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PubMed2000

Gene conversions may obscure actin gene family relationships.

Phylogenetic hypotheses of muscle actin evolution are significantly different when a sea urchin is used as a representative echinoderm than when a sea star is used. While sea urchin muscle actins support an echinoderm-chordate sister relationship, sea star sequences suggest that echinoderm muscle actins are convergent with chordate muscle actins. Our results suggest that gene conversion in the sea star muscle actin may be responsible for these discordant results.

Actins↗
PubMed1995

Polarity of meiotic gene conversion is 5' to 3' within the niaD gene of Aspergillus nidulans.

We have examined polarity of meiotic gene conversion in the niiA-niaD gene cluster of Aspergillus nidulans in two-point crosses. The type and position of the mutations represented by the niaD alleles and the correlation between the relative frequency of gene conversion and the physical position of these mutations were determined. We show that polarity of meiotic gene conversion is 5' to 3' (transcribed strand) within the niaD gene. Additional crosses involving a niiA allele and a niaD allele show little polarity of gene conversion, which suggests that the recombination events leading to restoration of the niaD gene are initiated upstream of the coding region of the niaD gene but within the niiA-niaD gene cluster, possibly within the intergenic promoter region.

Alleles↗
PubMed1989

A gene conversion located 5' to the A gamma gene in linkage disequilibrium with the Bantu haplotype in sickle cell anemia.

Cloning and sequencing of the gamma-globin gene of a sickle cell anemia patient homozygous for the Bantu haplotype has revealed a gene conversion that involves the replacement of an A gamma sequence by a G gamma sequence in the promoter area of the A gamma gene. This event is similar to another gene conversion believed to be responsible for the very high homology between gamma-globin genes, suggesting that the promoter area of these genes is prone to this type of genetic rearrangement. Further analysis demonstrated that the chromosome bearing this gene conversion has a very high frequency among Bantu chromosomes and a very low or nil frequency in other haplotypes linked to the beta s gene. No correlation was found between the G gamma/A gamma ratio and the presence of the gene conversion among Bantu haplotype patients, thus excluding a portion of the gamma gene sequence in the determination of this ratio.

Anemia, Sickle Cell↗
PubMed2006

Genome-wide identification of pseudogenes capable of disease-causing gene conversion.

Pseudogenes are remnants of gene duplication (nonprocessed pseudogenes) and retrotransposition (processed pseudogenes) events. This study describes methods for identifying gene conversion candidates from predicted pseudogenes. Pseudogenes may accumulate and harbor sequence variations over time that become disease-causing mutations when transferred to genes by gene conversion. A total of 14,476 pseudogenes were identified, including 3,426 nonprocessed pseudogenes. In addition, 1,945 nonprocessed pseudogenes that are localized near their progenitor gene were evaluated for their possible role in gene conversion and disease. All 11 known, human cases of gene conversion (with deleterious effects) involving pseudogenes were successfully identified by these methods. Among the pseudogenes identified is a retinitis pigmentosa 9 (RP9) pseudogene that carries a c.509A>G mutation which produces a p.Asp170Gly substitution that is associated with the RP9 form of autosomal dominant retinitis pigmentosa (adRP). The c.509A>G mutation in RP9 is a previously unrecognized example of gene conversion between the progenitor gene and its pseudogene. Notably, two processed pseudogenes also contain mutations associated with diseases. An inosine monophosphate dehydrogenase 1 (IMPDH1) pseudogene carries a c.676G>A mutation that produces a p.Asp226Asn substitution that causes the retinitis pigmentosa 10 (RP10) form of adRP; and a phosphoglycerate kinase 1 (PGK1) pseudogene (PGK1P1) carries a c.837T>C mutation that produces a p.Ile252Thr substitution that is associated with a phosphoglycerate kinase deficiency. Ranking of nonprocessed pseudogenes as candidates for gene conversion was also performed based on the sequence characteristics of published cases of pseudogene-mediated gene conversion. All results and tools produced by this study are available for download at: http://genome.uiowa.edu/pseudogenes.

Computational Biology↗
PubMed1988

Characterization of an inbred mouse exhibiting low responsiveness to phosphorylcholine. Antibodies from low-responder mice suggest gene conversion events within the S107VH gene family.

An inbred strain was derived from feral mice that respond poorly to phosphorylcholine (PC) but responded normally to a variety of other Ag. Low responsiveness is inherited as a single recessive autosomal trait, characterized by very low levels of both PC-binding serum antibody and PC-specific B cells. Analyses of PC-reactive clonotypes generated in limiting dilution culture, as well as analyses of PC-specific hybridomas, indicate that this strain expresses L and H chain V regions not previously associated with high affinity murine PC-binding antibodies. Further, sequence analyses suggest gene conversion events occurred within the S107VH gene family among the progenitors of this strain subsequent to their divergence from those of most common laboratory strains.

Amino Acid Sequence↗
PubMed1992

Formation of heteroduplex DNA during mammalian intrachromosomal gene conversion.

We have studied intrachromosomal gene conversion in mouse Ltk- cells with a substrate designed to provide genetic evidence for heteroduplex DNA. Our recombination substrate consists of two defective chicken thymidine kinase genes arranged so as to favor the selection of gene conversion products. The gene intended to serve as the recipient in gene conversion differs from the donor sequence by virtue of a palindromic insertion that creates silent restriction site polymorphisms between the two genes. While selection for gene conversion at a XhoI linker insertion within the recipient gene results in coconversion of the nearby palindromic site in more than half of the convertants, 4% of convertant colonies show both parental and nonparental genotypes at the polymorphic site. We consider these mixed colonies to be the result of genotypic sectoring and interpret this sectoring to be a consequence of unrepaired heteroduplex DNA at the polymorphic palindromic site. DNA replication through the heteroduplex recombination intermediate generates genetically distinct daughter cells that comprise a single colony. We believe that the data provide the first compelling genetic evidence for the presence of heteroduplex DNA during chromosomal gene conversion in mammalian cells.

Animals↗
PubMed1989

A novel telomeric gene conversion in Trypanosoma brucei.

Gene conversion is one mechanism of antigenic variation in Trypanosoma brucei. Variant surface glycoprotein (VSG) genes are duplicated by this process to telomeric locations from which they may be expressed. We examined four independent antigenic switches in which the IsTaR 1.1 minichromosomal VSG gene is duplicated to a large chromosome where it is expressed. An unusual feature of three of these telomeric gene conversions is that the distance between the VSG gene and the end of the chromosome is identical for both the basic and duplicated copies following the antigenic switch. This suggests that the gene conversion is initiated 5' to the VSG gene and extends to the end of the telomere. The data also suggest that events other than simple nucleotide addition account for telomeric growth.

Animals↗
PubMed1998

Frequent gene conversion between human red and green opsin genes.

To study the evolution of human X-linked red and green opsin genes, genomic sequences in large regions of the two genes were compared. The divergences in introns 3, 4, and 5 and the 3' flanking sequence of the two genes are significantly lower than those in exons 4 and 5. The homogenization mechanism of introns and the 3' flanking sequence of human red and green opsin genes is probably gene conversion, which also occurred in exons 1 and 6. At least one gene conversion event occurred in each of three regions (1, 3, and 5) in the sequences compared. In conclusion, gene conversion has occurred frequently between human red and green opsin genes, but exons 2, 3, 4, and 5 have been maintained distinct between the two genes by natural selection.

DNA↗
PubMed2004

Gene conversion and the evolution of protocadherin gene cluster diversity.

The synaptic cell adhesion molecules encoded by the protocadherin gene cluster are hypothesized to provide a molecular code involved in the generation of synaptic complexity in the developing brain. Variation in copy number and sequence content of protocadherin cluster genes among vertebrate species could reflect adaptive differences in protocadherin function. We have completed an analysis of zebrafish protocadherin cluster genes. Zebrafish have two unlinked protocadherin clusters, DrPcdh1 and DrPcdh2. Like mammalian protocadherin clusters, DrPcdh1 has both alpha and gamma variable and constant region exons. A consensus protocadherin promoter motif sequence identified in mammals is also conserved in zebrafish. Few orthologous relationships, however, are apparent between zebrafish and mammalian protocadherin proteins. Here we show that protocadherin cluster genes in human, mouse, rat, and zebrafish are subject to striking gene conversion events. These events are restricted to regions of the coding sequence, particularly the coding sequences of ectodomain 6 and the cytoplasmic domain. Diversity among paralogs is restricted to particular ectodomains that are excluded from conversion events. Conversion events are also strongly correlated with an increase in third-position GC content. We propose that the combination of lineage-specific duplication, restricted gene conversion, and adaptive variation in diversified ectodomains drives vertebrate protocadherin cluster evolution.

Animals↗
PubMed1994

A determination of the frequency of gene conversion in unmanipulated mouse sperm.

Gene conversion, sometimes also called micro gene conversion or gene conversion-like events, has been proposed to act on a number of genes in higher eukaryotes, such as gamma-globin, beta-tubulin, major urinary protein, and amyloid A genes. In the immune system, immunoglobulin genes and major histocompatibility complex class I and class II genes have been implicated. The notion that integral segments of DNA have been transferred from one gene to another in these cases has, however, met considerable resistance. We have devised a PCR assay detecting only the molecule that results if the E beta d-derived fragment analogous to that introduced in the bm12 mutation is transferred to the A beta k gene. We have proceeded to analyze sperm from the F1 cross C3H/HeJ (haplotype k) x BALB/c (haplotype d). In our assay, we find that the frequency for conversion of this particular DNA segment is 2 x 10(-6). This frequency is relevant only in the germ line; when liver cells were tested as an example of somatic cells, no events were observed, implying a frequency of < 2 x 10(-8) in liver. Fragments > 100 bp seem to be possible to transfer in this conversion.

Animals↗
PubMed2000

Gene conversion may aid adaptive peak shifts.

Gene conversion is often viewed as a homogenizing force that opposes adaptive evolution. The objective of this study is to suggest a potential role for gene conversion in adaptive evolution of proteins through aiding the transfer of a population from one adaptive peak to another. Our hypothesis starts with the observation that a tandem gene duplication may result in an extra gene copy that is released from selective constraints. In such cases, individually deleterious mutations may accumulate on the extra copy of the gene, and through gene conversion these mutations may subsequently be presented to the functioning gene for selection en masse. Thus, groups of mutations that jointly confer a selective advantage may regularly be made available for selection. We present a mathematical model of this process and identify the range of rates of gene conversion, gene duplication and mutation under which it may operate. The results indicate that the process may be biologically feasible if the rate of appearance of the potentially beneficial mutations is not too small in relation to the rates of null mutation and of gene conversion. This process appears to be a possible mechanism for effecting adaptive peak shifts in large populations. We show that all the evolutionary steps in the proposed model may have occurred in the evolution of primate gamma -globin genes. We suggest that hide-and-release mechanisms for genetic variation may constitute a more general principal of evolvability.

Adaptation, Physiological↗
PubMed1988

Mitotic gene conversion, reciprocal recombination and gene replacement at the benA, beta-tubulin, locus of Aspergillus nidulans.

We have developed a procedure for determining the rates of mitotic recombination of an interrupted duplication created by integration of transforming plasmid sequences at the benA, beta-tubulin, locus of Aspergillus nidulans. Transformation of a strain carrying a benomyl-resistant benA allele with plasmid AIpGM4, which carries the wild-type benA allele and the pyr4 (orotidine-5'-phosphate decarboxylase) gene of Neurospora crassa, creates an interrupted duplication with plasmid sequences flanked by two benA alleles, one wild type and one benomyl resistant. Such transformants will not grow in the presence of high levels of benomyl. Mitotic recombination causes the loss of the wild-type benA allele or conversion of the wild-type to the mutant allele resulting in nuclei carrying only the benomyl-resistant allele. Conidia containing such nuclei can be selected on media with high benomyl allowing easy quantitation of mitotic recombination. We found that the rate of recombination giving rise to benomyl-resistant conidia was 4.6 x 10(-4). Reciprocal recombination leading to benomyl-resistant conidia lacking plasmid sequences occurred at a rate of 2.0 x 10(-4) and gene conversion leading to benomyl-resistant conidia occurred at a rate of 2.6 x 10(-4). We selected for reciprocal recombination leading to loss of pyr4 sequences on 5-fluoro-orotic acid and used this selection for two-step gene replacement of a mutant benA allele with the wild-type allele.

Alleles↗
PubMed2005

Polymorphism and gene conversion of the 16S rRNA genes in the multiple rRNA operons of Vibrio parahaemolyticus.

The genome sequence of a strain of Vibrio parahaemolyticus holds 11 copies of rRNA operons (rrn) with identical 16S rRNA genes (rrs). Conversely, the species type strain contains two rrs classes differing in 10 nucleotide sites within a short segment of 25 bp. Furthermore, we show here that the sequence of this particular segment largely differs between some strains of this species. We also show that of the eleven rrn operons in the species type strain, seven contain one rrs class and four the other, indicating gene conversion. Our results support the hypothesis that the rrs differences observed between strains of this species were caused by lateral transfer of an rrs segment and subsequent conversion.

Base Sequence↗
PubMed1990

Gene conversion, linkage, and the evolution of repeated genes dispersed among multiple chromosomes.

The evolution of the probabilities of genetic identity within and between the loci of a multigene family dispersed among multiple chromosomes is investigated. Unbiased gene conversion, equal crossing over, random genetic drift, and mutation to new alleles are incorporated. Generations are discrete and nonoverlapping; the diploid, monoecious population mates at random. The linkage map is arbitrary, but the same for every chromosome; the dependence of the probabilities of identity on the location on each chromosome is formulated exactly. The greatest of the rates of gene conversion, random drift, and mutation is epsilon much less than 1. Under the assumption of loose linkage (i.e., all the crossover rates greatly exceed epsilon, though they may still be much less than 1/2), explicit approximations are obtained for the equilibrium values of the probabilities of identity and of the linkage of disequilibria. The probabilities of identity are of order one [i.e., O(1)] and do not depend on location; the linkage disequilibria are of O(epsilon) and, within each chromosome, depend on location through the crossover rates. It is demonstrated also that the ultimate rate and pattern of convergence to equilibrium are close to that of a much simpler, location-independent model. If intrachromosomal conversion is absent, the above results hold even without the assumption of loose linkage. In all cases, the relative errors are of O(epsilon). Even if the conversion rate between genes on nonhomologous chromosomes is considerably less than between genes on the same chromosome or homologous chromosomes, the probabilities of identity between the former genes are still almost as high as those between the latter, and the rate of convergence is still not much less than with equal conversion rates. If the crossover rates are much less than 1/2, then most of the linkage disequilibrium is due to intrachromosomal conversion. If linkage is loose, the reduction of the linkage disequilibria to O(epsilon) requires only O(-ln epsilon) generations.

Alleles↗
PubMed2004

Evidence against reciprocal recombination as the basis for tuf gene conversion in Salmonella enterica serovar Typhimurium.

The duplicate tuf genes on the Salmonella enterica serovar Typhimurium chromosome co-evolve by a RecA-, RecB-dependent gene conversion mechanism. Gene conversion is defined as a non-reciprocal transfer of genetic information. However, in a replicating bacterial chromosome there is a possibility that a reciprocal genetic exchange between different tuf genes sitting on sister chromosomes could result in "apparent" gene conversion. We asked whether the major mechanism of tuf gene conversion was classical or apparent. We devised a genetic selection that allowed us to isolate and examine both expected products from a reciprocal recombination event between the tuf genes. Using this selection we tested within individual cultures for a correlation in the frequency of jackpots as expected if recombination were reciprocal. We found no correlation, either in the frequency of each type of recombinant product, or in the DNA sequences of the products resulting from each recombination event. We conclude that the evidence argues in favor of a non-reciprocal gene conversion mechanism as the basis for tuf gene co-evolution.

Antiporters↗
PubMed1999

Gene conversion can create new MHC alleles.

It is possible to measure gene conversion of MHC genes with the help of a semi-nested PCR assay. Several considerations are of utmost importance when such an assay is set up. Using this assay, we have found that gene conversion occurs in MHC class II genes in mouse sperm, but not in somatic cells tested. Although this gene conversion occurs in germline cells, it is already completed in spermatogonia, and consequently is mitotic event unlinked to meiosis. The frequency of gene conversion events in MHC class II genes varies strongly from one allele to another, with the highest detected frequencies as high as 1/40,000 for an individual heterozygous for both donor and acceptor sequences. Deletions or insertions in one gene relative to the other seem to lower the efficiency of gene conversion considerably. Stretches within MHC genes amenable to gene conversion are located in CpG clusters, whereas MHC genes not involved in gene conversion have background CpG levels. DNA damage, either chemical or radiation induced, increases the frequency of gene conversion of MHC class II genes in cultured cells of the fibroblastoid lineage. The effect of chemical DNA damage seems roughly dose dependent, whereas irradiation has a maximal effect at low doses.

Alleles↗
PubMed1997

Evidence for gene conversion between tandemly duplicated cytoplasmic actin genes of Helicoverpa armigera (Lepidoptera:Noctuidae)

Tandemly duplicated actin genes have been isolated from a Helicoverpa armigera genomic library. Sequence comparisons with actin genes from other species suggest they encode cytoplasmic actins, being most closely related to the Bombyx mori A3 actin gene. The duplicated H. armigera actin genes, termed A3a and A3b, share 98.3% nucleotide sequence identity over their entire putative coding region. Analysis of the distribution of nucleotide differences shows the first 763 bp are identical between the two coding regions, with the 18 nucleotide changes occurring in the remaining 366 bp. This observation suggests a gene conversion event has taken place between the duplicated H. armigera A3a and A3b actin genes. Translation of the open-reading frames indicates the products of these genes are identical, apart from a single amino acid difference at codon 273. Polymerase chain reaction and northern blot analysis have shown both H. armigera A3a and A3b genes are expressed during pupal development and in the brain of newly enclosed adults. A region 5' of the H. armigera A3a actin gene start codon has been identified which contains regulatory sequences commonly found in the promoter region of actin genes, including TATA, CAAT, and CArG motifs.

Actins↗
PubMed1995

Gene conversions and unequal crossovers between CYP21 (steroid 21-hydroxylase gene) and CYP21P involve different mechanisms.

Most cases of congenital adrenal hyperplasia, the inherited inability to synthesize cortisol, are caused by mutations in the steroid 21-hydroxylase gene (CYP21). Steroid 21-hydroxylase deficiency is unusual among genetic diseases in that approximately 95% of the mutant alleles have apparently been generated by recombination between a normally active gene (CYP21) and a linked pseudogene (CYP21P). Approximately 20% of mutant alleles carry DNA deletions of 30 kb that have presumably been generated by unequal meiotic crossing-over, whereas 75% carry one or more mutations in CYP21 that are normally found in the CYP21P pseudogene. These latter mutations are termed "gene conversions," although the mechanism by which they are generated is not well understood. To assess the frequency at which these different recombination events occur, we have used PCR to detect de novo deletions and gene conversions in matched sperm and peripheral blood leukocyte DNA samples from normal individuals. Deletions with breakpoints in a 100-bp region in intron 2 and exon 3 were detected in sperm DNA samples with frequencies of approximately 1 in 10(5)-10(6) genomes but were never detected in the matching leukocyte DNA. Gene conversions in the same region occur in approximately 1 in 10(3)-10(5) genomes in both sperm and leukocyte DNA. These data suggest that whereas deletions occur exclusively in meiosis, gene conversions occur during both meiosis and mitosis, or perhaps only during mitosis. Thus, gene conversions must occur by a mechanism distinct from unequal crossing-over.

Adrenal Hyperplasia, Congenital↗