Imprinting in the 15q11-q13 region involves an 'imprinting centre' (IC), mapping in part to the promoter and first exon of SNRPN. Deletion of this IC abolishes local paternally derived gene expression and results in Prader-Willi syndrome (PWS). We have created two deletion mutations in mice to understand PWS and the mechanism of this IC. Mice harbouring an intragenic deletion in Snrpn are phenotypically normal, suggesting that mutations of SNRPN are not sufficient to induce PWS. Mice with a larger deletion involving both Snrpn and the putative PWS-IC lack expression of the imprinted genes Zfp127 (mouse homologue of ZNF127), Ndn and Ipw, and manifest several phenotypes common to PWS infants. These data demonstrate that both the position of the IC and its role in the coordinate expression of genes is conserved between mouse and human, and indicate that the mouse is a suitable model system in which to investigate the molecular mechanisms of imprinting in this region of the genome.
Prader-Willi syndrome (PWS) is an imprinted genetic obesity disorder characterized by abnormalities of growth and metabolism. Multiple mouse models with deficiency of one or more PWS candidate genes have partially correlated individual genes with aspects of the PWS phenotype, although the genetic origin of defects in growth and metabolism has not been elucidated. Gene-targeted mutation of the PWS candidate gene Magel2 in mice causes altered circadian rhythm output and reduced motor activity. We now report that Magel2-null mice exhibit neonatal growth retardation, excessive weight gain after weaning, and increased adiposity with altered metabolism in adulthood, recapitulating fundamental aspects of the PWS phenotype. Magel2-null mice provide an important opportunity to examine the physiological basis for PWS neonatal failure to thrive and post-weaning weight gain and for the relationships among circadian rhythm, feeding behavior, and metabolism.
Mammalian circadian rhythms of activity are generated within the suprachiasmatic nucleus (SCN). Transcripts from the imprinted, paternally expressed Magel2 gene, which maps to the chromosomal region associated with Prader-Willi Syndrome (PWS), are highly enriched in the SCN. The Magel2 message is circadianly expressed and peaks during the subjective day. Mice deficient in Magel2 expression entrain to light cycles and express normal running-wheel rhythms, but with markedly reduced amplitude of activity and increased daytime activity. These changes are associated with reductions in food intake and male fertility. Orexin levels and orexin-positive neurons in the lateral hypothalamus are substantially reduced, suggesting that some of the consequences of Magel2 loss are mediated through changes in orexin signaling. The robust rhythmicity of Magel2 expression in the SCN and the altered behavioral rhythmicity of null mice reveal Magel2 to be a clock-controlled circadian output gene whose disruption results in some of the phenotypes characteristic of PWS.
The long-range organization of arrays of a satellite DNA at the centromeres of human chromosomes was investigated by pulsed-field gel electrophoresis techniques.Both restriction-site and array-length polymorphisms were detected in multiple individuals and their meiotic segregation was observed in three-generation families. Such variation was detected in all of the et satellite arrays examined (chromosomes 1, 3, 7, 10, 11, 16, 17, X, and Y) and thus appears to be a general feature of human centromeric DNA. The length of individual centromeric arrays was found to range from an average of =680 kilobases (kb) for the Y chromosome to :3000 kb for chromosome 11. Furthermore, individual arrays appear to be meiotically stable, since no changes in fragment lengths were observed. In total, we analyzed 84 meiotic events involving -191,000 kb of a satellite DNA from six autosomal centromeres without any evidence for recombination within an array. High-frequency array length variation and the potential to detect meiotic recombination within them allow direct comparisons of genetic and physical distances in the region of the centromeres of human chromosomes. The generation of primary consensus physical maps of a satellite arrays is a first step in the characterization of the centromeric DNA of human chromosomes.Centromeres control the disjunction of homologous chromosomes in the first meiotic reductional division, and of sister chromatids in the second meiotic division and in mitosis. Centromeric DNA forms a distinct site for interactions with the spindle apparatus via the kinetochore, a complex proteinaceous structure (1, 2). The properties of centromeric DNA are therefore expected to be somewhat different from those of the rest of the chromosome in terms of replication, transcription, and recombination. Meiotic recombination is reduced near the centromere in many organisms (3-6). In the budding yeast Saccharomyces cerevisiae, meiotic recombination is reduced near the centromere both in wild-type yeast and in strains in which the cloned centromere has been displaced to another position on the chromosome (4, 7). In the fission yeast Schizosaccharomyces pombe, the centromere of chromosome II is contained in a 60-kilobase (kb) fragment containing repetitive DNA, in which meiotic recombination is greatly reduced (5). Limited data based on mapping of chiasmata suggest that this may also be the case in human chromosomes (6).The mammalian centromere is cytogenetically defined as the primary constriction in metaphase chromosomes. The human a satellite DNA family is the predominant class of DNA located at the centromere of each human chromosome and, in total, constitutes several percent of the genome (8). Multiple 171-base-pair (bp) monomer units of a satellite DNA are organized into higher-order repeat units, which are tandemly arranged to form arrays comprising up to millions of base pairs of DNA at human centromeres. At a molecular level, distinct chromosomal subsets from at least 12 autosomes and the X and Y chromosomes...
Human centromeres have been extensively studied over the past two decades. Consequently, more is known of centromere structure and organization in humans than in any other higher eukaryote species. Recent advances in the construction of a human (or mammalian) artificial chromosome have fostered increased interest in determining the structure and function of fully functional human centromeres. Here, we present an overview of currently identified human centromeric repetitive DNA families: their discoveries, molecular characterization, and organization with respect to other centromeric repetitive DNA families. A brief examination of some functional based studies is also included.
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