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Duplication of the genome during the S phase of the cell cycle does not occur simultaneously; rather, different sequences are replicated at different times. The replication timing of specific sequences can change during development; however, the determinants of this dynamic process are poorly understood. To gain insights into the contribution of developmental state, genomic sequence, and transcriptional activity to replication timing, we investigated the timing of DNA replication at high resolution along an entire human chromosome (chromosome 22) in two different cell types. The pattern of replication timing was correlated with respect to annotated genes, gene expression, novel transcribed regions of unknown function, sequence composition, and cytological features. We observed that chromosome 22 contains regions of early- and late-replicating domains of 100 kb to 2 Mb, many (but not all) of which are associated with previously described chromosomal bands. In both cell types, expressed sequences are replicated earlier than nontranscribed regions. However, several highly transcribed regions replicate late. Overall, the DNA replication-timing profiles of the two different cell types are remarkably similar, with only nine regions of difference observed. In one case, this difference reflects the differential expression of an annotated gene that resides in this region. Novel transcribed regions with low coding potential exhibit a strong propensity for early DNA replication. Although the cellular function of such transcripts is poorly understood, our results suggest that their activity is linked to the replication-timing program.

A gene on human chromosome 12 may be linked to late-onset Alzheimer's disease. Researchers used various genetic analyses to screen all chromosomes in 54 families with at least one member who had Alzheimer's disease. Fifteen chromosomes were identified as likely candidates and further analysis revealed that four of these chromosomes, namely 4, 6, 12, and 20, were the most likely candidates. Chromosome 12 in particular was most strongly linked to Alzheimer's disease, especially a region near the centromere. The centromere is a structure close to the midpoint of the chromosome., Context.--Four genetic loci have been identified as contributing to Alzheimer disease (AD), including the amyloid precursor protein gene, the presenilin 1 gene, the presenilin 2 gene, and the apolipoprotein E gene, but do not account for all the genetic risk for AD. Objective.--To identify additional genetic risk factors for late-onset AD. Design.--A complete genomic screen was performed (N=280 markers). Critical values for chromosomal regional follow-up were a P value of .05 or less for affected relative pair analysis or sibpair analysis, a parametric loaf score of 1.0 or greater, or both. Regional follow-up included analysis of additional markers and a second data set. Setting.--Clinic populations in the continental United States. Patients.--From a series of multiplex families affected with late-onset ([is greater than or equal to] 60 years) AD ascertained during the last 14 years (National Insititute of Neurological Disorders and Stroke-Alzheimer's Disease and Related Disorders Association diagnostic criteria) and for which DNA has been obtained, a subset of 16 families (135 total family members, 52 of whom were patients with AD) was used for the genomic screen. A second subset of 38 families (216 total family members, 89 of whom were patients with AD) was used for the follow-up analysis. Main Outcome Measures.--Linkage analysis results generated using both genetic model-dependent (loaf score) and model-independent methods. Results.--Fifteen chromosomal regions warranted initial follow-up. Follow-up analyses revealed 4 regions of continued interest on chromosomes 4,6,12, and 20, with the strongest results observed for chromosome 12. Peak 2-point affecteds-only loaf scores (n=54) were 1.3, 1.6, 2.7, and 2.2 and affected relative pairs P values (n=54) were .04, .03, .14, and .04 for D12S373, D12S1057, D12S1042, and D12S390, respectively. Sibpair analysis (n=54) resulted in maximum loaf scores (MLSs) of 1.5,2.6,3.2, and 2.3 for these markers, with a peak multipoint MLS of 3.5. A priori stratification by APOEgenotype identified 27 families that had at least 1 member with AD whose genotype did not contain an APOE*4 allele. Analysis of these 27 families resulted in MLSs of 1.0,2.4,3.7, and 3.3 and a peak multipoint MLS of 3.9. Conclusions.--A complete genomic screen in families affected with late-onset AD identified 4 regions of interest after follow-up. Chromosome 12 gave the strongest and most consistent results with a peak multipoint MLS of 3.5, suggesting that this region contains a new susceptibility gene for AD. Additional analyses are necessary to identify the chromosome 12 susceptibility gene for AD and to follow up the regions of interest on chromosomes 4, 6, and 20. JAMA, 1997;278:1237-1241

A possible link between a gene on chromosome 19 and multiple sclerosis (MS) has been identified. Researchers found the link after performing genetic analysis on 120 Caucasian MS patients and 32 Chinese MS patients. Both groups were compared with similar groups that did not have MS. A strong link was found on chromosome 19q13.2, but it was not due to the apolipoprotein E (APOE) gene, which is at that location. Links were also found to the HLA DRB1*1501, DQA1*0102, and DQB1*0602 genes, which are on chromosome 6p21.3. No link was found to the myelin basic protein (MBP) gene., Context.--Susceptibility to multiple sclerosis (MS) involves a genetically complex autoimmune component. However, except for genes in the HLA system, specific susceptibility loci are unknown or unconfirmed. Objective.--To investigate several loci spanning 3 candidate regions for a role in multiple sclerosis (MS) susceptibility in 2 ethnic groups using both single-locus and haplotype analyses. The 3 regions include HLA on chromosome 6p21.3, APOE on chromosome 19q13.2, and MBP (myelin basic protein) on chromosome 18q23. Design.--Case-control association testing. Subjects.--A total of 120 Caucasian patients with MS and 107 unrelated control individuals from California, and 32 patients and 32 unrelated control individuals from Beijing, China. All patients with MS were diagnosed as having clinically definite disease according to published criteria. Main Outcome Measures.--[chi square] Testing of loci and individual alleles and haplotypes. Haplotype frequencies were estimated with standard maximum likelihood methods. Results.--The HLA effect is due to the class 11 DR2 haplotype, DRB1*1501-DQA1 *0102-DRB1 *0602; contributions to MS susceptibility from additional DRB1-DQB1 alleles or other HLA region loci were not observed. Variation within the MBP locus on chromosome 18q23 showed no effect in MS. The distribution of haplotypes from 5 loci within the chromosome 19q13.2 region, including D19S178, D19S574, APOE, APOC2, and D19S219, differed between patient and control samples. D19S574 showed a significant effect (P=.015) in Caucasian patients with MS due to the increased frequency of a single allele (P=.002). The APOE variation, prominent in other neurological diseases, showed no influence on MS susceptibility, despite its location within the chromosome 19q13.2 region. Interaction effects between DR2 and chromosome 19q13.2 or MBP in MS susceptibility were not apparent. Conclusions.--The significant chromosome 19q13.2 single-locus and multilocus haplotype associations with MS in Caucasian and Chinese patient samples indicate an effect from a nearby disease susceptibility locus. These initial observations are an encouraging step toward the description of non-HLA genetic susceptibility to MS. JAMA. 1997;278:1256-1261

Protein tyrosine phosphatases (PTPs) have long been thought to play a role in tumor suppression due to their ability to antagonize the growth promoting protein tyrosine kinases. Recently, a candidate tumor suppressor from 10q23, termed P-TEN, was isolated, and sequence homology was demonstrated with members of the PTP family, as well as the cytoskeletal protein tensin. Here we show that recombinant P-TEN dephosphorylated protein and peptide substrates phosphorylated on serine, threonine, and tyrosine residues, indicating that P-TEN is a dual-specificity phosphatase. In addition, P-TEN exhibited a high degree of substrate specificity, showing selectivity for extremely acidic substrates in vitro. Furthermore, we demonstrate that mutations in P-TEN, identified from primary tumors, tumor cells lines, and a patient with Bannayan-Zonana syndrome, resulted in the ablation of phosphatase activity, demonstrating that enzymatic activity of P-TEN is necessary for its ability to function as a tumor suppressor.

The three-dimensional morphologies of the active (Xa) and inactive (Xi) regions of interphase X chromosomes from Barr body-positive cell nuclei were analyzed by confocal laser scanning microscope and chromosome painting. The Xa territories of the X chromosome exhibited a three-dimensional structure that is more similar to chromosome seven territories. The Xa and XI territories also exhibited significant difference in surface area measurements and dimensionless roundness factor.

Acquired interstitial loss of all or part of the long arm of human chromosome 5 (5q-) is an anomaly that is seen frequently in patients with preleukemic myelodysplasia and acute myelogenous leukemia. Loss of a critical region of overlap at band 5q31.1 in all of these cases, with various cytogenetic breaks, signifies the existence of a key negative regulator of leukemogenesis. Previous studies have defined the proximal and distal ends of the critical region to reside between the genes for IL9 and EGR1, respectively. In this report, we describe a yeast artificial chromosome contig spanning this myeloid tumor suppressor locus. The combined order of the polymorphic loci is centromere-IL9-(D5S525-DSS558-D5S89-D5S526-D5S393)-D5S399 -D5S396-D5S414-EGRI and telomere. The physical distance between the IL9 and EGRI genes is estimated to be

The synexin gene localized to a single copy at chromosome 10 with 13 introns and 14 exons and spanning a 34kb DNA section is structurally divergent from calpactin I and lipocortin I genes of the annexin family. Splice junctions in the synexin gene are divided into two clusters, one corresponding to a conserved tetrad repeat C-terminal domain and the other to a specific N-terminal domain. The introns surrounding the exon of the gene cause the unique synexin mRNA sequence in heart, skeletal, muscle and brain cells.

The localization of a tumor suppressor locus within human chromosome 3p21-p22 was reported. Previous studies have shown the correlation between cytogenetic abnormalities and high frequency losses in human chromosome 3 with a variety ofneoplasms. Interspecific microcell hybrids containing known segments of 3p wereconstructed and screened in nude mice. Hybrid clones that showed a dramatic tumor suppression were shown to contain chromosomal fragments containing the region 3p21-3p22. This indicates that the tumor suppression locus is within human chromosome 3p21-p22.

Determination of the chromosomal constitution of an individual usually involves growing peripheral blood lymphocytes in a tissue culture medium containing phytohaemagglutinin and analysis of cells in mitosis [1]. In developing [...]

The Biblical accounts that state that the Jewish priesthood was established 3,300 years ago with the appointment of the first Israelite high priest and that subsequent appointments was by strict patrilineal descent was confirmed by the discovery of clear differences in the frequency of Y-chromosome haplotypes between Jewish priests and their layman counterparts. This difference is observable in both the Ashkenazic and Shepardic populations. This result is consistent with an origin for the Jewish priesthood antedating the division of the world Jewry into the two communities.