Comparing human genome mapping data.
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Chromosomes, Human, Pair 4↗
Biomedical subjects
D J Porteous
Publications and source records attributed to D J Porteous.
WWOX: a candidate tumor suppressor gene involved in multiple tumor types.
We previously reported the construction of a P1-derived artificial chromosome (PAC) contig encompassing a set of homozygous deletions of chromosome 16q23-24.1 found in primary ovarian tumor material and several tumor cell lines. Using these PAC clones in a cDNA selection experiment, we have isolated a Sau3A fragment homologous to the WWOX transcript (GenBank accession no. ) from normal human ovarian surface epithelial (HOSE) cells. We demonstrate the homozygous deletion of WWOX exons from ovarian cancer cells and three different tumor cell lines. We also identify an internally deleted WWOX transcript from a further primary ovarian tumor. In three of these samples the deletions result in frameshifts, and in each case the resulting WWOX transcripts lack part, or all, of the short chain dehydrogenase domain and the putative mitochondrial localization signal. Sequencing revealed several missense polymorphisms in tumor cell lines and identified a high level of single nucleotide polymorphism (SNP) within the WWOX gene. This evidence strengthens the case for WWOX as a tumor suppressor gene in ovarian cancer and other tumor types.
Alternative Splicing↗
Adenoviral augmentation of elafin protects the lung against acute injury mediated by activated neutrophils and bacterial infection.
During acute pulmonary infection, tissue injury may be secondary to the effects of bacterial products or to the effects of the host inflammatory response. An attractive strategy for tissue protection in this setting would combine antimicrobial activity with inhibition of human neutrophil elastase (HNE), a key effector of neutrophil-mediated tissue injury. We postulated that genetic augmentation of elafin (an endogenous inhibitor of HNE with intrinsic antimicrobial activity) could protect the lung against acute inflammatory injury without detriment to host defense. A replication-deficient adenovirus encoding elafin cDNA significantly protected A549 cells against the injurious effects of both HNE and whole activated human neutrophils in vitro. Intratracheal replication-deficient adenovirus encoding elafin cDNA significantly protected murine lungs against injury mediated by Pseudomonas aeruginosa in vivo. Genetic augmentation of elafin therefore has the capacity to protect the lung against the injurious effects of both bacterial pathogens resistant to conventional antibiotics and activated neutrophils.
Acute Disease↗
Regulation of adenovirus-mediated elafin transgene expression by bacterial lipopolysaccharide.
Lipopolysaccharide (LPS) is a mediator of inflammatory lung injury. Selective augmentation of host defense molecules such as elafin (an elastase inhibitor with antimicrobial activity) at the onset of pulmonary inflammation is an attractive potential therapeutic strategy. The aim of this study was to determine whether elafin expression could be induced by LPS administered after transfection with adenovirus (Ad) encoding human elafin downstream of the murine cytomegalovirus (CMV) promoter (known to be potentially responsive to LPS). In addition, we aimed to determine the effect of local elafin augmentation on neutrophil migration to the lung. LPS significantly up-regulated elafin expression from pulmonary epithelial cells transfected with Ad-elafin in vitro. In murine airways expression of human elafin was achieved using doses low enough (3 x 10(7) plaque forming units) to circumvent overt vector-induced inflammation. LPS significantly up-regulated human elafin secretion in murine airways treated with Ad-elafin [117 ng/ml in bronchoalveolar lavage fluid (BALF) after LPS administration, 5.9 ng/ml after PBS, p < 0.01)]. Over-expression of elafin significantly augmented LPS-mediated neutrophil migration into the airways in vivo (1.30 x 10(6) neutrophils in BALF after Ad-elafin/LPS treatment, 0.54 x 10(6) after Ad-lacZ/LPS (p < 0.05), 0.63 x 10(6) after PBS/LPS (p < 0.05)) and significantly enhanced human neutrophil migration in vitro. These data suggest novel functions for elafin in neutrophil migration, and that judicious selection of promoters may allow single, low-dose adenoviral administration to effect inflammation-specific expression of potentially therapeutic transgenes.
Adenoviridae↗
Schizophrenia and affective disorders--cosegregation with a translocation at chromosome 1q42 that directly disrupts brain-expressed genes: clinical and P300 findings in a family.
A family with a (1;11)(q42;q14.3) translocation significantly linked to a clinical phenotype that includes schizophrenia and affective disorders is described. This translocation generates a LOD score of 3.6 when the disease phenotype is restricted to schizophrenia, of 4.5 when the disease phenotype is restricted to affective disorders, of 7.1 when relatives with recurrent major depression, with bipolar disorder, or with schizophrenia are all classed as affected. This evidence for linkage is among the strongest reported for a psychiatric disorder. Family members showed no distinctive features by which the psychiatric phenotype could be distinguished from unrelated cases of either schizophrenia or affective disorders, and no physical, neurological, or dysmorphic conditions co-occurred with psychiatric symptoms. Translocation carriers and noncarriers had the same mean intelligence quotient. Translocation carriers were similar to subjects with schizophrenia and different from noncarriers and controls, in showing a significant reduction in the amplitude of the P300 event-related potential (ERP). Furthermore, P300 amplitude reduction and latency prolongation were measured in some carriers of the translocation who had no psychiatric symptoms-a pattern found in other families with multiple members with schizophrenia, in which amplitude of and latency of P300 appear to be trait markers of risk. The results of karyotypic, clinical, and ERP investigations of this family suggest that the recently described genes DISC1 and DISC2, which are directly disrupted by the breakpoint on chromosome 1, may have a role in the development of a disease phenotype that includes schizophrenia as well as unipolar and bipolar affective disorders.
Adolescent↗
Identification of genes from a schizophrenia-linked translocation breakpoint region.
The translocation t(1:11)(q42.1,q14.3) has previously been found to be linked with schizophrenia. Genes present at the chromosome 1 breakpoint have been investigated in some detail but little was known about genes in the chromosome 11 breakpoint region. Here we report a BAC clone contig encompassing 2.51 Mb around the chromosome 11 breakpoint, which was constructed computationally using draft genomic sequence data and existing mapping data for the region. The contig includes 26 clones and has led to the identification and relative ordering of 10 candidate genes in the region, including 2 novel transcripts. It constitutes a resource for polymorphic marker discovery and association studies to validate or reject candidate genes. Four candidate genes appear to be particularly promising based upon their proximity to the breakpoint and their likely functional roles. Three of these are involved in glutamatergic neurotransmission (the glutamate receptor GRM5, NAALADase II, and a close homolog), perturbation of which is one of the most widely held theories on the underlying biochemistry of schizophrenia. The 4th gene, tyrosinase, has been previously linked to schizophrenia through the cosegregation of oculocutaneous albinism with psychosis in several pedigrees.
Antigens, Surface↗
Markers close to the dopamine D5 receptor gene (DRD5) show significant association with schizophrenia but not bipolar disorder.
Following the description of linkage of markers at chromosome 4p16 to bipolar disorder in several families [Blackwood et al., 1996], and the association of the alleles of a polymorphism closely linked to D5 dopamine receptor gene with schizophrenia [Williams et al., 1997], we have looked for linkage disequilibrium between a series of microsatellite markers from this region and major psychoses including schizophrenia, bipolar disorder, and unipolar major depressive disorder. A significant increase in the frequency of the 148 bp allele of DRD5 (P = 0.024) and the 244 bp allele of D4S615 (P = 0.001) was found in patients with schizophrenia (n = 158 DRD5; n = 133 D4S615), compared with patients with bipolar disorder (n = 270 DRD5; n = 107 D4S615), or controls without psychiatric illness (n = 437 DRD5; n = 309 D4S615). The frequency of the 148 bp allele of DRD5 was also increased in schizophrenia over unipolar major depressive disorder (n = 65). D4S615 was not typed in unipolar disorder. The estimated odds ratios confirmed that the 148 bp allele of DRD5 and the 244 bp allele of D4S615 conferred increased risk of schizophrenia. Estimated Haplotype (EH) analysis of 174 controls and 128 patients with schizophrenia who were typed for both markers confirmed the strong associations with these alleles but did not show evidence that the markers were in linkage disequilibrium with each other even though they lie approximately 150 kb apart. The data are consistent with an association between markers close to the D5 dopamine receptor and schizophrenia, but not bipolar disorder or unipolar major depression.
Alleles↗
Twin peaks: the draft human genome sequence.
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Computational Biology↗
A 6.9-Mb high-resolution BAC/PAC contig of human 4p15.3-p16.1, a candidate region for bipolar affective disorder.
Bipolar affective disorder (BPAD) is a complex disease with a significant genetic component and a population lifetime risk of 1%. Our previous work identified a region of human chromosome 4p that showed significant linkage to BPAD in a large pedigree. Here, we report the construction of an accurate, high-resolution physical map of 6.9 Mb of human chromosome 4p15.3-p16.1, which includes an 11-cM (5.8 Mb) critical region for BPAD. The map consists of 460 PAC and BAC clones ordered by a combination of STS content analysis and restriction fragment fingerprinting, with a single approximately 300-kb gap remaining. A total of 289 new and existing markers from a wide range of sources have been localized on the contig, giving an average marker resolution of 1 marker/23 kb. The STSs include 57 ESTs, 9 of which represent known genes. This contig is an essential preliminary to the identification of candidate genes that predispose to bipolar affective disorder, to the completion of the sequence of the region, and to the development of a high-density SNP map.
Bipolar Disorder↗
Nuts and bolts of psychiatric genetics: building on the Human Genome Project.
Schizophrenia and bipolar affective disorder are chronic, disabling illnesses that together affect 2% of the population. Genetic factors are known to be important in their development, but there are, as yet, no confirmed susceptibility genes. Here we discuss important issues in terms of alternative genetic strategies (linkage, association and/or cytogenetics) in the identification of candidate genes for the major psychoses. We discuss the impact of the Human Genome Project, the role of comparative genetics in finding and testing positional candidates, and the prospects for rational drug design and personalized medicine.
Female↗
Physical mapping: integrating computational and molecular genetic data.
A crucial step beyond the identification of genetic linkage of a disease to a chromosomal region is the production of a physical map that will allow the identification of candidate genes. Although the process of physical map building has been facilitated by the flow of data released by the Human Genome Project, gathering all the information together requires significant effort. In a previous study, we reported linkage between Bipolar Affective Disorder and the chromosomal location 4p15.3--p16.1. In this review we use this example to describe how to collect publicly available sequence, DNA fingerprint, and genetic marker data and integrate these with empirical data to build a large scale high resolution physical map of a region. Methods used to identify new genetic markers and candidate genes within a circumscribed region are also presented.
Databases, Factual↗
Genomic structure and localisation within a linkage hotspot of Disrupted In Schizophrenia 1, a gene disrupted by a translocation segregating with schizophrenia.
Two overlapping and antiparallel genes on chromosome 1, Disrupted In Schizophrenia 1 and 2 (DISC1 and DISC2), are disrupted by a (1;11)(q42.1;q14.3) translocation which segregates with schizophrenia through at least four generations of a large Scottish family. Consequently, these genes are worthy of further investigation as candidate genes potentially involved in the aetiology of major psychiatric illness. We have constructed a contiguous clone map of PACs and cosmids extending across at least 400 kb of the chromosome 1 translocation breakpoint region and this has provided the basis for examination of the genomic structure of DISC1. The gene consists of thirteen exons, estimated to extend across at least 300 kb of DNA. The antisense gene DISC2 overlaps with exon 9. Exon 11 contains an alternative splice site that removes 66 nucleotides from the open reading frame. The final intron of DISC1 belongs to the rare AT-AC class of introns. We have also mapped marker DIS251 in close proximity to DISC1, localising the gene within a critical region identified by several independent studies. Information regarding the structure of the DISC1 gene will facilitate assessment of its involvement in the aetiology of major mental illness in psychotic individuals unrelated to carriers of the translocation.
Cell Line↗
The genomic organisation of the metabotropic glutamate receptor subtype 5 gene, and its association with schizophrenia.
The G-protein coupled metabotropic glutamate receptors (GRMs/mGluRs) have been implicated in the aetiology of schizophrenia as they modulate the NMDA response and that of other neurotransmitters including dopamine and GABA.(1-3) Electrophysiological studies in GRM subtype 5 knockout mice reveal, in one study, a sensorimotor gating deficit characteristic of schizophrenia and in another, a key rôle for this gene in the modulation of hippocampal NMDA-dependent synaptic plasticity. In humans, GRM5 levels are increased in certain pyramidal cell neurons in schizophrenics vs controls.(6) Finally, GRM5 has been mapped to 11q14, neighbouring a translocation that segregates with schizophrenia and related psychoses in a large Scottish family, F23 (MLOD score 6.0). We determined the intron/exon structure of GRM5 and identified a novel intragenic microsatellite. A case-control association study identified a significant difference in allele frequency distribution between schizophrenics and controls (P = 0.04). This is suggestive of involvement of the GRM5 gene in schizophrenia in this population.
Case-Control Studies↗
Identification of polymorphisms within Disrupted in Schizophrenia 1 and Disrupted in Schizophrenia 2, and an investigation of their association with schizophrenia and bipolar affective disorder.
We have undertaken a search for polymorphic sequence variation within Disrupted in Schizophrenia 1 and Disrupted in Schizophrenia 2 (DISC1 and DISC2), which are both novel genes that span a translocation breakpoint strongly associated with schizophrenia and related psychoses in a large Scottish family. A scan of the coding sequence, intron/exon boundaries, and part of the 5' and 3' untranslated regions of DISC1, plus 2.7 kb at the 3' end of DISC2, has revealed a novel microsatellite and 15 novel single nucleotide polymorphisms (SNPs). We have tracked the inheritance of four of the SNPs through multiply affected families, and carried out case-control association studies using the microsatellite and four common SNPs on populations of patients with schizophrenia or bipolar affective disorder versus normal control subjects. Neither co-segregation with disease status nor significant association was detected; however, we could not detect linkage disequilibrium between all these markers in the control population, arguing that an even greater density of informative markers is required to test rigorously for association in this genomic region.
Alleles↗
Chromosomal location and genomic structure of the human translin-associated factor X gene (TRAX; TSNAX) revealed by intergenic splicing to DISC1, a gene disrupted by a translocation segregating with schizophrenia.
Two candidate genes, DISC1 and DISC2 on chromosome 1, are disrupted by a translocation that segregates with major psychiatric illness. Several DISC1 transcripts contain TRAX (HGMW-approved symbol TSNAX) sequence at the 5' end. These transcripts initiate at the 5' end of TRAX and terminate at the final exon of DISC1. Five species of transcript resulting from intergenic splicing have been identified; one encodes a novel TRAX/DISC1 fusion protein. The remaining four transcripts are bicistronic and encode a series of novel truncated isoforms of TRAX and DISC1. Demonstration that the various TRAX/DISC1 transcripts are translated awaits further experimentation. As a consequence of the observation of intergenic splicing, the human TRAX gene has been mapped at least 35 kb proximal to DISC1 and within approximately 150-250 kb of the translocation breakpoint at 1q42.1. The TRAX gene consists of six exons with a putative CpG island at the 5' end. Four major transcripts are produced from this gene, of which the smallest, at 2.7 kb, had previously been identified.
Bacterial Outer Membrane Proteins↗
Disruption of two novel genes by a translocation co-segregating with schizophrenia.
A balanced (1;11)(q42.1;q14.3) translocation segregates with schizophrenia and related psychiatric disorders in a large Scottish family (maximum LOD = 6.0). We hypothesize that the translocation is the causative event and that it directly disrupts gene function. We previously reported a dearth of genes in the breakpoint region of chromosome 11 and it is therefore unlikely that the expression of any genes on this chromosome has been affected by the translocation. By contrast, the corresponding region on chromosome 1 is gene dense and, not one, but two novel genes are directly disrupted by the translocation. These genes have been provisionally named Disrupted-In-Schizophrenia 1 and 2 ( DISC1 and DISC2 ). DISC1 encodes a large protein with no significant sequence homology to other known proteins. It is predicted to consist of a globular N-terminal domain(s) and helical C-terminal domain which has the potential to form a coiled-coil by interaction with another, as yet, unidentified protein(s). Similar structures are thought to be present in a variety of unrelated proteins that are known to function in the nervous system. The putative structure of the protein encoded by DISC1 is therefore compatible with a role in the nervous system. DISC2 apparently specifies a non-coding RNA molecule that is antisense to DISC1, an arrangement that has been observed at other loci where it is thought that the antisense RNA is involved in regulating expression of the sense gene. Altogether, these observations indicate that DISC1 and DISC2 should be considered formal candidate genes for susceptibility to psychiatric illness.
3' Untranslated Regions↗
Mutational analysis of the Wolfram syndrome gene in two families with chromosome 4p-linked bipolar affective disorder.
Bipolar affective disorder (BPAD) is a complex disease with a significant genetic component. Heterozygous carriers of Wolfram syndrome (WFS) are at increased risk of psychiatric illness. A gene for WFS (WFS1) has recently been cloned and mapped to chromosome 4p, in the general region we previously reported as showing linkage to BPAD. Here we present sequence analysis of the WFS1 coding sequence in five affected individuals from two chromosome 4p-linked families. This resulted in the identification of six polymorphisms, two of which are predicted to change the amino acid sequence of the WFS1 protein, however none of the changes segregated with disease status. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:158-160, 2000.
Bipolar Disorder↗
A 700-kb physical map of a region of 16q23.2 homozygously deleted in multiple cancers and spanning the common fragile site FRA16D.
We have identified a >600-kb region at 16q23.2 that is homozygously deleted from malignant ovarian ascites using representational difference analysis. Overlapping homozygous deletions were also observed in the colon carcinoma cell line HCT116 and a xenograft established from the small cell lung cancer cell line WX330. This region coincides with that described previously by others as showing loss of heterozygosity in prostate and breast cancers (C. Li et al., Genes Chromosomes Cancer, 24: 175-182, 1999; A. Latil et al., Cancer Res., 57: 1058-1062, 1997; K. Driouch et al., Genes Chromosomes Cancer, 19: 185-191, 1997; A. Iida et al., Br. J. Cancer, 75: 264-267, 1997). In addition, the minimally deleted region spans the common fragile site FRA16D. We have constructed a 700-kb physical map encompassing the deleted region. By fluorescence in situ hybridization of aphidicolin-induced metaphase chromosomes, we have preliminary data to suggest that P1-derived bacterial artificial chromosome clones from the contig lie on both sides of FRA16D. This is confirmed by extensive fluorescence in situ hybridization analysis of the region reported in the accompanying article (M. Mangelsdorf et al., Cancer Res., 60: 1683-1689, 2000) and is consistent with an involvement of this common fragile site in the loss of 16q23.2 material in various cancer types. The minimally deleted region of approximately 210 kb has been characterized using our own markers and public domain markers. Eleven distinct expressed sequences mapped to the region, providing a basis for identifying the predicted tumor suppressor gene in this region.
Bacteriophage P1↗