Cre-loxP chromosome engineering of a targeted deletion in the mouse corresponding to the 3p21.3 region of homozygous loss in human tumours.
(25/1023)
Chromosomal deletions are a common feature of epithelial tumours and when further defined by homozygous deletions, are often the location of tumour suppressor genes. Deletions within the short arm of chromosome 3 occur very frequently in human carcinomas: a minimal region of loss at 3p21.3 (the Luca) region has been defined by overlapping homozygous deletions in lung and breast cancer cell lines. Using a rapid strategy for Cre-loxP chromosome engineering, a deletion of approximately 370 kb was created in the mouse germline corresponding to the deleted region at 3p21.3. The deletion when homozygous is embryonic lethal. Heterozygotes develop normally despite being haplo-insufficient for twelve genes including the candidate tumour suppressor gene Rassf1. Because damage to 3p21.3 often occurs very early in the sequence of genetic changes that lead to malignancy, particularly in lung and breast cancer, further genetic damage to these mice will provide the opportunity to model multi-step tumorigenesis of these tumours. (+info)
Molecular characterization of the pericentric inversion that causes differences between chimpanzee chromosome 19 and human chromosome 17.
(26/1023)
A comparison of the human genome with that of the chimpanzee is an attractive approach to attempts to understand the specificity of a certain phenotype's development. The two karyotypes differ by one chromosome fusion, nine pericentric inversions, and various additions of heterochromatin to chromosomal telomeres. Only the fusion, which gave rise to human chromosome 2, has been characterized at the sequence level. During the present study, we investigated the pericentric inversion by which chimpanzee chromosome 19 differs from human chromosome 17. Fluorescence in situ hybridization was used to identify breakpoint-spanning bacterial artificial chromosomes (BACs) and plasmid artificial chromosomes (PACs). By sequencing the junction fragments, we localized breakpoints in intergenic regions rich in repetitive elements. Our findings suggest that repeat-mediated nonhomologous recombination has facilitated inversion formation. No addition or deletion of any sequence element was detected at the breakpoints or in the surrounding sequences. Next to the break, at a distance of 10.2-39.1 kb, the following genes were found: NGFR and NXPH3 (on human chromosome 17q21.3) and GUC2D and ALOX15B (on human chromosome 17p13). The inversion affects neither the genomic structure nor the gene-activity state with regard to replication timing of these genes. (+info)
Localization of a human lung adenocarcinoma susceptibility locus, possibly syntenic to the mouse Pas1 locus, in the vicinity of the D12S1034 locus on chromosome 12p11.2-p12.1.
(27/1023)
Pulmonary adenoma susceptibility 1 (Pas1) is a major locus affecting inherited predisposition to the development of lung adenocarcinoma in mice, and is mapped to chromosome 6q near the Kras2 gene. However, it is still unclear whether the PAS1 locus on human chromosome 12p11.2-p12.1, the region showing synteny to the mouse Pas1 region, is involved in susceptibility to human lung adenocarcinoma development. Thus, we conducted a case-control study of 100 lung adenocarcinoma cases and 100 controls using 20 highly polymorphic microsatellite markers dispersed in a 13 cM region covering a putative PAS1 locus. The differences in the allele and genotype distributions were observed at several loci, and the difference was at a maximum at the D12S1034 locus (P = 0.034 and P = 0.036, respectively). The differences in the allele and genotype distributions at D12S1034 remained significant in the analysis in which 239 lung adenocarcinoma cases and 63 controls were added to the 100 cases and 100 controls used for the initial screening (P = 0.031 and P = 0.027, respectively). The D12S1034 locus was located 800-1350 kb proximal to the KRAS2 locus, and in the region syntenic to the core Pas1 region of approximately 1.5 Mb in size where a single haplotype is shared by several mouse-inbred strains susceptible to lung adenocarcinoma development. These results indicate that the PAS1 locus is located in the vicinity of D12S1034 and a genetic variation(s) at this locus is involved in susceptibility to human lung adenocarcinoma. (+info)
The transformer gene in Ceratitis capitata provides a genetic basis for selecting and remembering the sexual fate.
(28/1023)
The medfly Ceratitis capitata contains a gene (Cctra) with structural and functional homology to the Drosophila melanogaster sex-determining gene transformer (tra). Similar to tra in Drosophila, Cctra is regulated by alternative splicing such that only females can encode a full-length protein. In contrast to Drosophila, however, where tra is a subordinate target of Sex-lethal (Sxl), Cctra seems to initiate an autoregulatory mechanism in XX embryos that provides continuous tra female-specific function and act as a cellular memory maintaining the female pathway. Indeed, a transient interference with Cctra expression in XX embryos by RNAi treatment can cause complete sexual transformation of both germline and soma in adult flies, resulting in a fertile male XX phenotype. The male pathway seems to result when Cctra autoregulation is prevented and instead splice variants with truncated open reading frames are produced. We propose that this repression is achieved by the Y-linked male-determining factor (M). (+info)
Identification, analysis, and utilization of conserved ortholog set markers for comparative genomics in higher plants.
(29/1023)
We have screened a large tomato EST database against the Arabidopsis genomic sequence and report here the identification of a set of 1025 genes (referred to as a conserved ortholog set, or COS markers) that are single or low copy in both genomes (as determined by computational screens and DNA gel blot hybridization) and that have remained relatively stable in sequence since the early radiation of dicotyledonous plants. These genes were annotated, and a large portion could be assigned to putative functional categories associated with basic metabolic processes, such as energy-generating processes and the biosynthesis and degradation of cellular building blocks. We further demonstrate, through computational screens (e.g., against a Medicago truncatula database) and direct hybridization on genomic DNA of diverse plant species, that these COS markers also are conserved in the genomes of other plant families. Finally, we show that this gene set can be used for comparative mapping studies between highly divergent genomes such as those of tomato and Arabidopsis. This set of COS markers, identified computationally and experimentally, may further studies on comparative genomes and phylogenetics and elucidate the nature of genes conserved throughout plant evolution. (+info)
Whole-genome shotgun assembly and analysis of the genome of Fugu rubripes.
(30/1023)
The compact genome of Fugu rubripes has been sequenced to over 95% coverage, and more than 80% of the assembly is in multigene-sized scaffolds. In this 365-megabase vertebrate genome, repetitive DNA accounts for less than one-sixth of the sequence, and gene loci occupy about one-third of the genome. As with the human genome, gene loci are not evenly distributed, but are clustered into sparse and dense regions. Some "giant" genes were observed that had average coding sequence sizes but were spread over genomic lengths significantly larger than those of their human orthologs. Although three-quarters of predicted human proteins have a strong match to Fugu, approximately a quarter of the human proteins had highly diverged from or had no pufferfish homologs, highlighting the extent of protein evolution in the 450 million years since teleosts and mammals diverged. Conserved linkages between Fugu and human genes indicate the preservation of chromosomal segments from the common vertebrate ancestor, but with considerable scrambling of gene order. (+info)
Telomere dysfunction provokes regional amplification and deletion in cancer genomes.
(31/1023)
Telomere dysfunction and associated fusion-breakage in the mouse encourages epithelial carcinogenesis and a more humanized genomic profile that includes nonreciprocal translocations (NRTs). Here, array comparative genomic hybridization was used to determine the pathogenic significance of NRTs and to determine whether telomere dysfunction also drives amplifications and deletions of cancer-relevant loci. Compared to tumors arising in mice with intact telomeres, tumors with telomere dysfunction possessed higher levels of genomic instability and showed numerous amplifications and deletions in regions syntenic to human cancer hotspots. These observations suggest that telomere-based crisis provides a mechanism of chromosomal instability, including regional amplifications and deletions, that drives carcinogenesis. This model provides a platform for discovery of genes responsible for the major cancers affecting aged humans. (+info)
Four-hundred million years of conserved synteny of human Xp and Xq genes on three Tetraodon chromosomes.
(32/1023)
The freshwater pufferfish Tetraodon nigroviridis (TNI) has become highly attractive as a compact reference vertebrate genome for gene finding and validation. We have mapped genes, which are more or less evenly spaced on the human chromosomes 9 and X, on Tetraodon chromosomes using fluorescence in situ hybridization (FISH), to establish syntenic relationships between Tetraodon and other key vertebrate genomes. PufferFISH revealed that the human X is an orthologous mosaic of three Tetraodon chromosomes. More than 350 million years ago, an ancestral vertebrate autosome shared orthologous Xp and Xq genes with Tetraodon chromosomes 1 and 7. The shuffled order of Xp and Xq orthologs on their syntenic Tetraodon chromosomes can be explained by the prevalence of evolutionary inversions. The Tetraodon 2 orthologous genes are clustered in human Xp11 and represent a recent addition to the eutherian X sex chromosome. The human chromosome 9 and the avian Z sex chromosome show a much lower degree of synteny conservation in the pufferfish than the human X chromosome. We propose that a special selection process during vertebrate evolution has shaped a highly conserved array(s) of X-linked genes long before the X was used as a mammalian sex chromosome and many X chromosomal genes were recruited for reproduction and/or the development of cognitive abilities. [Sequence data reported in this paper have been deposited in GenBank and assigned the following accession no: AJ308098.] (+info)