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PubMed2004

Dynamics of a human interparalog gene conversion hotspot.

Gene conversion between paralogs can alter their patterns of sequence identity, thus obscuring their evolutionary relationships and affecting their propensity to sponsor genomic rearrangements. The details of this important process are poorly understood in the human genome because allelic diversity complicates the interpretation of interparalog sequence differences. Here we exploit the haploid nature of the Y chromosome, which obviates complicating interallelic processes, together with its known phylogeny, to understand the dynamics of conversion between two directly repeated HERVs flanking the 780-kb AZFa region on Yq. Sequence analysis of a 787-bp segment of each of the HERVs in 36 Y chromosomes revealed one of the highest nucleotide diversities in the human genome, as well as evidence of a complex patchwork of highly directional gene conversion events. The rate of proximal-to-distal conversion events was estimated as 2.4 x 10(-4) to 1.2 x 10(-3) per generation (3.9 x 10(-7) to 1.9 x 10(-6) per base per generation), and the distal-to-proximal rate as about one-twentieth of this. Minimum observed conversion tract lengths ranged from 1 to 158 bp and maximum lengths from 19 to 1365 bp, with an estimated mean of 31 bp. Analysis of great ape homologs shows that conversion in this hotspot has a deep evolutionary history.

Animals↗
PubMed1999

Gene conversion of major histocompatibility complex genes is associated with CpG-rich regions.

We examined 32 DNA sequences of mouse and human major histocompatibility complex (MHC) genes believed to have been subjected to gene conversion events. All regions of the mouse H2 genes as well as the human HLA genes which have been implied to be involved in gene conversion events had elevated levels of CpG dinucleotides, whereas the rest of the genes showed extensive CpG suppression. Mouse MHC genes which have been suspected but not directly implied to be involved in gene conversion events also showed elevated levels of CpG dinucleotides. Moreover, both mouse and human MHC genes which have never been suspected of undergoing gene conversion had low levels of CpG throughout the genes. These results indicate that high CpG levels are correlated with gene conversion rather than with polymorphism, as non-polymorphic genes that have been implicated as gene conversion donors also have elevated levels of CpG dimers in the involved regions, whereas polymorphic genes which have never been considered to undergo gene conversion events have a low level of CpG dinucleotides. We also studied the methylation pattern of CpG dimers in the Abk gene by restriction enzyme digestion of mouse testis DNA followed by Southern blot and hybridization to an Abk-specific probe. The examined CpG dimers in prepubescent mice, where the latest germline stages are spermatogonia, leptene, or pachytene, are respectively non-methylated. Accordingly, the CpG dimers appear to be non-methylated in germline DNA from the testis of prepubescent mice, where gene conversions have been reported to occur.

Animals↗
PubMed2002

Enhancer of terminal gene conversion, a new mutation in Drosophila melanogaster that induces telomere elongation by gene conversion.

Telomeres of Drosophila melanogaster contain arrays of the retrotransposon-like elements HeT-A and TART. Terminally deleted chromosomes can be maintained for many generations. Thus, broken chromosome ends behave as real telomeres. It was previously shown that gene conversion may extend the broken ends. Here we found that the frequency of terminal DNA elongation by gene conversion strongly depends on the genotype. A dominant E(tc) (Enhancer of terminal gene conversion) mutation markedly increases the frequency of this event but does not significantly influence the frequency of HeT-A and TART attachment to the broken chromosome end and recombination between directly repeated sequences at the end of the truncated chromosome. The E(tc) mutation was mapped to the 91-93 region on chromosome 3. Drosophila lines that bear the E(tc) mutation for many generations have telomeres, consisting of HeT-A and TART elements, that are longer than those found in wild-type lines. Thus, the E(tc) mutation plays a significant role in the control of telomere elongation in D. melanogaster.

Animals↗
PubMed1997

Gene conversion of major histocompatibility complex genes in the mouse spermatogenesis is a premeiotic event.

The molecular genetic mechanism of gene conversion in higher eukaryotes remains unknown. We find it of considerable interest to determine when during spermatogenesis gene conversion occurs. We have therefore purified pachytene spermatocytes and haploid spermatocytes from adult mice and analyzed these fractions for the presence of gene conversion products resulting from the transfer between the major histocompatibility complex class II genes Ebd and Abk in a polymerase chain reaction assay. We have further isolated spermatogenic cells from prepubescent mice and analyzed them for the presence of the same gene conversion products. We can detect gene conversion products in testis cells as early as in 8-d-old mice where the only existing spermatogenic cells are spermatogonia. The frequency of gene conversion products remains the same as the cells reach meiosis in 18-d-old mice, and is unchanged after meiosis is completed in haploid spermatocytes. Gene conversion of this specific fragment therefore appears to be a premeiotic event and, consequently, relies on genetic mechanisms other than normal meiotic recombination.

Aging↗
PubMed2005

Gene conversion between functional trypsinogen genes PRSS1 and PRSS2 associated with chronic pancreatitis in a six-year-old girl.

Gene conversion--the substitution of genetic material from another gene--is recognized as the underlying cause of a growing number of genetic diseases. While in most cases conversion takes place between a normal gene and its pseudogene, here we report an occurrence of disease-associated gene conversion between two functional genes. Chronic pancreatitis in childhood is frequently associated with mutations of the cationic trypsinogen gene (serine protease 1; PRSS1). We have analyzed PRSS1 in 1106 patients with chronic pancreatitis, and identified a novel conversion event affecting exon 2 and the subsequent intron. The recombination replaced at least 289 nucleotides with the paralogous sequence from the anionic trypsinogen gene (serine protease 2; PRSS2), and resulted in the PRSS1 mutations c.86A > T and c.161A > G, causing the amino acid substitutions N29I and N54S, respectively. Analysis of the recombinant N29I-N54S double mutant cationic trypsinogen revealed increased autocatalytic activation, which was solely due to the N29I mutation. In conclusion, we have demonstrated that gene conversion between two functional paralogous trypsinogen genes can occur and cause genetically determined chronic pancreatitis.

Adolescent↗
PubMed1997

Timing and effects of template number for gene conversion of major histocompatibility complex genes in the mouse.

Pachytene spermatocytes and haploid spermatocytes from adult mice, as well as testis cells from prepubescent mice were analysed for the presence of gene conversion products resulting from the transfer between the MHC class II genes Ebd and Abk in a PCR assay. Gene conversion products were detected in testis cells as early as in 8 days old mice, where the only existing spermatogenic cells are spermatogonia. The frequency of gene conversion products remains the same as the cells reach meiosis in 18 days old mice or in pachytene cells, and is unchanged after meiosis is completed in haploid spermatocytes, thus indicating that gene conversion is largely completed already in the mitotically dividing spermatogonia. We have furthermore analysed the frequency of gene conversion between the Eb and Ab loci within the same MHC haplotype, the k haplotype. The frequency of such events is the same in animals with one and two copies of the same haplotype, and consequently seems to be independent of template number.

Animals↗
PubMed1990

CYP21B gene conversion and complete CYP21A gene deletion in congenital adrenal hyperplasia.

We studied a family in which one out of two children presented a non-salt wasting form of CAH. Genomic DNA of the patient, his brother, his parents and a normal control were digested by the Taq I and Bgl II restriction enzymes. The fragments were electrophoresed, transferred onto a nitrocellulose membrane and hybridized with two specific probes: pC21a for the CYP21 genes and pAT-A for the C4 genes. We performed simultaneous RFLP analyses of the CYP21 and C4 genes and determined the relative hybridization intensity of the genes using scanning densitometry of the X-ray films. The affected child had a CYP21B gene conversion in the CYP21A pseudogene on one chromosome inherited from his mother and a mutated CYP21B gene on the second chromosome inherited from his father. The second maternal chromosome, inherited by the unaffected brother, presented an unusual CYP21A gene deletion without a C4A or C4B gene deletion. Although CYP21A is a pseudogene, this type of complete CYP21A gene deletion associated with a CYP21B gene conversion has never been previously described.

Adrenal Hyperplasia, Congenital↗
PubMed1992

Detecting gene conversion: primate visual pigment genes.

The effects of gene conversion can be detected in the DNA sequences of multigene families. We develop a permutation test of the significance of patterns of sequence mismatches, and apply it to the sequences of the red- and green-sensitive visual pigment genes of human and the diana monkey. Whereas conventional tests of the rate of sequence divergence are equivocal, the permutation test convincingly excludes divergence in the absence of gene conversion (p = 10(-6)).

Animals↗
PubMed2006

Gene conversion in human rearranged immunoglobulin genes.

Over the past 20 years, many DNA sequences have been published suggesting that all or part of the V(H) segment of a rearranged immunoglobulin gene may be replaced in vivo. Two different mechanisms appear to be operating. One of these is very similar to primary V(D)J recombination, involving the RAG proteins acting upon recombination signal sequences, and this has recently been proven to occur. Other sequences, many of which show partial V(H) replacements with no addition of untemplated nucleotides at the V(H)-V(H) joint, have been proposed to occur by an unusual RAG-mediated recombination with the formation of hybrid (coding-to-signal) joints. These appear to occur in cells already undergoing somatic hypermutation in which, some authors are convinced, RAG genes are silenced. We recently proposed that the latter type of V(H) replacement might occur by homologous recombination initiated by the activity of AID (activation-induced cytidine deaminase), which is essential for somatic hypermutation and gene conversion. The latter has been observed in other species, but not in human Ig genes, so far. In this paper, we present a new analysis of sequences published as examples of the second type of rearrangement. This not only shows that AID recognition motifs occur in recombination regions but also that some sequences show replacement of central sections by a sequence from another gene, similar to gene conversion in the immunoglobulin genes of other species. These observations support the proposal that this type of rearrangement is likely to be AID-mediated rather than RAG-mediated and is consistent with gene conversion.

Base Sequence↗
PubMed1999

Evolution of class I alcohol dehydrogenase genes in catarrhine primates: gene conversion, substitution rates, and gene regulation.

The three class I alcohol dehydrogenases (ADHs) in humans comprise homo- and heterodimers of three subunits (alpha, beta, and gamma) with greater than 90% sequence identity. These are encoded by distinct genes (ADH1, ADH2, and ADH3, respectively) and are all expressed in the liver. In baboons, only the beta ADH subunit is expressed in liver. A second class I ADH is expressed in the kidney; we isolated, cloned, and sequenced the cDNA corresponding to this ADH and conclude that it is of the gamma ADH lineage. We also amplified and sequenced the 5' noncoding regions of all three class I baboon ADH genes and the rhesus monkey ADH1 gene and compared their nucleotide sequences with the corresponding human sequences. There is clear evidence that the evolution of these genes has been reticulate. At least three gene conversion events, affecting the coding and 3' noncoding regions of the genes, are inferred from compatibility and partition matrices and phylogenetic analysis of the sequences. Our estimation of the evolutionary history of these genes provides a framework for the investigation of relative substitution rates and functional variation among the sequences. Relative-rate tests, designed to account for the reticulate evolution of these genes, indicate no difference in substitution rate either between genes encoding different subunits or between human and Old World monkey lineages. The human and baboon gamma ADH sequences do not show clear differences at functionally important sites within the coding region, but they do differ at a number of sites in regions previously proposed to be regulatory sites for transcriptional control. This variation may explain the different patterns of gene expression in humans and baboons.

Alcohol Dehydrogenase↗
PubMed1988

Evidence for gene conversion between the phosphoglycerate kinase genes of Trypanosoma brucei.

Trypanosoma brucei contains a tandem array of three genes for phosphoglycerate kinase (PGKase), genes A, B and C, each coding for a different protein. We have compared allelic variants of this gene array and find evidence for gene conversion between the three genes. Near the 3' end, the different alleles and gene B contain a variable sequence that is similar to the corresponding sequence in either gene A or gene C. This sequence is flanked by glycine triplets that are conserved in all PGKases from bacteria to mammals. The triplets are encoded by (GGT)n, resulting in sequences that resemble the recombination-promoting chi-sites of Escherichia coli. Upstream of the variable sequence, there is an area of 800 base-pairs in which genes A, B and C are highly homologous; in all three genes this region ends with a sharp boundary at which gene B again shows segmental homology with both genes A and C. These results suggest that repeated gene conversion events partially erase the differences between genes A, B and C that arise in evolution and suggest that chi-like sequences may act as recombinational hotspots in protozoa such as T. brucei.

Amino Acid Sequence↗
PubMed1996

Gene conversion in the CYP11B2 gene encoding P450c11AS is associated with, but does not cause, the syndrome of corticosterone methyloxidase II deficiency.

Cytochrome P450c11AS (aldosterone synthase) has 11 beta-hydroxylase, 18-hydroxylase, and 18-oxidase activities and is expressed solely in the adrenal zona glomerulosa. Corticosterone methyloxidase II (CMOII) deficiency denotes a rare disorder of adrenal steroidogenesis in which only the 18-oxidase activity of P450c11AS is disrupted, while the 11 beta-hydroxylase and 18-hydroxylase activities persist. Such patients have elevated serum concentrations of corticosterone and 18-hydroxycorticosterone and very low or unmeasurable concentrations of aldosterone, often resulting in a clinical salt-losing crisis in infancy. One pair of point mutations, Arg181-->Trp and Val386-->Ala, has been previously characterized to cause this disorder in an inbred Iranian Jewish population. We have sought mutations causing CMOII deficiency in outbred populations. In three of four unrelated P450c11AS alleles from two unrelated patients with CMOII deficiency, we found a gene conversion event in which exons 3 and 4 of the CYP11B2 gene encoding P450c11AS were changed to the sequence of the nearby CYP11B1 gene, which encodes the related enzyme P450c11 beta. This conversion resulted in a mutant P450c11AS protein carrying three changes: Asp141-->Glu, Lys151-->Asn, and Ile246-->Thr. We built seven vectors expressing P450c11AS carrying each mutation singly, each of the three possible pairs of mutations, and the triple mutation as found in the proband. The activities of both the normal P450c11AS and the various mutants in transfected nonsteroidogenic COS-1 cells were very low, but their activities in steroidogenic MA-10 and JEG-3 cells were 10- to 20-fold higher. In these systems all of the mutants retained normal 18-oxidase activity, indicating that the detected gene conversion event is associated with but does not cause CMOII deficiency. None of the four CYP11B2 alleles in these two patients bore other identifiable mutations. These patients might have mutations in the promoters or other noncoding regions, or mutations in genes other than CYP11B2 may cause the syndrome of CMOII deficiency.

Base Sequence↗
PubMed1987

The sequence of a sea urchin muscle actin gene suggests a gene conversion with a cytoskeletal actin gene.

We report the nucleotide sequence of the single muscle actin gene of the sea urchin Strongylocentrotus purpuratus. Comparison of the protein-coding sequence of this muscle actin gene (pSpG28) with that of two linked sea urchin cytoskeletal actin genes (pSpG17 and CyIIa) reveals a region of exceptional sequence conservation from codon 61 through codon 120. Furthermore, when silent nucleotide changes are compared, the conservation of this region is still evident (7.9% silent site differences in the conserved region vs 43.3% silent site differences in the rest of the gene when pSpG28 and CyIIa are compared), indicating that the conservation is not due to particularly stringent selection on the portion of the protein encoded by this region of the genes. These observations suggest that a gene conversion has occurred between the muscle actin gene and a cytoskeletal actin gene recently in the evolution of the sea urchin genome. Gene conversion between nonallelic actin genes may thus play a role in maintaining the homogeneity of this highly conserved gene family.

Actins↗
PubMed1987

An interchromosomal gene conversion of the Drosophila dunce locus identified with restriction site polymorphisms: a potential involvement of transposable elements in gene conversion.

Females heterozygous for the two alleles dnc2 and dncM14 of the X-linked gene dunce (dnc), and carrying a copy of dnc+ on the second chromosome, have produced a cluster of six dnc+ progeny X-chromosomes from recombination experiments. Restriction site polymorphisms have been used as genetic markers to follow the parentage of dnc locus segments in these chromosomes. All six chromosomes are identical with respect to the spectrum of restriction site markers they carry in the dnc+ chromosomal region. In the progeny chromosomes, this region is comprised of sequences like the dncM14 X-chromosome and the translocation copy of dnc+. Sequences flanking the dnc gene in the progeny chromosomes are like the dncM14 chromosome. Internal to the gene but near the 5' end, is a segment from the dnc+ translocation which has apparently originated from an interchromosomal and premeiotic gene conversion event. In addition, two transposable elements have inserted into the progeny chromosomes, one towards the 5' end of dnc and the other near the 3' end. The insertion of these elements occurred premeiotically since all six chromosomes are structurally identical. The data are interpreted with respect to a potential role of transposable element transposition in the process of gene conversion.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1995

Can tetraplex recombination models explain observations in induced mitotic gene conversion?

Induced mitotic gene conversion studies on the CYC1 gene of yeast have shown that the actual base pair changes, the types of changes (base substitution, deletion or addition) and the distances between mutations all affect gene conversion yields. In crosses between mutations less than four bases apart, gene conversion rates are as low as back mutation rates. The same mutants crossed to alleles more than five bases away may recombine 50-fold more. In crosses between mutations five or more base pairs apart, recombination rates varying by up to ten-fold are observed when comparing mutations at the same codon sites. The actual mutations in crosses affect recombination rates at these distances. The data rules out models in which mutants are repaired independently. Models with large gaps at the initiation site are ruled out if the mutants are within the gap. Recombination models are favoured in which both mutations can interact at a distance to affect the probability of recombination; such interactions may reflect the geometry of the recombinational junctions. The specific interactions proposed are that the actual mutations, and residual mismatches arising on excision resynthesis, affect both the further migration of the recombinational junction, and the probability that excision-repair will detect and correct residual mismatches. Junction models in which interactions are expected include those composed of base tetraplexes. The data is interpreted in terms of these models. Meiotic recombination data is consistent with these models.

Cytochrome c Group↗
PubMed2004

Gene duplication and gene conversion in class II MHC genes of New Zealand robins (Petroicidae).

In contrast to mammals, the evolution of MHC genes in birds appears to be characterized by high rates of gene duplication and concerted evolution. To further our understanding of the evolution of passerine MHC genes, we have isolated class II B sequences from two species of New Zealand robins, the South Island robin (Petroica australis australis), and the endangered Chatham Island black robin (Petroica traversi). Using an RT-PCR based approach we isolated four transcribed class II B MHC sequences from the black robin, and eight sequences from the South Island robin. RFLP analysis indicated that all class II B loci were contained within a single linkage group. Analysis of 3'-untranslated region sequences enabled putative orthologous loci to be identified in the two species, and indicated that multiple rounds of gene duplication have occurred within the MHC of New Zealand robins. The orthologous relationships are not retained within the coding region of the gene, instead the sequences group within species. A number of putative gene conversion events were identified across the length of our sequences that may account for this. Exon 2 sequences are highly diverse and appear to have diverged under balancing selection. It is also possible that gene conversion involving short stretches of sequence within exon 2 adds to this diversity. Our study is the first report of putative orthologous MHC loci in passerines, and provides further evidence for the importance of gene duplication and gene conversion in the evolution of the passerine MHC.

Amino Acid Sequence↗