Long-range restriction map of the terminal part of the short arm of the human X chromosome.

Petit, Christine; Levilliers, Jacqueline; Weissenbach, Jean

doi:10.1073/pnas.87.10.3680

Cited by 54 publications

(28 citation statements)

References 39 publications

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“…In contrast to M 1 A , which has a map position 4.4-5.5 M b from Xptel (Petit et al 1990b), M115 and all pseudoautosomal markers do not hybridize to cell line 815 x 175K7, which has a transloca- (Figs. 1, 2), thus confirming the presence of an interstitial rather than a terminal deletion.…”

Section: Resultsmentioning

confidence: 82%

A patient with an interstitial deletion in Xp22.3 locates the gene for X-linked recessive chondrodysplasia punctata to within a one megabase interval

et al. 1994

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A male patient carrying an interstitial deletion in Xp22.3 and affected by Kallmann syndrome, X-linked ichthyosis and mental retardation, but without chondrodysplasia punctata or short stature, was investigated with molecular probes from the distal Xp22.3 region. By means of a novel probe, M115, from the relevant region, the distal deletion breakpoint was shown to be between 3.18 and 3.57 Mb from Xptel. As the patient is not affected by X-linked recessive chondrodysplasia punctata, the gene for this disease can therefore be located to within an interval of less than one megabase proximal to the pseudoautosomal boundary. If the chondrodysplasia punctata gene is associated with a CpG island, this leaves only two islands at 2760 and 3180 kb from the Xp telomere as the most promising candidate sites for this gene.

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Section: Resultsmentioning

confidence: 82%

A patient with an interstitial deletion in Xp22.3 locates the gene for X-linked recessive chondrodysplasia punctata to within a one megabase interval

et al. 1994

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“…In fact, when longrange physical maps are compared with their genetic counterparts, different regions of the X chromosome have widely different recombination rates. For example, 1 cM corresponds to 190 kb in the DMD region (van Ommen et al 1986;Abbs et al 1990), 340-800 kb near the end of the long arm [Xq27.2-qter (Kenwrick and Gitschier 1989;Poustka et al 1991)], 600 kb near the end of the short arm [Xp22.3-pter (Petit et al 1990)], 640 kb in Xq26 (Little et al 1992), and>5 Mb in Xq13.3-q21.3 (Nagaraja et al 1997). Whereas recombination rates may be reported more frequently for regions of high recombination, recombination rates approaching that reported here for the centromere have not been documented for other regions on the X or, until recently (Jackson et al 1996), for other regions of the genome.…”

Section: Discussionmentioning

confidence: 99%

Physical and Genetic Mapping of the Human X Chromosome Centromere: Repression of Recombination

Mahtani¹,

Willard²

1998

Genome Res.

122

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Classical genetic studies in Drosophila and yeast have shown that chromosome centromeres have a cis-acting ability to repress meiotic exchange in adjacent DNA. To determine whether a similar phenomenon exists at human centromeres, we measured the rate of meiotic recombination across the centromere of the human X chromosome. We have constructed a long-range physical map of centromeric ␣-satellite DNA (DXZ1) by pulsed-field gel analysis, as well as detailed meiotic maps of the pericentromeric region of the X chromosome in the CEPH family panel. By comparing these two maps, we determined that, in the proximal region of the X chromosome, a genetic distance of 0.57 cM exists between markers that span the centromere and are separated by at least the average 3600 kb physical distance mapped across the DXZ1 array. Therefore, the rate of meiotic exchange across the X chromosome centromere is <1 cM/6300 kb (and perhaps as low as 1 cM/17,000 kb on the basis of other physical mapping data), at least eightfold lower than the average rate of female recombination on the X chromosome and one of the lowest rates of exchange yet observed in the human genome.Meiotic exchange is not distributed randomly along the length of eukaryotic chromosomes; indeed, much regional variation in recombination frequency has been observed. Perhaps the most conspicuous departure from uniformity is the dramatic repression of exchange found near eukaryotic chromosome centromeres and some telomeres (Mather 1936(Mather , 1939. Repression of meiotic recombination adjacent to the centromere (the centromere effect) is most obvious on the Drosophila X chromosome in which the centric heterochromatin, comprising half of the chromosome's cytogenetic length, barely contributes to its genetic length (Mather 1939;Roberts 1965); a similar centromere-associated repression of recombination is found on the autosomes of Drosophila (Beadle 1932;Painter 1935;Thompson 1963). Some of this repression of exchange is caused by the large blocks of heterochromatin present at the centromeres of higher eukaryotes (Willard 1990;Murphy and Karpen 1995), because heterochromatin, at least in Drosophila, is a poor substrate for recombination regardless of chromosomal location (Baker 1958). Because deletions of centric heterochromatin result in lowered levels of meiotic exchange in centromere-adjacent euchromatin (Yamamoto and Miklos 1978), the presence alone of heterochromatin at Drosophila centromeres does not fully explain the centromere effect. Rather, the centromere seems to exert a suppression of recombination that spreads to adjacent DNA.Studies in yeast support a similar centromeric suppression of meiotic exchange in proximal chromosome regions, although this effect may be less pronounced. In both Saccharomyces cerevisiae and Schizosaccharomyces pombe, mitotic recombination is relatively more frequent than meiotic recombination in the proximity of centromeres (Malone et al. 1980;Minet et al. 1980). Direct evidence for the centromere effect in yeast has come from studies of c...

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“…As a case in point, KAL1 was identified in a male infant who displayed abnormal genitalia, hypogonadotropic hypogonadism, agenesis of the olfactory bulbs and tracts (i.e., KS) associated with chondrodysplasia punctata and ichthyosis (34). Karyotype analysis and positional cloning revealed a large deletion in the Xp22.31 region that included the genes KAL1, ARSE, and STS (that together caused KS, chondrodysplasia punctata, and ichthyosis, respectively) and thus established KAL1 as an X-linked KS gene (34)(35)(36)(37)(38). Several years later, overlapping interstitial deletions in chromosome 8p11 were discovered in patients suffering from KS and hereditary spherocytosis and were mapped by fluorescence in situ hybridization and bacterial artificial chromosome cloning (39).…”

Section: The Past: Previous Strategies Used To Discover Genes In Igdmentioning

confidence: 99%

Discovering Genes Essential to the Hypothalamic Regulation of Human Reproduction Using a Human Disease Model: Adjusting to Life in the “-Omics” Era

2015

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The neuroendocrine regulation of reproduction is an intricate process requiring the exquisite coordination of an assortment of cellular networks, all converging on the GnRH neurons. These neurons have a complex life history, migrating mainly from the olfactory placode into the hypothalamus, where GnRH is secreted and acts as the master regulator of the hypothalamicpituitary-gonadal axis. Much of what we know about the biology of the GnRH neurons has been aided by discoveries made using the human disease model of isolated GnRH deficiency (IGD), a family of rare Mendelian disorders that share a common failure of secretion and/or action of GnRH causing hypogonadotropic hypogonadism. Over the last 30 years, research groups around the world have been investigating the genetic basis of IGD using different strategies based on complex cases that harbor structural abnormalities or single pleiotropic genes, endogamous pedigrees, candidate gene approaches as well as pathway gene analyses. Although such traditional approaches, based on well-validated tools, have been critical to establish the field, new strategies, such as next-generation sequencing, are now providing speed and robustness, but also revealing a surprising number of variants in known IGD genes in both patients and healthy controls. Thus, before the field moves forward with new genetic tools and continues discovery efforts, we must reassess what we know about IGD genetics and prepare to hold our work to a different standard. The purpose of this review is to: 1) look back at the strategies used to discover the "known" genes implicated in the rare forms of IGD; 2) examine the strengths and weaknesses of the methodologies used to validate genetic variation; 3)substantiate the role of known genes in the pathophysiology of the disease; and 4) project forward as we embark upon a widening use of these new and powerful technologies for gene discovery.

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Long-range restriction map of the terminal part of the short arm of the human X chromosome.

Cited by 54 publications

References 39 publications

A patient with an interstitial deletion in Xp22.3 locates the gene for X-linked recessive chondrodysplasia punctata to within a one megabase interval

A patient with an interstitial deletion in Xp22.3 locates the gene for X-linked recessive chondrodysplasia punctata to within a one megabase interval

Physical and Genetic Mapping of the Human X Chromosome Centromere: Repression of Recombination

Discovering Genes Essential to the Hypothalamic Regulation of Human Reproduction Using a Human Disease Model: Adjusting to Life in the “-Omics” Era

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