b showed normal distributions; both gave dispersed distributions, sometimes multi-modal for b; c and b were not usually correlated. y, the force of meiotic gene conversion on allele frequencies, had a large range of positive and negative values, with different loci often having quite different limits and mean absolute values. For different mutations at a locus, y showed dispersed distributions, with little tendency to cluster around zero. The high proportion of non-zero y values in all fungi where this could be studied, with large departures from zero being most extreme in Ascobolus and Sordaria brevicollis, shows that gene conversion could often be an important force in changing allele frequencies in favour of mutant or wild-type in these organisms. Even in organisms with much lower c or absolute d values, conversion could still be important, depending on dominance, selection coefficients and mutation rates. Presumed frame-shifts tended to have more extreme disparity and hence higher absolute y values than did presumed base-substitutions, but with no consistent c differences. Induced mutations had similar or slightly higher absolute y values compared with spontaneous mutations.

Animals↗
PubMed1989

The effects of gene conversion control factors on conversion-induced changes in allele frequencies in populations and on linkage disequilibrium.

Conversion control factors (ccfs) are widespread. They control conversion properties at their target loci, affecting the conversion frequency and the amount and even the direction of gene conversion disparity. Three major types of ccf can be recognised. Experimental studies of the effects of ccfs have been combined with theoretical studies and modelling to examine the effects of ccfs on the evolutionary population genetics of alleles at the target locus. The ccf alleles present can greatly affect the rate and the direction of conversion-induced changes in target locus allele frequencies. Gene conversion can both cause and remedy linkage disequilibrium, with causation being related to polymorphism for ccfs. Disparity in conversion direction does not by itself necessarily cause linkage disequilibrium.

Alleles↗
PubMed1985

Genetic differentiation of transposable elements under mutation and unbiased gene conversion.

A model is developed to predict the extent of genetic differentiation in a family of transposable elements under the combined effects of genetic drift, transposition, mutation and unbiased gene conversion. The model is based on simplifying assumptions that are valid when transposition is always to new sites and copy number per site is low. In the absence of gene conversion, the degree of differentiation as measured by the probability of identity of different elements is the same as at a single locus with the same mutation rate but in a population of effective size Nc/2, where N is the population size and c is the number of copies per individual. The inclusion of unbiased gene conversion does not significantly change this result. If, as seems to be the case, families of transposable elements are relatively homogeneous, then the model implies either that mutation rates for transposable elements are much lower than at comparable single-copy loci or that some other force, such as natural selection or biased gene conversion, is at work. Transposition is a very ineffective force for homogenizing a family of transposable elements.

DNA Transposable Elements↗
PubMed1984

The evolution of multigene families under intrachromosomal 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 intrachromosomal 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. Formulas for the equilibrium values of the probabilities of identity and a cubic equation for the rate of convergence are deduced. Numerical examples indicate the following. The amount of homology at equilibrium generally decreases as the mutation rate, the population size and the number of repeats increase; it may increase or decrease with increasing crossover rate. The intralocus homology has an intermediate minimum, whereas the interlocus homology increases, as the rate of gene conversion increases. The intralocus homology decreases, whereas the interlocus homology increases, as the proportion of symmetric heteroduplexes increases. The characteristic convergence time can be sufficiently short to imply that intrachromosomal gene conversion may be an important mechanism for maintaining sequence homogeneity among repeated genes. The convergence time decreases as the conversion rate and the proportion of symmetric heteroduplexes increase; although exceptions occur, it generally increases as the population size and the number of repeats increase; it may increase or decrease with increasing crossover rate.

Animals↗
PubMed1986

Inducibility of gene conversion in Saccharomyces cerevisiae treated with MMS.

At high survival levels (85%), point mutation and gene conversion frequencies were determined in strain D7 of Saccharomyces cerevisiae after treatment with methyl methanesulfonate (MMS) either after cells were incubated in complete medium before plating or following a split-dose protocol. It is shown that induction of gene conversion by MMS post-incubation leads to an additional enhancement in frequency. This increase is not observed for point mutation. By fractionation of the MMS dose (1 mM + 1 mM) with incubation in complete medium between the 2 doses the frequency of gene conversion is twice as high as with a single equal total dose (2 mM). This treatment does not modify the frequencies of point mutation. These data support the notion that an inducible recombinogenic function exists in wild-type yeast.

DNA Repair↗
PubMed1990

The rat P450 IID subfamily: complete sequences of four closely linked genes and evidence that gene conversions maintained sequence homogeneity at the heme-binding region of the cytochrome P450 active site.

Four genes in the P450 IID gene subfamily were isolated from Sprague-Dawley rat lambda EMBL 3 and Charon 4A genomic libraries and completely sequenced. Their transcription start sites were determined by primer extension analysis. The four genes designated IID2, IID3, IID4, and IID5 span 4036, 4371, 4678, and 4567 bp, respectively, and are closely linked head to tail on a 60-kb segment of DNA. All IID genes contained nine exons, and interestingly, the IID2, IID3, and IID4 genes possessed an atypical GC5' splice junction in intron 2. All four genes are transcribed, however, IID4 mRNA is produced at a level of less than one-tenth of those of IID2, IID3, and IID5. The exonic regions of these genes displayed from 79 to 84% sequence similarties. Several regions of extremely high nucleotide similarity were found within the introns, exons, and in the flanking regions of the four genes. These localized areas of high nucleotide similarities are the result of former gene conversion events. Of interest was the finding that the most highly similar region of all IID genes that was maintained by gene conversion covers portions of the eighth and ninth exons and the eighth intron. The ninth exon codes for a region of the P450 protein that is well conserved among all P450 gene families and in all species and that is associated with the noncovalently bound heme iron at the enzyme's active site. These data indicate that gene conversions have maintained sequence homogeneity within a critical region of the four P450 IID proteins.

Amino Acid Sequence↗
PubMed1994

Polarity of meiotic gene conversion in fungi: contrasting views.

The frequency of meiotic gene conversion often varies linearly from one end of the gene to the other. This phenomenon has been called 'polarity'. In this review, we will primarily studies of polarity that have been done in the yeast Saccharomyces cerevisiae (ARG4 and HIS4 loci) and in Ascobolus (b2 locus) with an emphasis on possible mechanisms. The genetic and physical data obtained at these 'hotspots' of recombination strongly suggests that the formation of a polarity gradient reflects both the frequency of heteroduplex formation and the processing of this recombination intermediate by mismatch-repair-dependent processes.

Ascomycota↗
PubMed2000

Novel mutations in the duplicated region of the polycystic kidney disease 1 (PKD1) gene provides supporting evidence for gene conversion.

Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common human single-gene disorders, and is the most common inherited form of cystic kidney disease. It is estimated that approximately 85% of ADPKD is due to mutations in the PKD1 gene, which is located on chromosome 16p13.3. Mutation analysis in this gene is difficult, because more than two-thirds of reiterated several times at 16p13.1. In this study, mutation screening in 90 ADPKD patients was carried out on exons in the duplicated region of the PKD1 gene (23-34), using genomic long-range PCR followed by nested PCR and single-strand conformation polymorphism (SSCP), and finally cycle sequencing. Two nonconservative missense mutations were detected in exons 25 and 31, and two conservative mutations were found in exons 24 and 29. A novel splicing mutation, which is expected to cause skipping of exon 30, was detected in one case. Moreover, six intronic variants, three silent variants, and one polymorphic variant were detected in this study. Comparison between some of these changes and published sequences from the homologous genes on 16p13.1, revealed supporting evidence for the gene conversion theory as a mechanism responsible for some of the mutations in the PKD1 gene. Factors likely to facilitate gene conversion in this region of the PKD1 gene are discussed.

Alu Elements↗
PubMed1995

New HLA-DPB1 alleles generated by interallelic gene conversion detected by analysis of sperm.

The rate at which allelic diversity at the HLA loci evolves has been the subject of considerable controversy. The patchwork pattern of sequence polymorphism within the second exon of the HLA class II loci, particularly in the DPB1 locus, may have been generated by segmental exchange (gene conversion). We have analysed the frequency of variant DPB1 sequences that have been created by interallelic gene conversion in the germline by screening pools of sperm using PCR amplification and oligonucleotide probe typing. Our results indicate that about 1/10,000 sperm represents a new DPB1 sequence generated by short tracts of segmental exchange (gene conversion) within the second exon, suggesting that interallelic gene conversion may have an important role in generating the extensive allelic diversity at the HLA loci.

Alleles↗