Gene conversion and the evolution of gene families in mammals.
Explore the source record for details and available documents.
Animals↗
SEARCH · Search PubMed
Results for “Gene Conversion”
Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.
Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.
Genetic analysis of the ADGF multigene family by homologous recombination and gene conversion in Drosophila.
Many Drosophila genes exist as members of multigene families and within each family the members can be functionally redundant, making it difficult to identify them by classical mutagenesis techniques based on phenotypic screening. We have addressed this problem in a genetic analysis of a novel family of six adenosine deaminase-related growth factors (ADGFs). We used ends-in targeting to introduce mutations into five of the six ADGF genes, taking advantage of the fact that five of the family members are encoded by a three-gene cluster and a two-gene cluster. We used two targeting constructs to introduce loss-of-function mutations into all five genes, as well as to isolate different combinations of multiple mutations, independent of phenotypic consequences. The results show that (1) it is possible to use ends-in targeting to disrupt gene clusters; (2) gene conversion, which is usually considered a complication in gene targeting, can be used to help recover different mutant combinations in a single screening procedure; (3) the reduction of duplication to a single copy by induction of a double-strand break is better explained by the single-strand annealing mechanism than by simple crossing over between repeats; and (4) loss of function of the most abundantly expressed family member (ADGF-A) leads to disintegration of the fat body and the development of melanotic tumors in mutant larvae.
Animals↗
Yeast intrachromosomal recombination: long gene conversion tracts are preferentially associated with reciprocal exchange and require the RAD1 and RAD3 gene products.
A yeast intrachromosomal recombination system based on an inverted repeat has been designed to examine mitotic gene conversion tract length and the association of crossing over with gene conversion as a function of the conversion tract length. Short conversion tracts are found to be preferentially noncrossover while conversion tracts longer than 1.16 kb show a 50% association with crossover. Mutation in the excision repair gene RAD1 leads to a reduction in conversion tracts of at least 1.16 kb and a reduction in crossovers associated with conversion, regardless of the length of the conversion tract. Mutation in the excision repair gene RAD3, which encodes a DNA helicase, also leads to a reduction in conversion tracts of at least 1.16 kb, but has no effect on the frequency of associated crossovers. The roles of RAD1 and RAD3 in recombination are discussed.
Chromosome Inversion↗
Intrachromosomal gene conversion frequency in the H2 differs between haplotypes.
We examined two intrachromosomal gene conversion events with a polymerase chain reaction assay at the DNA level between the two major histocompatibility complex class II genes Eb and Ab in mice sperm before selection has occurred. The frequency of the intrachromosomal gene conversion event between Ebd and Abd was found to be at least one order of magnitude higher than between Ebk and Abk in the same mice. Parental imprinting of the genes appears not to have an effect on gene conversion, as both (dxk)F1 and (kxd)F1 mice have indistinguishable frequencies in both haplotypes. The number of DNA copies of the donor and acceptor genes present in the cell at the time of mutation does not seem to influence the frequency of the intrachromosomal gene conversion in the k haplotype, whereas the frequency in the d haplotype is increased when double the number of donor and acceptor genes is present. The DNA fragment transferred between Ebd and Abd is invariably short, and need not comprise more than six nucleotides. The fragment transferred within the k haplotype varies in length, and can attain at least 100 nucleotides. The difference between the haplotypes both in length and frequency might be attributed to a six-nucleotide deletion in the Abk gene, which might make base-pairing between the genes less efficient and less precise.
Amino Acid Sequence↗
Duplication, gene conversion, and genetic diversity in the species-specific acyl-CoA synthetase gene family of Plasmodium falciparum.
While genes encoding antigens and other highly polymorphic proteins are commonly found in subtelomeres, it is unusual to find a small family of housekeeping genes in these regions. We found that in the species Plasmodium falciparum only, a non-subtelomeric acyl-CoA synthetase (ACS) gene has expanded into a family of duplicated genes mainly located in the subtelomeres of the genome. We identified the putative parent of the duplicated family by analysis of synteny and phylogeny relative to other Plasmodium ACS genes. All ten ACS paralogs are transcribed in erythrocytic stages of laboratory and field isolates. We identified and confirmed a recent double gene conversion event involving ACS genes on three different chromosomes of isolate 3D7, resulting in the creation of a new hybrid gene. Southern hybridization analysis of geographically diverse P. falciparum isolates provides evidence for the strikingly global conservation of the ACS gene family, but also for some chromosomal events, including deletion and recombination, involving the duplicated paralogs. We found a dramatically higher rate of non-synonymous substitutions per non-synonymous site than synonymous substitutions per synonymous site in the closely related ACS paralogs we sequenced, suggesting that these genes are under a form of selection that favors change in the state of the protein. We also found that the gene encoding acyl-CoA binding protein has expanded and diversified in P. falciparum. We have described a new class of subtelomeric gene family with a unique capacity for diversity in P. falciparum.
Animals↗
The disease resistance gene Dm3 is infrequent in natural populations of Lactuca serriola due to deletions and frequent gene conversions at the RGC2 locus.
Resistance genes can exhibit heterogeneous patterns of variation. However, there are few data on their frequency and variation in natural populations. We analysed the frequency and variation of the resistance gene Dm3, which confers resistance to Bremia lactucae (downy mildew) in 1033 accessions of Lactuca serriola (prickly lettuce) from 49 natural populations. Inoculations with an isolate of Bremia lactucae carrying avirulence gene Avr3 indicated that the frequency of Dm3 in natural populations of L. serriola was very low. Molecular analysis demonstrated that Dm3 was present in only one of the 1033 wild accessions analysed. The sequence of the 5' region of Dm3 was either highly conserved among accessions, or absent. In contrast, frequent chimeras were detected in the 3' leucine-rich repeat-encoding region. Therefore low frequency of the Dm3 specificity in natural populations was due to either the recent evolution of Dm3 specificity, or deletions of the whole gene as well as variation in 3' region caused by frequent gene conversions. This is the most extensive analysis of the prevalence of a known disease resistance gene to date, and indicates that the total number of resistance genes in a species may be very high. This has implications for the scales of germplasm conservation and exploitation of sources of resistance.
5' Untranslated Regions↗
Mitotic gene conversion of large DNA heterologies in Saccharomyces cerevisiae.
Gene conversion of large DNA heterologous fragments has been shown to take place efficiently in Saccharomyces cerevisiae. It has been found that a 2.6 kb LEU2 DNA fragment in a multicopy plasmid was replaced by a 3.1 kb PGI1 chromosomal DNA fragment, when both fragments were flanked by homologous DNA regions. Gene conversion was asymmetric in a total of 481 recombinants analyzed. In contrast, truncated PGI1 or LEU2 genes in multicopy plasmids, gave no recombinants that restored a complete plasmid copy of these genes in a total of 242 recombinants studied, confirming that a conversion tract is disrupted by a heterologous region. The asymmetry of the events detected suggest that gene conversion of large DNA heterologies involves a process whereby a gap first covers one heterologous fragment and then this is followed by new DNA synthesis using the other heterologous fragment as a template. Therefore, it is likely that large DNA heterologies are converted by a double-strand gap repair mechanism.
DNA, Fungal↗
Analysis of individual immunoglobulin lambda light chain genes amplified from single cells is inconsistent with variable region gene conversion in germinal-center B cell somatic mutation.
Responding B cells in specific immune responses diversify their immunoglobulin genes and are selected on their variant antigen receptors in the microenvironment of the germinal center. The patterns of mutations previously reported for immunglobulin (Ig) genes have supported mechanistic hypotheses of either error-prone DNA synthesis or templated variable region gene conversion as the underlying mechanism in the generation of these mutations. To assess the role of gene conversion in germinal-center somatic mutation, we chose to examine nucleotide changes in mouse lambda light chain genes which arose in response to a specific antigen. Laboratory mice possess three V lambda subexons, two of which differ from one another by only seven nucleotides, making these two subexons ideal for gene conversion. In the current study, we used six-parameter flow cytometry to isolate single lambda light chain-expressing germinal-center B cells from two different time points in a primary immune response. We then individually amplified and sequenced individual V lambda 1 genes from these single cells for mutational analysis. None of the 32 V lambda 1 genes, containing a total of 40 mutations, showed evidence of gene conversion from either of the other V lambda subexons. Features such as the replacement to silent ratio of the mutations documented at the earlier time point indicate an absence of antigen-driven selection. These data indicate that V region gene conversion does not contribute to germinal-center somatic mutation and that gene conversion is not responsible for targeting mutation specifically to rearranged Ig genes. The biological implications are discussed.
Amino Acid Sequence↗
Requirement of the activation-induced deaminase (AID) gene for immunoglobulin gene conversion.
Three phenotypically distinct processes-somatic hypermutation, gene conversion, and switch recombination-remodel the functionally rearranged immunoglobulin (Ig) loci in B cells. Somatic hypermutation and switch recombination have recently been shown to depend on the activation-induced deaminase (AID) gene product. Here, we show that the disruption of the AID gene in the chicken B cell line DT40 completely blocks Ig gene conversion and that this block can be complemented by reintroduction of the AID complementary DNA. This demonstrates that the AID master gene controls all B cell-specific modifications of vertebrate Ig genes.
Alleles↗
Gene conversion: a mechanism for generation of heterogeneity in the tprK gene of Treponema pallidum during infection.
The tprK gene sequence of Treponema pallidum subspecies pallidum (T. pallidum) is heterogeneous within and among isolates. Heterogeneity in the tprK open reading frame is localized in seven discrete variable (V) regions, and variability results from apparent base changes, insertions or deletions. The TprK V regions are the focus of anti-TprK antibodies arising during infection. To test our hypothesis that V region sequences change during infection and passage, we developed a clonal isolate from the Chicago strain of T. pallidum and confirmed V region diversification during passage of this isolate. We describe the sequence anatomy of the seven V regions of tprK and the identification of putative donor sites for new V region sequences, and we propose a model for generation of new V regions by segmental gene conversion. These findings suggest that antigenic variation of TprK occurs in T. pallidum and may be important in immune evasion and persistence.
Amino Acid Sequence↗
Gene conversion and differential regulation in the rat P-450 IIA gene subfamily. Purification, catalytic activity, cDNA and deduced amino acid sequence, and regulation of an adult male-specific hepatic testosterone 15 alpha-hydroxylase.
Previous studies on regulation of the rat hepatic P-450 IIA1 cDNA have provided evidence for a second gene closely related to but regulated in a manner quite distinct from P-450 IIA1. Experiments were carried out to isolate the cDNA for this second P-450 gene, designated IIA2, in order to study more directly its regulation and relationship to IIA1. A full length cDNA to IIA2 was isolated from an adult male rat liver lambda gt11 library and sequenced completely. The IIA2 cDNA shared 93% nucleotide and 88% deduced amino acid similarities with the previously characterized IIA1 cDNA (Nagata, K., Matsunaga, T., Gillette, J., Gelboin, H. V., and Gonzalez, F. J. (1987) J. Biol. Chem. 262, 2787-2793). The protein, deduced from the cDNA, contained 492 amino acids and a calculated Mr of 56,352. Comparison of the IIA1 and IIA2 cDNAs revealed areas of low nucleotide similarity interspersed with areas of absolute identity, suggesting that gene conversions have played a role in the evolution of the IIA subfamily. Expression of IIA1 and IIA2 mRNAs in rat liver during development was studied with use of specific oligonucleotide probes. IIA1 mRNA was increased within 1 week after birth in both male and female rats; however, its postpubertal expression was decreased in males yet remained elevated in females. In contrast, IIA2 mRNA was markedly induced in male rat liver at puberty but was not detectable in females at any age examined. Furthermore, only IIA1 mRNA was induced by treatment of rats with 3-methylcholanthrene. Although IIA1 and IIA2 mRNAs were actively expressed in hepatic tissue, no evidence for their expression was found in lung, kidney, or intestine, suggesting that the IIA genes have tissue-specific promoters. Reconstituted enzyme assays on the purified protein products P-450 IIA1 and P-450 IIA2 showed that, although both enzymes share considerable sequence similarity, their positional specificities toward the prototype substrate testosterone are strikingly different.
Amino Acid Sequence↗
Gene conversion within regulatory sequences generates maize r alleles with altered gene expression.
The maize r locus encodes a transcription factor that regulates the developmental expression of the plant pigment anthocyanin. In an unusual example of gene regulatory diversity, the R-sc (Sc, strong seed color) and the R-p (P, plant color) alleles of r have nonoverlapping tissue specificity and nonhomologous 5' flanking sequences. Heterozygotes between wild-type P and Sc mutants with Ds6 transposable element inserts (r-sc:m::Ds6 or sc:m) produce colored seed derivatives (Sc+) during meiotic recombination. The sc:m alleles with Ds6 insertion in 3' regions of r produce crossover Sc+ derivatives. sc:m alleles with Ds6 elements inserted in 5' regions produce rare Sc+ derivatives borne on nonrecombinant chromosomes. Among 52 such noncrossover Sc+ derivatives, 18 are indistinguishable from the Sc progenitor in phenotype and DNA sequence [Scp(+) alleles]. The remaining 34 derivatives have strong Sc+ expression, including darkly pigmented aleurone, scutellum, coleoptile, and scutellar node [Scp(e) alleles]. The coleoptile and scutellar node phenotypes are unique from either progenitor but are similar to those of some naturally occurring r alleles. Both classes of Sc+ derivatives are explained by gene conversion between the promoter region of Sc:124 and a homologous region located proximal to P. The recombinational intermediate formed between sc:m alleles and P results in deletion of the Ds6 element alone or both Ds6 and a nearby unrelated transposable element-like sequence.
Alleles↗
Gene conversion events contribute to the polymorphic variation of the surrogate light chain gene lambda 5/14.1.
Normally occurring and experimentally induced models of immunodeficiency indicate that B cell development and antibody production are influenced by genetic factors. It is highly likely that polymorphic variants in genes that encode receptors for growth and differentiation factors, signal transduction molecules, and components of the B cell and pre-B-cell receptor complex contribute to this genetic control. We have identified a surprisingly large number of polymorphic variants in lambda5/14.1. Together with VpreB, lambda5/14.1 forms the surrogate light chain in the pre-B-cell receptor complex. Thirteen variant alleles of lambda5/14.1 were found in 134 unrelated individuals. Nine of these variants result in changes in the amino acid sequence of this small protein. The majority of the single base pair substitutions in lambda5/14.1 could be attributed to gene conversion events in which donor sequences from the lambda5 pseudogenes, 16.1, 16.2, and Glambda1, replace the wild-type sequence in the lambda5/14.1 functional gene. These findings indicate that gene conversion events play a major role in generating diversity that could affect stability or expression of the pre-B-cell receptor complex.
Alleles↗
Gene conversion and natural selection in the evolution of X-linked color vision genes in higher primates.
During higher primate evolution, gene conversion seems to have occurred often between the red and green photo-pigment genes, which are tandemly linked on the X chromosome. To understand this phenomenon better, intron 4 sequences of the red and green pigment genes of a male human (an Asian Indian), a male chimpanzee, and a male baboon were amplified by PCR and sequenced. The data show that the intron 4 sequences between the two genes have been strongly or completely homogenized in the three species studied. Apparently recent gene conversion events have occurred in introns 4 of the red and green pigment genes in humans and chimpanzees. Two or more conversion events may have occurred at different times in introns 4 of the two pigment genes in baboons. The divergence between the two genes is significantly lower in intron 4 than in exons 4 and 5 in each species, contrary to the usual situation that introns evolve faster than exons. It is most likely that strong natural selection for maintaining the distinct functions of exons 4 and 5 of the red and green pigment genes has acted against sequence homogenization of these exons.
Animals↗
Association of reciprocal exchange with gene conversion between the repeated segments of 2-micron circle.
The occurrence of reciprocal exchange of flanking DNA during gene conversion between the repeated segments of the yeast plasmid, 2-micron circle has been examined. The conversion event is induced by making a double-stranded gap within one of the repeats in vitro and allowing the gap to be repaired in vivo. The repair takes place with frequent recombination of flanking markers. Neither the topology of the plasmid substrates (linear or circular) nor the relative orientation of the repeats affects the association rule significantly. These events are reminiscent of meiotic gene conversion between homologous chromosomes but contrast sharply with mitotic or meiotic intrachromosomal gene conversion. It would appear that the difference between the outcomes of intramolecular gene conversion on a chromosome and on a plasmid gapped in vitro does not result from the different physical states of intracellular versus transformed DNA. A gene conversion event in a 2-micron circle : : Tn5 plasmid mediated by the 2-micron circle recombinase (FLP) in vivo, which is formally analogous to the yeast mating type interconversion, often results in recombination of flanking markers. The reaction can be mimicked, in the absence of FLP, by gapping the plasmid within one of the 2-micron circle repeats in vitro and carrying out gap repair in vivo.
DNA Nucleotidyltransferases↗
Mechanisms for gene conversion and homologous recombination: the double-strand break repair model and the successive half crossing-over model.
Two mechanisms for gene conversion and homologous recombination were discussed. (1) The double-strand break repair model. A double-strand break is expanded to a gap, which is then repaired by copying a homologous sequence. The gene conversion is often accompanied by crossing-over of the flanking sequences. We obtained evidence for this model in Red pathway of bacteriophage lambda and RecE pathway of E. coli. (2) The successive half crossing-over model. Half crossing-over leaves one recombinant duplex and one or two end(s) out of two parental duplexes. The resulting ends are, in turn, recombinogenic. Successive rounds of the half crossing-over mechanism explains why apparent plasmid gene conversion in RecF pathway of E. coli is not accompanied by crossing-over. This model can explain chromosomal gene conversion if we assume that the donor is first replicated. Gene conversion during mating-type switching in yeast, antigenic variation in unicellular microorganisms, and chromosomal gene conversion in mammalian somatic cells are explained by this model. Distinguishing between these two mechanisms is important in understanding recombination in yeast and mammalian cells and also in its application to gene targeting.
Animals↗
Length and distribution of meiotic gene conversion tracts and crossovers in Saccharomyces cerevisiae.
We have measured gene conversion tract length in strains of the yeast Saccharomyces cerevisiae containing three to six restriction site heterozygosities in a 9-kb interval. Tetrads containing a conversion were identified genetically by nonmendelian segregation of a marker in the middle of the interval. Gene conversions accompanied by a crossover have a tract length of 1.4 kb +/- 0.7 kb, which is indistinguishable from a tract length of 1.6 +/- 0.8 for conversions without an associated exchange. Among tetrads identified first as having a crossover in the interval, the average gene conversion tracts were apparently significantly shorter (0.71 +/- 1). We provide evidence that this apparent difference is due to the method of measuring conversion tracts and does not reflect a real difference in tract length. We also provide evidence that the number and position of restriction site markers alters the apparent distribution of the conversion tracts. More than ninety percent of the conversion tracts spanning three or more sites were continuous.
Chromosome Mapping↗
Gene conversion accounts for pilin structural changes and for reversible piliation "phase" changes in gonococci.
Pilus+ "wild-type" gonococci (Gc) frequently display gene conversion of their expressed complete pilin gene (CPG); a copy of DNA derived from one of the Gc genome's multiple silent partial pilin genes (PPG) is recombinationally-inserted into the CPG's central and 3' portions with formation of a new, chimeric CPG. Expression of that new CPG leads to either 1) retention of pilus+ phenotype but change in pilin primary structure/antigenicity, or 2) phase change to pilus- phenotype capable of reverting. This study utilizes pilus revertants of P-rp +/- Gc and P+ colony morphotype variants spawned by P++ Gc to examine pilin gene conversion in strain MS11mk Gc in greater detail. Each revertant's and variant's expressed pilin gene's sequence (as pilin mRNA) was defined to learn whether their differences are due to gene conversion by different PPGs, or by varying stretches from the same PPG, or both. Gene conversion by PPG pilS1 copy 2 has been documented in Gc recovered from a human volunteer's urethra previously inoculated with pilus Gc (strain MS11). The pilus+ Gc isolated expressed structurally/antigenically distinct pilins.
Amino Acid Sequence↗