High concentrations of toxaphene in fishes from a subarctic lake.

Concentrations of toxaphene and other organochlorine compounds are high in fishes from subarctic Lake Laberge, Yukon Territory, Canada. Nitrogen isotope analyses of food chains and contaminant analyses of biota, water, and dated lake sediments show that the high concentrations of toxaphene in fishes from Laberge resulted entirely from the biomagnification of atmospheric inputs. A combination of low inputs of toxaphene from the atmosphere and transfer through an exceptionally long food chain has resulted in concentrations of toxaphene in fishes that are considered hazardous to human health.

Assignment of the 5HT7 receptor gene (HTR7) to chromosome 10q and exclusion of genetic linkage with Tourette syndrome.

A novel serotonin receptor designated 5HT7 (genetic locus HTR7) was cloned in 1993. This receptor has interesting properties related to ligand affinity and CNS distribution that render HTR7 a very interesting candidate gene for neuropsychiatric disorders. We mapped this gene, first by physical methods and then by genetic linkage.

Apparent monomorphism of ALDH2 in seven American Indian populations.

Deficiency of mitochondrial aldehyde dehydrogenase (ALDH2) has been previously reported in South American Indians. We therefore assayed five individuals from each of five South American Indian populations (Quechua, Karitiana, Ticuna, Surui, Guahiba), and two North American populations (Maya and Moskoke) for the presence of the Oriental ALDH2(2) variant. These samples were also surveyed for other alleles altering ALDH2 function.

Correlation between stable nitrogen isotope ratios and concentrations of organochlorines in biota from a freshwater food web.

The relationship between total concentrations of hexachlorocyclohexane (sigma HCH), sigma DDT, and chlorinated bornanes (toxaphene, sigma CHB) and the trophic position of biota from a subarctic lake was investigated using stable isotope ratios of nitrogen (15N/14N). Zooplankton, benthic invertebrates, and forage and piscivorous fishes were analysed for 15N/14N and organochlorines using mass spectrometry and high resolution capillary gas chromatography (GC-ECD), respectively. The trophic relationships of the biota were clearly defined, with 15N/14N increasing an average of 3.

Network-based informatics support of research collaborations in the Human Genome Project and the Human Brain Project.

Sophisticated network-based informatics support will increasingly be required for collaborating biomedical laboratories located in different geographic locations, both to accommodate the massive amount of data being generated in certain fields, and to allow different types of data produced at different laboratories to be analyzed in an integrated fashion. The paper describes the experience of the Yale Center for Medical Informatics in providing informatics support for collaborative projects in gene mapping (as part of the national Human Genome Project) and neuroscience (as part of the national Human Brain Project). The paper describes the informatics needs of the two projects and the solutions being developed, describes certain lessons learned, and discusses certain broader issues that arise.

The CEPH consortium linkage map of human chromosome 16.

A Centre d'Etude du Polymorphisme Humain (CEPH) consortium map of human chromosome 16 has been constructed. The map contains 158 loci defined by 191 different probe/restriction enzyme combinations or primer pairs. The marker genotypes, contributed by 9 collaborating laboratories, originated from the CEPH families DNA.

Computer-assisted restriction mapping: an integrated approach to handling experimental uncertainty.

Building a map of restriction sites from double-digest gel data can be a complex and frustrating task, especially when many DNA fragments are detected or when the gel results are ambiguous. 'Double Digester' is an interactive, graphical computer program which helps researchers understand and resolve such data. It explicitly represents the experimental data, the associated uncertainties, the researcher's hypotheses and possible map interpretations.

D2 dopamine receptor alleles do not influence severity of Tourette's syndrome. Results from four large kindreds.

Objective: We investigated the recently proposed hypothesis that the A1 allele of the Taq I polymorphic system at the D2 dopamine receptor gene (DRD2) influences the severity of Tourette's syndrome (TS). We have previously demonstrated that DRD2 is not linked to TS, establishing that it cannot be the major locus determining the susceptibility to develop TS.

Method: We studied alleles at the DRD2 A system in patients with TS or chronic multiple tics in four extended kindreds segregating TS.

Detection of DNA sequence variation via deliberate heteroduplex formation from genomic DNAs amplified en masse in "population tubes".

We have developed the population tube (poptube) system for sensitive detection and large-scale sampling of DNA sequence variation in several human populations of wide geographic distribution. In this methodology, genomic DNAs from five individuals in a population are PCR amplified en masse to maximize deliberately the chances of forming heteroduplexes among allelic variants. Interpopulation mixing is performed in a separate set of tubes containing one individual from each of five populations as well as a reference chimpanzee sample deliberately chosen to be different from all humans.

Linkage study of a susceptibility locus for schizophrenia in the pseudoautosomal region.

Several lines of evidence suggest that the sex chromosomes have a role in the expression of schizophrenia. Gender differences in response to treatment, age at onset of illness, and prognosis indicate an influence of sex in differential expression of schizophrenia. On the basis of a higher-than-expected concordance for sex among siblings with schizophrenia, as well as the findings of cytogenetic abnormalities of the sex chromosomes in some schizophrenia patients, a pseudoautosomal location for a schizophrenia susceptibility locus has been proposed.

Alleles at the dopamine D4 receptor locus do not contribute to the genetic susceptibility to schizophrenia in a large Swedish kindred.

The discovery of a functional polymorphism within the dopamine D4 receptor gene (DRD4) has not only strengthened the hypotheses implicating DRD4 in the etiology of neuropyschiatric disorders, but also provided a genetic marker for testing these hypotheses. The possibility of the dopamine D4 receptor as a candidate gene for schizophrenia was investigated in a large Swedish kindred segregating for schizophrenia. Linkage to schizophrenia was tested by linkage analyses of 6 polymorphic markers (at 4 loci) in chromosome 11p15.

Assignment of the norepinephrine transporter protein (NET1) locus to chromosome 16.

The norepinephrine transporter protein (NET) is the presynaptic reuptake site for norepinephrine and a site of action for several drugs with CNS effects, some of which are therapeutically useful and some of which are drugs of abuse. We used PCR with a somatic cell hybrid panel to obtain a provisional assignment to chromosome 16. We then typed a genetic polymorphism at the NET1 locus in three large multigenerational families and used linkage analysis to confirm the preliminary assignment and to refine the localization to 16q, near the HP locus.

Genomic and yeast artificial chromosome long-range physical maps linking six loci in 10q11.2 and spanning the multiple endocrine neoplasia type 2A (MEN2A) region.

Multiple endocrine neoplasia types 2A and 2B (MEN 2A and MEN 2B) and familial medullary thyroid carcinoma (FMTC) are dominantly inherited cancers that have in common the clinical feature of medullary thyroid carcinoma (MTC). We have performed both genomic long-range restriction mapping and yeast artificial chromosome (YAC) contig assembly and restriction mapping to establish physical linkage, order, and distances between six loci in 10q11.2 near the genes responsible for these hereditary cancers.

Population frequencies of the A1 allele at the dopamine D2 receptor locus.

The reported association of a polymorphic allele at the dopamine D2 receptor locus (DRD2) and alcoholism has recently been the focus of considerable interest and controversy. Evidence both for and against an association of the A1 allele of the TaqI A system have been reported. One of the inconsistencies in these studies is the frequency of the A1 allele in the controls.

Eliminating mitochondrial DNA competition for nuclear DNA primers.

Mitochondrial DNA (mtDNA) sequences were synthesized with nuclear DNA (nucDNA) sequence-tagged site (STS) primers by mismatch priming in three independent studies of the human nuclear genome. Mismatch primer binding sites on the mtDNA were identified with from 6- to 10-bp identity at the 3' ends of the primers. In two of three cases, single-stranded mtDNA copies were gel-isolated with intended nucDNA PCR products.

A hypervariable segment in the human dopamine receptor D4 (DRD4) gene.

The human dopamine D4 receptor contains a novel polymorphism within the putative third cytoplasmic loop of the protein. The polymorphism is characterized by a varying number of direct imperfect 48-bp repeats in the gene. Pharmacological characterization has suggested that this receptor is the site through which the atypical neuroleptic clozapine exerts its antipsychotic action and that some polymorphic variants display different pharmacological properties.

Physical and genetic maps for chromosome 10.

A fluorescence in situ hybridization (FISH) physical map of 14 polymorphic loci on chromosome 10 covers over 62% of the fractional length of chromosome 10. The positions of three previously mapped loci are confirmed, nine more are refined, and two new loci are cytogenetically mapped. The order of loci determined by FISH agrees with that obtained by genetic linkage studies.

Nuclear DNA polymorphisms in a wild population of yellow baboons (Papio hamadryas cynocephalus) from Mikumi National Park, Tanzania.

Yellow baboons (Papio hamadryas cynocephalus) from Mikumi National Park, Tanzania were studied for polymorphisms in nuclear DNA. The study population consists of four social groups that inhabit overlapping home ranges and exchange males. As a result, these groups are considered to be members of a single interbreeding population.

Glutathione depletion increases the cytotoxicity of melphalan to PC-3, an androgen-insensitive prostate cancer cell line.

Prostate cancer that is androgen-insensitive is unresponsive to a wide spectrum of cytotoxic agents, including all of the alkylating agents. Since a major pathway for the detoxification of the alkylating agents is conjugation with glutathione (GSH), GSH depletion has proved to be effective as a technique to restore melphalan sensitivity in melphalan-resistant cancer cell lines. However, the effect of GSH depletion has not been widely studied in tumor cell lines that have not developed resistance due to previous exposure to alkylating agents.

Interfaces between host and uncemented femoral hip prostheses.

The authors analyzed 200 uncemented hip prostheses that were retrieved. They determined the type and extent of host-implant interfaces, but found little correlation between subjective pain relief and the histology of the interfaces. Wear debris, bone resorption and looseness were related to pain, although even with these the relationship was not statistically significant.