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PubMed1992

The Saccharomyces cerevisiae ARG4 initiator of meiotic gene conversion and its associated double-strand DNA breaks can be inhibited by transcriptional interference.

In the yeast Saccharomyces cerevisiae, as in other eukaryotes, some regions of the genome have a much higher level of meiotic gene conversion than others. Previous deletion analysis indicated that the sequence necessary for the high level of gene conversion within the ARG4 region defined an initiation site located between positions -316 and -37 [relative to the first base pair (+1) of the ARG4 coding sequence] of the ARG4 promoter. To test whether this sequence is sufficient to promote gene conversion in a novel chromosomal context, we inverted on the chromosome various DNA fragments including the implicated region and the ARG4 coding sequence. Surprisingly, these inversions resulted in the loss of the normal recombination properties and double-strand-break formation associated with this process. By Northern analysis, we found that a transcript traverses the ARG4 initiation site in these inversion mutants but not in the wild type. When transcription through this region was prevented by a transcription terminator, the activity of the initiation site and the formation of double-strand breaks were restored. From these results and from complementary deletion analysis in the normal ARG4 orientation, we conclude that the activity of the ARG4 initiation site requires protection from transcriptional interference.

Chromosome Inversion↗
PubMed1999

Multiple heterologies increase mitotic double-strand break-induced allelic gene conversion tract lengths in yeast.

Spontaneous and double-strand break (DSB)-induced allelic recombination in yeast was investigated in crosses between ura3 heteroalleles inactivated by an HO site and a +1 frameshift mutation, with flanking markers defining a 3.4-kbp interval. In some crosses, nine additional phenotypically silent RFLP mutations were present at approximately 100-bp intervals. Increasing heterology from 0.2 to 1% in this interval reduced spontaneous, but not DSB-induced, recombination. For DSB-induced events, 75% were continuous tract gene conversions without a crossover in this interval; discontinuous tracts and conversions associated with a crossover each comprised approximately 7% of events, and 10% also converted markers in unbroken alleles. Loss of heterozygosity was seen for all markers centromere distal to the HO site in 50% of products; such loss could reflect gene conversion, break-induced replication, chromosome loss, or G2 crossovers. Using telomere-marked strains we determined that nearly all allelic DSB repair occurs by gene conversion. We further show that most allelic conversion results from mismatch repair of heteroduplex DNA. Interestingly, markers shared between the sparsely and densely marked interval converted at higher rates in the densely marked interval. Thus, the extra markers increased gene conversion tract lengths, which may reflect mismatch repair-induced recombination, or a shift from restoration- to conversion-type repair.

Alleles↗
PubMed1981

Gene conversion at the var1 locus on yeast mitochondrial DNA.

Alleles of the var1 locus on yeast mtDNA determine the apparent size of the mitochondrial translation product, var1 polypeptide. We have analyzed most of the different var1 alleles in our collection, which number at least 15, and have developed procedures and a genetic rationale for determining their origin and predicting their behavior in crosses. The var1 alleles are characterized by two genetically defined segments, designated a and b, which can move from one var1 allele to another by asymmetric gene conversion. We show that the a segment behaves as an entity in recombination; it is either present in or absent from different var1 alleles. The b segment usually, but not always, recombines as an entity; in some cases, only portions of the b segment recombine by gene conversion. Thus, the total number of electrophoretically resolvable var1 species we observe is explained by the assortment of a, b, and partial b segments. Each segment recombines at a characteristic frequency; however, one example is presented which shows that the recipient can modulate the frequency of gene conversion. Finally, we show that, like the 21S rDNA region (omega), there is polarity of gene conversion within var1.

Alleles↗
PubMed1982

[Lysogenic conversion induced by phages phi 80. I. A description of the phenomenon and the cloning of the conversion gene].

Escherichia coli cells lysogenic for coliphage phi 80 stop adsorbing the superinfecting phi 80 phage after having been kept under anaerobic conditions for a long time, which conferred on these cells the TonA phenotype. To determine the location of the gene for lysogenic conversion (cor), BamHI fragments of phi 80 DNA were cloned in pBR322 plasmid. The cells transformed with the recombinant plasmid pDK01 = pBR322 + phi 80 BamHI fragment 1 immediately acquire the TonA phenotype. So, the cor gene(s) is contained in the central phi 80 BamHI fragment (fragment 1) which includes gene 13, the b2 region and the att site.

Adsorption↗
PubMed2006

CYP21A2 mutations in Portuguese patients with congenital adrenal hyperplasia: identification of two novel mutations and characterization of four different partial gene conversions.

More than 90% of congenital adrenal hyperplasia (CAH) cases are caused by 21-hydroxylase deficiency. In this study, the CYP21 gene was genotyped in 56 Portuguese unrelated patients with clinical symptoms of 21-hydroxylase deficiency, in a total of 112 independent alleles. CYP21A2 mutations were identified in 99.1% of the alleles. The most common point mutation was 1688G>T (25.9%). A previously unreported partial gene conversion, extending from exon 1 to 7, was found in 16.1% of the alleles, in most cases associated to the mutation 1688G>T in the other chromosome, and in patients with nonclassical CAH. Other three distinct partial gene conversions were also identified, with lower frequencies: one extends from exon 1 to 3 and the others from exons 3 to 7 and 3 to 8. Two novel mutations were identified in two salt-wasting patients: a putative splicing mutation, IVS2+5G>A, and the transition 2557C>T, that gives rise to the nonsense mutation R445X. Seven point mutations and a partial gene conversion were responsible for 88 of the studied disease causing alleles, and the overall concordance between genotype and phenotype was 92.9%. With this study the molecular basis of CAH was characterized, for the first time, in Portuguese patients, providing useful results for clinicians in terms of prediction of disease severity, genetic and prenatal counseling.

Adrenal Hyperplasia, Congenital↗
PubMed1985

Interaction of selection and biased gene conversion in a multigene family.

A model of the evolutionary dynamics of a multigene family in a finite population under the joint effects of selection and (possibly biased) gene conversion is analyzed. It is assumed that the loss or fixation of a polymorphism at any particular locus in the gene family occurs on a much faster time scale than the introduction of new alleles to a monomorphic locus by gene conversion. A general formula for the fixation of a new allele throughout a multigene family for a wide class of selection functions with biased gene conversion is given for this assumption. Analysis for the case of additive selection shows that (i) unless selection is extremely weak or bias is exceptionally strong, selection usually dominates the fixation dynamics, (ii) if selection is very weak, then even a slight conversion bias can greatly alter the fixation probabilities, and (iii) if both selection and conversion bias are sufficiently small, the substitution rate of new alleles throughout a multigene family is approximately the single locus mutation rate, the same result as for neutral alleles at a single-copy gene. Finally, I analyze a fairly general class of underdominant speciation models involving multigene families, concluding for these models under weak conversion that although the probability of fixation may be relatively high, the expected time to fixation is extremely long, so that speciation by "molecular drive" is unlikely. Furthermore, speciation occurs faster by fixing underdominant alleles of the same effect at single-copy genes than by fixing the same number of loci in a single multigene family under the joint effects of selection, conversion, and drift.

Alleles↗
PubMed1993

Gene conversions and crossing over during homologous and homeologous ectopic recombination in Saccharomyces cerevisiae.

The pma1-105 mutation reduces the activity of the yeast plasma membrane H(+)-ATPase and causes cells to be both low pH and ammonium ion sensitive and resistant to the antibiotic hygromycin B. Revertants that can grow at pH 3.0 and on ammonium-containing plates frequently arise by ectopic recombination between pma1-105 and PMA2, a diverged gene that shares 85% DNA sequence identity with PMA1. The gene conversion tracts of revertants of pma1-105 were determined by DNA sequencing the hybrid PMA1::PMA2 genes. Gene conversion tracts ranged from 18-774 bp. The boundaries of these replacements were short (3-26 bp) regions of sequences that were identical between PMA1 and PMA2. These boundaries were not located at the regions of greatest shared identity between the two PMA genes. Similar results were obtained among low pH-resistant revertants of another mutation, pma1-147. One gene conversion was obtained in which the resulting PMA1::PMA2 hybrid was low pH-resistant but still hygromycin B-resistant. This partially active gene differs from a wild-type revertant only by the presence of two PMA2-encoded amino acid substitutions. Thus, some regions of PMA2 are not fully interchangeable with PMA1. We have also compared the efficiency of recombination between pma1-105 and either homeologous PMA2 sequence or homologous PMA1 donor sequences inserted at the same location. PMA2 x pma1-105 recombination occurred at a rate approximately 75-fold less than PMA1 x pma1-105 events. The difference in homology between the interacting sequences did not affect the proportion of gene conversion events associated with a cross-over, as in both cases approximately 5% of the Pma+ recombinants had undergone reciprocal translocations between the two chromosomes carrying pma1-105 and the donor PMA sequences. Reciprocal translocations were identified by a simple and generally useful nutritional test.

Crossing Over, Genetic↗
PubMedDate not supplied

The induction of mitotic gene conversion in the yeast, Saccharomyces cerevisiae JD1 by 4-chloromethylbiphenyl (4CMB), benzyl chloride (BC) and 4-hydroxymethylbiphenyl (4HMB).

The induction of mitotic gene conversion by 4CMB, BC and 4HMB was studied in both log-phase and stationary-phase cultures of the yeast, Saccharomyces cerevisiae JD1. Assays were performed both in the presence and in the absence of S9 microsomal fraction obtained from a liver homogenate from rats pretreated with Aroclor 1254. Exposure of both stationary-phase and log-phase cultures to 4CMB and BC resulted in an increase in mitotic gene conversion, both in the presence and in the absence of a microsomal activation system; the magnitude of response was greater in stationary-phase cultures. 4HMB did not increase the gene conversion frequency in log-phase or stationary-phase cultures.

Animals↗
PubMed2003

Abundant gene conversion between arms of palindromes in human and ape Y chromosomes.

Eight palindromes comprise one-quarter of the euchromatic DNA of the male-specific region of the human Y chromosome, the MSY. They contain many testis-specific genes and typically exhibit 99.97% intra-palindromic (arm-to-arm) sequence identity. This high degree of identity could be interpreted as evidence that the palindromes arose through duplication events that occurred about 100,000 years ago. Using comparative sequencing in great apes, we demonstrate here that at least six of these MSY palindromes predate the divergence of the human and chimpanzee lineages, which occurred about 5 million years ago. The arms of these palindromes must have subsequently engaged in gene conversion, driving the paired arms to evolve in concert. Indeed, analysis of MSY palindrome sequence variation in existing human populations provides evidence of recurrent arm-to-arm gene conversion in our species. We conclude that during recent evolution, an average of approximately 600 nucleotides per newborn male have undergone Y-Y gene conversion, which has had an important role in the evolution of multi-copy testis gene families in the MSY.

Animals↗
PubMed1991

Evidence for biased gene conversion in concerted evolution of ribosomal DNA.

Concerted evolution is the production and maintenance of homogeneity within repeated families of DNA. Two mechanisms--unequal crossing over and biased gene conversion--have been the principal explanations of concerted evolution. Concerted evolution of ribosomal DNA (rDNA) arrays is thought to be largely the result of unequal crossing over. However, concerted evolution of rDNA in parthenogenetic lizards of hybrid origin is strongly biased toward one of two parental sequences, which is consistent with biased gene conversion as the operative mechanism. The apparent gene conversions are independent of initial genome dosage and result in homogenization of rDNA arrays across all nucleolar organizer regions.

Animals↗
PubMed1985

Rad52-independent mitotic gene conversion in Saccharomyces cerevisiae frequently results in chromosomal loss.

We have examined spontaneous, interchromosomal mitotic recombination events between his4 alleles in both Rad+ and rad52 strains of Saccharomyces cerevisiae. In Rad+ strains, 74% of the His+ prototrophs resulted from gene conversion events without exchange of flanking markers. In diploids homozygous for the rad52-1 mutation, the frequency of His+ prototroph formation was less than 5% of the wild-type value, and more than 80% of the gene conversion events were accompanied by an exchange of flanking markers. Most of the rad52 intragenic recombination events arose by gene conversion accompanied by an exchange of flanking markers and not by a simple reciprocal exchange between the his4A and his4C alleles. There were also profound effects on the kinds of recombinant products that were recovered. The most striking effect was that RAD52-independent mitotic recombination frequently results in the loss of one of the two chromosomes participating in the gene conversion event.

Chromosomes↗
PubMed1984

Origin of the beta S-globin gene in blacks: the contribution of recurrent mutation or gene conversion or both.

In order to investigate the origin(s) of the mutation(s) leading to the beta S-globin gene in North American populations of African ancestry, we analyzed DNA polymorphisms in the beta-globin gene cluster in a large number of both beta A- and beta S-globin gene-bearing chromosomes in U.S. and Jamaican Blacks. We found 16 different haplotypes of polymorphic sites associated with 170 beta S-globin gene-bearing chromosomes. The three most common beta S haplotypes, which account for 151/170 of the beta S-globin gene-bearing chromosomes, are only rarely seen in the chromosomes bearing the beta A-globin gene in these populations (6/47). Two observations suggest multiple origins or interallelic gene conversion, or both, of the beta S mutation. First, the mutation is present in all three beta-globin gene frameworks. Second, the beta S haplotypes can be divided into four groups, each of which cannot be derived from any other by less than two crossing-over events. In summary, our observation of the beta S mutation on 16 different haplotypes in African populations can be best explained by (i) a number of simple recombination events 5' to the beta-globin gene and (ii) up to four independent mutations and/or interallelic gene conversions.

Alleles↗
PubMed1996

Optional elements in the chloroplast DNAs of chlamydomonas eugametos and C. moewusii: unidirectional gene conversion and co-conversion of adjacent markers in high-viability crossses.

Unlike most polymorphic markers in the Chlamydomonas eugametos and Chlamydomonas moewusii chloroplast DNAs (cpDNAs), the C. moewusii 6- and 21-kb extra sequences and the C. eugametos-specific CeLSU small middle dot 5 intron are transmitted to all of the few viable progeny in reciprocal crosses between the two green algae. To determine whether this unidirectional transmission pattern is due to gene conversion or to selection for F1 hybrid survival, we followed the inheritance of the parental alleles at the loci featuring these three deletions/additions and at several other polymorphic cpDNA loci in zygospore clones derived from high-viability crosses. The great majority of the zygospore clones examined inherited exclusively the long alleles from the mt- parent at the loci containing the three optional cpDNA elements, but as expected, they preferentially inherited the markers from the mt+ parent at most other loci. Our results therefore indicate that all three optional cpDNA sequences propagate themselves very efficiently by gene conversion in crosses between strains differing by the presence of these elements. The co-conversion tracts associated with these sequences are longer (>3 kb) than those previously reported for mobile elements spreading by gene conversion. Our results also revealed that less efficient gene conversion events occurred at two other cpDNA loci.

Alleles↗
PubMed1999

Involvement of the essential yeast DNA polymerases in induced gene conversion.

In the yeast Saccharomyces cerevisiae three different DNA polymerases alpha, delta and epsilon are involved in DNA replication. DNA polymerase alpha is responsible for initiation of DNA synthesis and polymerases delta and epsilon are required for elongation of DNA strand during replication. DNA polymerases delta and epsilon are also involved in DNA repair. In this work we studied the role of these three DNA polymerases in the process of recombinational synthesis. Using thermo-sensitive heteroallelic mutants in genes encoding DNA polymerases we studied their role in the process of induced gene conversion. Mutant strains were treated with mutagens, incubated under permissive or restrictive conditions and the numbers of convertants obtained were compared. A very high difference in the number of convertants between restrictive and permissive conditions was observed for polymerases alpha and delta, which suggests that these two polymerases play an important role in DNA synthesis during mitotic gene conversion. Marginal dependence of gene conversion on the activity of polymerase epsilon indicates that this DNA polymerase may be involved in this process but rather as an auxiliary enzyme.

DNA Damage↗
PubMed2005

Gene conversion and deletion frequencies during double-strand break repair in human cells are controlled by the distance between direct repeats.

Homologous recombination (HR) repairs DNA double-strand breaks and maintains genome stability. HR between linked, direct repeats can occur by gene conversion without an associated crossover that maintains the gross repeat structure. Alternatively, direct repeat HR can occur by gene conversion with a crossover, or by single-strand annealing (SSA), both of which delete one repeat and the sequences between the repeats. Prior studies of different repeat structures in yeast and mammalian cells revealed disparate conversion:deletion ratios. Here, we show that a key factor controlling this ratio is the distance between the repeats, with conversion frequency increasing linearly with the distances from 850 to 3800 bp. Deletions are thought to arise primarily by SSA, which involves extensive end-processing to reveal complementary single-strands in each repeat. The results can be explained by a model in which strand-invasion leading to gene conversion competes more effectively with SSA as more extensive end-processing is required for SSA. We hypothesized that a transcription unit between repeats would inhibit end-processing and SSA, thereby increasing the fraction of conversions. However, conversion frequencies were identical for direct repeats separated by 3800 bp of transcriptionally silent or active DNA, indicating that end-processing and SSA are not affected by transcription.

Animals↗
PubMed1998

Gene conversion is a likely cause of mutation in PKD1.

Approximately 70% of the gene responsible for the most common form of autosomal dominant polycystic kidney disease ( PKD1 ) is replicated in several highly homologous copies located more proximally on chromosome 16. We recently have described a novel technique for mutation detection in the duplicated region of PKD1 that circumvents the difficulties posed by these homologs. We have used this method to identify two patients with a nearly identical cluster of base pair substitutions in exon 23. Since pseudogenes are known to be reservoirs for mutation via gene conversion events for a number of other diseases, we decided to test whether these sequence differences in PKD1 could have arisen as a result of this mechanism. Using changes in restriction digest patterns, we were able to show that these sequence substitutions are also present in N23HA, a rodent-human somatic cell hybrid that contains only the PKD1 homologs. Moreover, these changes were also detected in total DNA from several affected and unaffected individuals that did not harbor this mutation in their PKD1 gene copy. This is the first example of gene conversion in PKD1 , and our findings highlight the importance of using gene-specific reagents in defining PKD1 mutations.

Gene Conversion↗
PubMed2000

A novel St(a) glycophorin produced via gene conversion of pseudoexon III from glycophorin E to glycophorin A gene.

Stone (St(a)) is a variant antigen carried on human erythrocyte MNSs glycophorins (GPSt(a)) that are genetically associated with splicing mutations in GPA genes or with hybrid formation between GPA and GPB genes. Here we identify the first and rare gene conversion event in which GPE, the third member of the family, recombined with GPA, giving rise to a GPA-E-A hybrid gene encoding the St(a) antigen. Western blot detected expression in the proband of both GPA and GPSt(a) on the plasma membrane. Southern blot showed a new restriction fragment from the GPSt(a) gene, indicating an altered exon III-intron 3 junction. Sequencing of RT-PCR products identified one full-length and two shortened glycophorin cDNAs. The shortened forms were derived from GPSt(a) lacking one (exon III) and two exons (exon III and IV), respectively. To define the molecular basis for exon skipping, the genomic region spanning exon III of the GPSt(a) gene was amplified and sequenced. This revealed transfer from GPE to GPA of a DNA segment containing the pseudoexon III and its silent donor splice site. Thus, the inactivation of GPA exon III by conversion of a silent GPE donor splice site portrays a new molecular mechanism for St(a) antigen expression in human erythrocytes.

Alleles↗
PubMed1999

CYS3, a hotspot of meiotic recombination in Saccharomyces cerevisiae. Effects of heterozygosity and mismatch repair functions on gene conversion and recombination intermediates.

We have examined meiotic recombination at the CYS3 locus. Genetic analysis indicates that CYS3 is a hotspot of meiotic gene conversion, with a putative 5'-3' polarity gradient of conversion frequencies. This gradient is relieved in the presence of msh2 and pms1 mutations, indicating an involvement of mismatch repair functions in meiotic recombination. To investigate the role of mismatch repair proteins in meiotic recombination, we performed a physical analysis of meiotic DNA in wild-type and msh2 pms1 strains in the presence or absence of allelic differences at CYS3. Neither the mutations in CYS3 nor the absence of mismatch repair functions affects the frequency and distribution of nearby recombination-initiating DNA double-strand breaks (DSBs). Processing of DSBs is also similar in msh2 pms1 and wild-type strains. We conclude that mismatch repair functions do not control the distribution of meiotic gene conversion events at the initiating steps. In the MSH2 PMS1 background, strains heteroallelic for frameshift mutations in CYS3 exhibit a frequency of gene conversion greater than that observed for either marker alone. Physical analysis revealed no modification in the formation of DSBs, suggesting that this marker effect results from subsequent processing events that are not yet understood.

Alleles↗