Molecular Characterization of the Pb Recombination Hotspot in the Mouse Major Histocompatibility Complex Class II Region

Isobe, Toshiro; Yoshino, Masayasu; Mizuno, Ken-ichi; Lindahl, Kirsten Fischer; Koide, Tsuyoshi; Gaudieri, Silvana; Gojobori, Takashi; Shiroishi, Toshihiko

doi:10.1006/geno.2002.6817

Cited by 15 publications

(10 citation statements)

References 27 publications

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“…1, and in more detail in online supplementary material and poster included with this issue) reveals regions that have high or low recombination per cR. High resolution recombination hotspots and cold spots are well documented in previously reported data (e.g., Wahls 1998; Isobe et al 2002). This study reveals the distribution of recombination on a whole-chromosome and genome-wide scale.…”

Section: Distribution Of Recombinationsupporting

confidence: 80%

The Comprehensive Mouse Radiation Hybrid Map Densely Cross-Referenced to the Recombination Map: A Tool to Support the Sequence Assemblies

Rowe

Barter²,

Kelmenson³

et al. 2002

Genome Res.

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We have developed a unique comprehensive mouse radiation hybrid (RH) map of nearly 23,000 markers integrating data from three international genome centers and over 400 independent laboratories. We have cross-referenced this map to the 0.5-cM resolution recombination-based Jackson Laboratory (TJL) backcross panel map, building a complete set of RH framework chromosome maps based on a high density of known-ordered anchor markers. We have systematically typed markers to improve coverage and resolve discrepancies, and have reanalyzed data sets as needed. The cross-linking of the RH and recombination maps has resulted in a highly accurate genome-wide map with consistent marker order. We have compared these linked framework maps to the Ensembl mouse genome sequence assembly, and show that they are a useful medium resolution tool for both validating sequence assembly and elucidating chromosome biology.

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Section: Distribution Of Recombinationsupporting

confidence: 80%

The Comprehensive Mouse Radiation Hybrid Map Densely Cross-Referenced to the Recombination Map: A Tool to Support the Sequence Assemblies

Rowe

Barter²,

Kelmenson³

et al. 2002

Genome Res.

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“…Further, they lie at the 3Ј end of the transcribed region. Unlike the Pb and Psmb9 hot spots, where transcriptional activity is not seen in meiotic cells (18), we have seen that the 2.4-kb noncoding RNA is present in the testis and flanks the MAR domain in the 17.2-kb fragment.…”

Section: Discussionmentioning

confidence: 56%

“…The Ea hot spot is observed in genetic crosses involving the p haplotype, while the Eb hotspot is active in the b, d, and k haplotypes (22). Similarly, the Psmb9 and Pb hot spots show maximal recombination activity in the cas3 and wm7 and the cas4 and wm7 haplotypes, respectively (18). We have used a different population genetics-based approach to show the presence of a recombination hot spot close to the previously determined meiotic repair site.…”

Section: Discussionmentioning

confidence: 99%

“…Among the few hot spots that have been mapped to a fine resolution, the human hotspots include (i) minisatellite-associated hot spot MS 32 (20), (ii) the CMT1A/HNPP hot spot associated with hereditary neuropathies (39), and (iii) the major histocompatibility complex (MHC)-associated TAP2 and DNA2 hot spots (19,21). In the mouse, a total of eight hotspots have been identified so far (56), and the ones that have been characterized to a high degree of resolution include (i) the Lmp2/Psmb9 hot spot (32), (ii) the hot spot located in the Eb second intron (57), (iii) the Pb hot spot (18), and (iv) the hot spot located in the Ea fourth intron (22). All the known mouse recombination hot spots have been identified in the MHC region by pedigree analysis, hence not much is known about the hot spot morphology and the recombination processes operating within them, except for the recently published study of the mouse MHC Eb hot spot showing crossover asymmetry and the re-sulting biased gene conversion of markers (56).…”

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confidence: 99%

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Characterization of a Mouse Recombination Hot Spot Locus Encoding a Novel Non-Protein-Coding RNA

Nishant

Ravishankar

Rao

2004

Molecular and Cellular Biology

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Our current knowledge of recombination hot spot activity in mammalian systems implicates a role for both the primary DNA sequence and the nature of the chromatin domain around it. In mice, the only recombination hot spots mapped to date have been confined to a cluster within the major histocompatibility complex (MHC) region. We present a high resolution analysis of a new recombination hot spot in the mouse genome which maps to mouse chromosome 8 C-D. Haplotype diversity analysis across 40 different strains of mice has enabled us to map recombination breakpoints to a 1-kb interval. This hot spot has a recombination intensity that is 10-to 100-fold above the genome average and has a mean gene conversion tract length of 371 bp. This meiotically active locus happens to be flanked by a transcribed region encoding a non-protein-coding RNA polymerase II transcript and the previously characterized repair site. Many of the primary DNA sequence features that have been reported for the mouse MHC hot spots are also shared by this hot spot locus and in addition, along with three other MHC hot spot loci, we show a new parallel feature of association of the crossover sites with the nuclear matrix.Most of the advances in our understanding of meiosis and recombination have come from studies of lower eukaryotes, in particular Saccharomyces cerevisiae. Recombination initiates via programmed double-strand breaks at the leptotene interval which are resected and undergo strand exchange and finally give rise to double Holliday junctions by the mid-pachytene interval. Mature crossover products follow around the end of pachytene (14,24). It is generally believed that a similar process operates in higher eukaryotes, including mammals. The rate of recombination is not a uniform function of the physical distance between two markers, leading to the concept of recombination hot spots and cold spots (36). In mice and humans, regions are generally termed as hot spots if their recombination frequency significantly exceeds 1 centimorgan (cM)/ Mb. There are three methods that have been used to map hot spots in mammals. The classical method is to correlate physical distances with genetic distances established by standard pedigree-based linkage analysis. The resolution of this method is limited by the density of markers, the number of individuals examined, and the number of recombination events that occur in a typical pedigree. Methods based on linkage disequilibrium (LD), which refers to the nonrandom association of alleles at linked sites, take into account ancestral recombination events, which would be far greater than those observed from any pedigree-based linkage study, leading to a finer mapping of recombination hot spots. Most measures of LD quantify the degree of association between pairs of markers which decreases as a function of physical distance between them due to increased probability of recombination between the markers. However, both of these techniques do not have the resolution to characterize crossovers at a molecular level. The ...

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“…1), a region rich in genes that control immune function (reviewed in references 14, 31, 38, 45, 49, and 54). Among the best characterized are hot spots associated with loci located in the class II region of the MHC: Eb1 (7,25,57,62), Ea (19,24,27,28), Pb (20,45,59), and Lmp-2 (now called Psmb9) (17,44,46). At each locus, the bulk of the crossover events localize to regions of a few hundred to a few thousand base pairs and recombination rates per unit of physical distance (centimorgan [cM] per megabase) vary from ϳ175 to ϳ2,600 times that expected for DNA segments of the same size based on the mouse genome average rate (0.5 cM/Mb).…”

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confidence: 99%

Mouse Strains with an Active H2-Ea Meiotic Recombination Hot Spot Exhibit Increased Levels of H2-Ea-Specific DNA Breaks in Testicular Germ Cells

Qin

Richardson

Jasin

et al. 2004

Molecular and Cellular Biology

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We devised a sensitive method for the site-specific detection of rare meiotic DNA strand breaks in germ cell-enriched testicular cell populations from mice that possess or lack an active recombination hot spot at the H2-Ea gene. Using germ cells from adult animals, we found an excellent correlation between the frequency of DNA breaks in the 418-bp H2-Ea hot spot and crossover activity. The temporal appearance of DNA breaks was also studied in 7-to 18-day-old mice with an active hot spot during the first waves of spermatogenesis. The number of DNA breaks detected rose as leptotene and zygotene spermatocytes populate the testis with a peak at day 14 postpartum, when leptotene, zygotene, and early pachytene spermatocytes are the most common meiotic prophase I cell types. The number of DNA breaks drops precipitously 1 day later, when middle to late pachytene spermatocytes become the dominant subtype. The recombination-related breaks in the hot spot likely reflect SPO11-induced double-strand breaks and/or recombination intermediates containing free 3 hydroxyl groups.Meiotic recombination leads to crossover events critical for the proper segregation of homologous chromosomes. It has been known for decades that recombination events may not be randomly distributed along each chromosome. The result is that some regions exhibit a recombination frequency greater than that expected based on the genome average relationship between physical distance and crossing over (reviewed in references 2, 31, 37, 38, and 54). These so-called recombination hot spots have been found in every organism examined carefully. A number of crossover hot spots exist in the mouse major histocompatibility complex (MHC; also called H-2) (see Fig.

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Molecular Characterization of the Pb Recombination Hotspot in the Mouse Major Histocompatibility Complex Class II Region

Cited by 15 publications

References 27 publications

The Comprehensive Mouse Radiation Hybrid Map Densely Cross-Referenced to the Recombination Map: A Tool to Support the Sequence Assemblies

The Comprehensive Mouse Radiation Hybrid Map Densely Cross-Referenced to the Recombination Map: A Tool to Support the Sequence Assemblies

Characterization of a Mouse Recombination Hot Spot Locus Encoding a Novel Non-Protein-Coding RNA

Mouse Strains with an Active H2-Ea Meiotic Recombination Hot Spot Exhibit Increased Levels of H2-Ea-Specific DNA Breaks in Testicular Germ Cells

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