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

Zangenberg, G.; Huang, Meimei; Arnheim, Norman; Erlich, Henry A.

doi:10.1038/ng0895-407

Cited by 131 publications

(70 citation statements)

References 28 publications

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“…Indirect evidence for interallelic conversion comes from seemingly anomalous low levels of linkage disequilibrium seen between some closely linked markers 13 and from patchwork patterns of allelic diversity 14,15 (though such patchworks could arise from sequential crossovers). Sperm analysis at the HLA-DPB1 locus has provided direct evidence that true interallelic conversions do occur, though at low frequency 16 . The relationship between crossover and conversion in humans, however, is unclear.…”

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confidence: 99%

Intense and highly localized gene conversion activity in human meiotic crossover hot spots

2004

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Meiotic gene conversion has an important role in allele diversification and in the homogenization of gene and other repeat DNA sequence families 1-5 , sometimes with pathological consequences 6,7 . But little is known about the dynamics of gene conversion in humans and its relationship to meiotic crossover. We therefore developed screening and selection methods to characterize sperm conversions in two meiotic crossover hot spots in the major histocompatibility complex (MHC) 8 and one in the sex chromosomal pseudoautosomal pairing region PAR1 (ref. 9). All three hot spots are active in gene conversion and crossover. Conversion tracts are short and define a steep bidirectional gradient centered at the peak of crossover activity, consistent with crossovers and conversions being produced by the same recombination-initiating events. These initiations seem to be spread over a narrow zone, rather than occurring at a single site, and seem preferentially to yield conversions rather than crossovers. Crossover breakpoints are more broadly diffused than conversion breakpoints, suggesting either differences between conversion and crossover processing after initiation or the existence of a quality control checkpoint at which short interactions between homologous chromosomes are preferentially aborted as conversions.Meiotic gene conversion in humans is defined as the recombinational transfer of information between alleles or loci without crossover. (This definition, though widely used, is not necessarily congruent with conversion classically defined by non-2:2 meiotic segregation ratios and does not include crossovers accompanied by conversion.) Homogenization events in multigene and dispersed repeat sequence families and in palindromic DNA 3-5 , as well as the direct detection of de novo conversion events in families 6,10 and in sperm 11,12 , provide extensive evidence for interlocus conversion. Indirect evidence for interallelic conversion comes from seemingly anomalous low levels of linkage disequilibrium seen between some closely linked markers 13 and from patchwork patterns of allelic diversity 14,15 (though such patchworks could arise from sequential crossovers). Sperm analysis at the HLA-DPB1 locus has provided direct evidence that true interallelic conversions do occur, though at low frequency 16 . The relationship between crossover and conversion in humans, however, is unclear.The high-resolution definition of human crossover hot spots by sperm typing 8,9,15 has allowed us to investigate the connection between crossover and interallelic conversion without crossover. We chose the hot spot DNA3 located in the MHC for analysis 8 , because of its intense crossover activity and the availability of sperm donors with multiple single nucleotide polymorphism (SNP) heterozygosities needed to monitor recombination events. Our initial approach was similar to that used to detect conversion in HLA-DPB1 (ref. 16; Fig. 1a). We amplified pools of sperm DNA by PCR using allele-specific primers outside the hot spot to amplify one haplo...

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Intense and highly localized gene conversion activity in human meiotic crossover hot spots

2004

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“…Six of these events were documented by more than one genotype and are likely to be actual occurrences. If the rates of mutation (4.5 × 10 -4 for CA repeats; Zahn and Kwiatkowski 1995) and interallelic gene conversion (10-4; Zangenberg et al 1995) in humans are similar to swine, then at least 10 (>100,000 genotypes total) of these aberrant genotypes could have arisen from one of these genetic phenomena. However, the mutation rate of CA repeats in swine may be lower because Ellegren (1995) found only one mutation in 17,514 gametes studied.…”

Section: Resultsmentioning

confidence: 99%

A comprehensive map of the porcine genome.

Rohrer¹,

Alexander²,

Hu³

et al. 1996

Genome Res.

448

382

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We report the highest density genetic linkage map for a livestock species produced to date. Three published maps for Sus scrofa were merged by genotyping virtually every publicly available microsatellite across a single reference population to yield 1042 linked loci, 536 of which are novel assignments, spanning 2286.2 cM (average interval 2.23 cM) in 19 linkage groups 08 autosomal and X chromosomes, n = 19). Linkage groups were constructed de novo and mapped by locus content to avoid propagation of errors in older genotypes. The physical and genetic maps were integrated with 123 informative loci assigned previously by fluorescence in situ hybridization {FISH). Fourteen linkage groups span the entire length of each chromosome. Coverage of chromosomes 11, 12, 15, and 18 will be evaluated as more markers are physically assigned. Marker-deficient regions were identified only on Ilql.7-qter and 14 cen-ql.2. Recombination rates [cM/Mbp) varied between and within chromosomes. Short chromosomal arms recombined at higher rates than long arms, and recombination was more frequent in telomeric regions than in pericentric regions. The high-resolution comprehensive map has the marker density needed to identify quantitative trait loci [QTL), implement marker-assisted selection or introgression and YAC contig construction or chromosomal microdissection.

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“…Interallelic gene conversion has been described as a source of allelic diversity at the HLA loci, with a frequency of approximately 1 in 10,000 sperm. 17 Gene conversion during mitosis involving the transfer of genetic material between maternal and paternal alleles, as may have occurred in our patient, has been described for the autosomal genes causing epidermolysis bullosa 18 and Fanconi's anemia. 19 Isolated hypogonadotropic hypogonadism may occur in families or sporadically and is five to seven times as common in males as in females.…”

Section: Discussionmentioning

confidence: 99%

Hypogonadotropic Hypogonadism in a Female Caused by an X-Linked Recessive Mutation in theDAX1Gene

et al. 1999

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

Cited by 131 publications

References 28 publications

Intense and highly localized gene conversion activity in human meiotic crossover hot spots

Intense and highly localized gene conversion activity in human meiotic crossover hot spots

A comprehensive map of the porcine genome.

Hypogonadotropic Hypogonadism in a Female Caused by an X-Linked Recessive Mutation in theDAX1Gene

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