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L M Tarantino

Publications and source records attributed to L M Tarantino.

18 recordsLinked to original sources
PubMed2001

Physical mapping of the mouse tilted locus identifies an association between human deafness loci DFNA6/14 and vestibular system development.

The tilted (tlt) mouse carries a recessive mutation causing vestibular dysfunction. The defect in tlt homozygous mice is limited to the utricle and saccule of the inner ear, which completely lack otoconia. Genetic mapping of tlt placed it in a region orthologous with human 4p16.3-p15 that contains two loci, DFNA6 and DFNA14, responsible for autosomal dominant, nonsyndromic hereditary hearing impairment. To identify a possible relationship between tlt in mice and DFNA6 and DFNA14 in humans, we have refined the mouse genetic map, assembled a BAC contig spanning the tlt locus, and developed a comprehensive comparative map between mouse and human. We have determined the position of tlt relative to 17 mouse chromosome 5 genes with orthologous loci in the human 4p16.3-p15 region. This analysis identified an inversion between the mouse and human genomes that places tlt and DFNA6/14 in close proximity.

Animals↗
PubMed2000

A high-resolution radiation hybrid map of the proximal portion of mouse chromosome 5.

Radiation hybrid (RH) mapping of the mouse genome provides a useful tool in the integration of existing genetic and physical maps, as well as in the ongoing effort to generate a dense map of expressed sequence tags. To facilitate functional analysis of mouse Chromosome 5, we have constructed a high-resolution RH map spanning 75 cM of the chromosome. During the course of these studies, we have developed RHBase, an RH data management program that provides data storage and an interface to several RH mapping programs and databases. We have typed 95 markers on the T31 RH panel and generated an integrated map, pooling data from several sources. The integrated RH map ranges from the most proximal marker, D5Mit331 (Chromosome Committee offset, 3 cM), to D5Mit326, 74.5 cM distal on our genetic map (Chromosome Committee offset, 80 cM), and consists of 138 markers, including 89 simple sequence length polymorphic markers, 11 sequence-tagged sites generated from BAC end sequence, and 38 gene loci, and represents average coverage of approximately one locus per 0.5 cM with some regions more densely mapped. In addition to the RH mapping of markers and genes previously localized on mouse Chromosome 5, this RH map places the alpha-4 GABA(A) receptor subunit gene (Gabra4) in the central portion of the chromosome, in the vicinity of the cluster of three other GABA(A) receptor subunit genes (Gabrg1-Gabra2-Gabrb1). Our mapping effort has also defined a new cluster of four genes in the semaphorin gene family (Sema3a, Sema3c, Sema3d, and Sema3e) and the Wolfram syndrome gene (Wfs1) in this region of the chromosome.

Animals↗
PubMed2000

Dissection of behavior and psychiatric disorders using the mouse as a model.

Mouse genetic models have played an important role in the elucidation of molecular pathways underlying human disease. This approach is becoming an increasingly popular way to study the genetic underpinning of psychiatric disorders. Genes within candidate regions for susceptibility to psychiatric illness can be evaluated through the phenotypic assessment of mutants mapped to the corresponding regions in the mouse genome. Alternatively, one can search for mouse mutants displaying characteristics that might correspond to physiological and behavioral markers of a psychiatric disorder, sometimes referred to as endophenotypes. Mice with anomalies in these traits can be generated by targeted mutagenesis in known genes (gene-based mutagenesis or reverse genetics), or can be identified among progeny of mice in a random mutagenesis screen (phenotype-based mutagenesis or forward genetics). In this review, we discuss recently generated behavioral mutants in the mouse. We also give an overview of several robust and commonly used behavioral phenotypes, their relevance to human disease and lessons learned from recent successes in mouse behavioral genetics.

Animals↗
PubMed2000

Behavior and mutagenesis screens: the importance of baseline analysis of inbred strains.

Random mutagenesis as a means of identifying the function of genes has been used extensively in a variety of model organisms. Until recently it has been used primarily in the identification of single-gene traits that cause visible and developmental mutations. However, this genetic approach also has the power to identify genes that control complex biological systems such as behavior. Mutagenesis screens for behavioral mutations require careful consideration of many factors, including choice of both assays and background strains for use in mutagenesis and subsequent mapping of the affected gene or genes. This paper describes behavioral assays for monitoring motor coordination on the accelerating rotarod, anxiety-related behaviors in the elevated zero maze and sensorimotor reactivity, gating, and habituation of acoustic startle. These five physiological or neurological behaviors can represent potential endophenotypes for a variety of neurological and psychiatric disorders. The significant degree of strain- and sex-specific differences in the performance of four inbred strains of mice (C57BL/6J, C3HeB/FeJ, DBA/2J, and 129/SvlmJ) in these behavioral assays illustrates the importance of performing baseline analysis prior to behavioral mutagenesis screens and genetic mapping of selected mutations.

Animals↗
PubMed2000

Epistatic quantitative trait loci for alcohol preference in mice.

Alcohol consumption is a complex trait, responding to the influence of various genes and environmental influences acting in a quantitative fashion. Various studies in alcohol consumption processes have identified quantitative trait locus (QTL) regions across the mouse genome that appear to contribute to this phenotype. The purpose of this study was to examine the influence of interactions between alleles at different loci, a phenomenon known as epistasis, on previously identified QTLs for alcohol consumption in mice. A multiple regression model was developed and applied to test for the significance of the interaction between two QTLs and to quantify this interaction. Our results indicate the presence of epistasis between loci on mouse chromosomes 2 and 3 accounting for 7-8% of the variation in alcohol preference, respectively.

Alcohol Drinking↗
PubMed2000

Sperm antigen 6 is the murine homologue of the Chlamydomonas reinhardtii central apparatus protein encoded by the PF16 locus.

A cDNA encoding sperm antigen 6 (Spag6), the murine homologue of the Chlamydomonas reinhardtii PF16 protein-a component of the flagella central apparatus-was isolated from a mouse testis cDNA library. The cDNA sequence predicted a 55.3-kDa polypeptide containing 8 contiguous armadillo repeats with 65% amino acid sequence identity and 81% similarity to the Chlamydomonas PF1 protein. An antipeptide antibody generated against a C-terminal sequence recognized a 55-kDa protein in sperm extracts and localized Spag6 to the principal piece of permeabilized mouse sperm tails. When expressed in COS-1 cells, Spag6 colocalized with microtubules. The Spag6 gene was found to be highly expressed in testis and was mapped using the T31 radiation hybrid panel to mouse chromosome 16. Mutations in the Chlamydomonas PF16 gene cause flagellar paralysis. The presence of a highly conserved mammalian PF16 homologue (Spag6) raises the possibility that Spag6 plays an important role in sperm flagellar function.

Algal Proteins↗
PubMed2000

Interdigitated deletion complexes on mouse chromosome 5 induced by irradiation of embryonic stem cells.

Chromosome deletions have several applications in the genetic analysis of complex organisms. They can be used as reagents in region-directed mutagenesis, for mapping of simple or complex traits, or to identify biological consequences of segmental haploidy, the latter being relevant to human contiguous gene syndromes and imprinting. We have generated three deletion complexes in ES (Embryonic Stem) cells that collectively span approximately 40 cM of proximal mouse chromosome 5. The deletion complexes were produced by irradiation of F(1) hybrid ES cells containing herpes simplex virus thymidine kinase genes (tk) integrated at the Dpp6, Hdh (Huntington disease locus), or Gabrb1 loci, followed by selection for tk-deficient clones. Deletions centered at the adjacent Hdh and Dpp6 loci ranged up to approximately 20 cM or more in length and overlapped in an interdigitated fashion. However, the interval between Hdh and Gabrb1 appeared to contain a locus haploinsufficient for ES cell viability, thereby preventing deletions of either complex from overlapping. In some cases, the deletions resolved the order of markers that were previously genetically inseparable. A subset of the ES cell-bearing deletions was injected into blastocysts to generate germline chimeras and establish lines of mice segregating the deletion chromosomes. At least 11 of the 26 lines injected were capable of producing germline chimeras. In general, those that failed to undergo germline transmission bore deletions larger than the germline-competent clones, suggesting that certain regions of chromosome 5 contain haploinsufficient developmental genes, and/or that overall embryonic viability is cumulatively decreased as more genes are rendered hemizygous. Mice bearing deletions presumably spanning the semidominant hammertoe locus (Hm) had no phenotype, suggesting that the classic allele is a dominant, gain-of-function mutation. Overlapping deletion complexes generated in the fashion described in this report will be useful as multipurpose genetic tools and in systematic functional mapping of the mouse genome.

Animals↗
PubMed1999

Sex-exclusive quantitative trait loci influences in alcohol-related phenotypes.

During the past half century, researchers have identified and examined sex differences in alcohol-related phenotypes, focusing more recently on understanding of the mechanisms underlying these differences. In general, the genetic contributions influencing these differences are not consistent with an interpretation of sex linkage and must, therefore, reflect some form of sex limitation in which allelic differences at particular autosomal loci have different consequences in males and females. Significant sex differences in measures of alcohol consumption in mice have been demonstrated in previous work in our laboratory. To investigate these differences further, we explore the limiting case of sex-exclusive effects using data from (BXD) recombinant inbred (RI) strains of mice and from an intercross derived from the same progenitors, C57BL/6J (B) and DBA/2J (D). By the use of two statistical approaches (examination of residual scores as a sex-exclusive phenotypic value for the RI strains and multivariate regression on sex and genotype in the F(2)) we have identified and confirmed female-exclusive markers for alcohol acceptance on chromosomes 9 and 12 and one marker for alcohol preference on chromosome 2. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 88:647-652, 1999.

Alcohol-Related Disorders↗
PubMed1999

Gender-influenced obesity QTLs identified in a cross involving the KK type II diabetes-prone mouse strain.

The inheritance of adiposity and related traits has been investigated in the obese, diabetes-prone KK/HlLt (KK) and the lean, normoglycemic C57BL/6J (B6) mouse strains, their F(1) hybrids, and a large intercross generation. Adiposity index (AI) was defined as the sum of four fat depot weights divided by body weight. Both male and female KK mice were obese, but AI values averaged twofold higher in females than in males. In contrast, B6 females were slightly more lean than males. A genome-wide search revealed several qualitative trait loci (QTLs) affecting AI. The proximal region of Chromosome (Chr) 9 has a large effect on AI, with a much stronger effect in females (lod = 6.3) than in males (lod = 2.7). The data for females fit a model in which a dominant allele from KK increases AI by 30%, with the lod score peak falling between markers D9Mit66 and D9Mit328. This QTL has large effects on inguinal and mesenteric fat pad weights, with smaller effects on gonadal and retroperitoneal fat pads. The region of Chr 9 containing this QTL has extensive homology to human Chr 11q. An X-linked QTL affecting AI was evident in males (lod = 3.77), but not females (lod = 0.7). Exclusion of mesenteric fat from male AI resulted in an increased lod score (lod = 5.0) at 8 cM distal to DXMit166. A suggestive AI QTL (lod = 4.2), differentially affecting males, was localized to Chr 18 near the glucocorticoid receptor locus. A region of Chr 7 had a strong effect on body weight (lod = 6.9), a significant effect on inguinal fat% (lod = 4.4), and a suggestive effect on AI in females (lod = 4.1). Plasma leptin levels were associated with genotypes on Chr 9 (lod = 5.9) and Chr 7 (lod = 4.2). A region of Chr 1 had a suggestive effect on fasted blood glucose (lod = 3.6).

Adipose Tissue↗
PubMed1999

Quantitative-trait loci analysis of cocaine-related behaviours and neurochemistry.

We recently conducted a dose-response study of the effects of cocaine on several activity measures in the panel of BxD/Ty recombinant inbred mice. Animals were tested in an automated activity chamber over 2 days with i.p. saline on day 1 and i.p. cocaine on day 2, at one of four doses, 5, 15, 30 or 45 mg kg(-1). The monitor recorded total distance traveled, nosepokes in a holeboard, repeated movements and time spent by an individual in proximity to the centre of the apparatus. Dose-response curves for locomotor activation, i.e. the difference between cocaine and saline scores, showed that for all strains tested, scores increased 5-30 mg kg(-1). With few exceptions, locomotor activity at 45 mg kg(-1) was not significantly higher than that at 30 mg kg(-1). Repeated movement scores showed patterns similar to locomotor activity and nosepokes tended to be progressively inhibited by increasing doses of cocaine. Recombinant inbred strain mean distributions for all behaviours and at all doses exhibited continuous, rather than discrete variation, thus providing evidence of multiple-gene effects on cocaine-related behaviours. Quantitative trait loci (QTL) analysis pointed to several chromosomal locations associated with variations in cocaine-related behaviours and some are either identical or close to QTL reported by others. In separate groups of animals, densities of dopamine D1, and D2 receptors and dopamine uptake transporters were measured in the medial prefrontal cortex, caudate-putamen, nucleus accumbens and ventral midbrain. In all areas, all measures showed distributions consistent with polygenic influence and were associated with QTL. Of particular interest was our finding of a large segment on chromosome 15, which is related to dopamine receptor densities and cocaine-related behaviours.

Animals↗
PubMed1998

High genetic susceptibility to ethanol withdrawal predicts low ethanol consumption.

C57BL/6J (B6) inbred mice are well known to drink large amounts of alcohol (ethanol) voluntarily and to have only modest ethanol-induced withdrawal under fixed dose conditions. In contrast, DBA/2J (D2) mice are "teetotallers" and exhibit severe ethanol withdrawal. Speculation that an inverse genetic relationship existed between these two traits was substantiated by meta-analysis of existing data collected in multiple genetic models, including large panels of standard and recombinant inbred strains, their crosses, and selectively bred mouse lines. Despite methodological differences among laboratories in measurement of both preference drinking and withdrawal, a nearly universal finding was that genotypes consuming large amounts of 10% ethanol (calculated as g/kg/day) during two-bottle choice preference drinking were genetically predisposed to low withdrawal scores in independent studies after either acute or chronic ethanol treatment. Conversely, low-drinking genotypes had higher withdrawal severity scores. The genetic relationship appears to be strongest in populations derived from B6 and D2, where data from more genotypes (BXD RIs, B6D2F2s, BXD RI F1s, and B6D2F2-derived selectively bred lines) were available for analysis. Gene mapping studies in these populations identified four chromosome regions [on Chromosomes (Chrs) 1, 2, 4, and 15] where genes might potentially influence both traits. Among genotypes with greater genetic diversity (for example, a panel of standard inbred strains or selectively bred lines), the relationship was less pronounced. Thus, reduced susceptibility to the development of high alcohol use may be supported by increased genetic susceptibility to ethanol withdrawal symptoms.

Alcohol Drinking↗
PubMed1998

Developmental loss of effect of a Chromosome 15 QTL on alcohol acceptance.

Human alcohol abuse and alcoholism have clear developmental features, suggesting the possibility of changes over time in heritability and in quantitative genetic architecture, and raising prospects of identifying individual genes or quantitative trait loci (QTLs) that display different influence on alcohol-related phenotypes at different ages. The identification of specific loci showing such age-related changes will open up opportunities of focused association studies and of genotype manipulation by various mating procedures. Most animal model research in alcohol assesses the phenotypes of the animals at an early age; developmental studies are rare. Here we report on a QTL on Chromosome (Chr) 15 of the mouse that has been shown in several populations, including BXD recombinant inbred strains, an F2, and genotypically selected lines, to affect a measure of alcohol consumption. In the present study, we measured alcohol acceptance in the genotypically selected animals and in an F4 sample at about 100 days and again at about 300 days of age. In both groups, and in both sexes, significant differences were observed at 100 days between animals that were homozygous for the "increasing" haplotype defining the QTL region and those homozygous for the "decreasing" haplotype. At 300 days of age, the effect is absent in females and has diminished or disappeared in males. The results provide a further confirmation of the Chr 15 QTL in young mice, offer a new perspective on the development of alcohol-related phenotypes, and have strong implications for research design.

Alcohol Drinking↗
PubMed1998

Confirmation of quantitative trait loci for alcohol preference in mice.

An F2 intercross derived from C57BL/6 and DBA/2 progenitor inbred strains was used to test for replication of quantitative trait loci (QTLs) for alcohol preference nominated by a previous study using BXD recombinant inbred (RI) strains (Rodriguez et al., Alcohol. Clin. Exp. Res. 19:367-379, 1995). Fourteen provisional QTLs were nominated in the original RI study with a p < 0.05 criterion. In the present study, a genome scan (101 microsatellite markers) was conducted on an F2 population (n = 218). Three significant QTLs were detected on chromosomes 1, 4, and 9, and three suggestive QTLs were detected on chromosomes 2, 3, and 10. Of these six QTLs, four were consistent with the previous RI nominations. The replication rate of 28.6% (4 of 14) is in agreement with the results of simulation studies performed by Belknap et al. (Behav. Genet. 26:149-160, 1996) and supports the methodological argument for a multistage research design for nominating and replicating QTLs.

Alcohol Drinking↗
PubMed1997

A multivariate model for the analysis of sibship covariance structure using marker information and multiple quantitative traits.

A model was developed to detect effects of quantitative trait loci (QTLs) in sibships from simulated nuclear family data using the full covariance structure of the data and analyzing all five quantitative traits simultaneously in a multivariate model. Evidence of the presence of loci was detected on chromosomes 4, 8, 9, and 10. The method provided stable results and is worth further exploration for its performance and optimal sample size requirements under realistic conditions.

Alleles↗
PubMedDate not supplied

Genotypic selection provides experimental confirmation for an alcohol consumption quantitative trait locus in mouse.

Quantitative genetic research has produced a wealth of basic information concerning genetic influence on alcohol-related processes. Recent developments in quantitative trait locus (QTL) methodology were promptly applied to the task of individuating polygenes affecting alcohol-related attributes in animal models and a body of reliable data is gradually coming into focus as a result of replication and convergence of evidence from a variety of methods. A key issue in QTL research is the need to distinguish true positive results from the false positive results that are inherent in analytical procedures requiring large numbers of significance tests. One school of thought holds that stringent significance levels should be imposed; another suggests more modest criteria for QTL nomination, with subsequent confirmation trials with independent samples. Recombinant inbred strains and various types of intercrosses have been used in correlational designs, both for nomination and confirmation studies. Alternative experimental procedures include knockout preparations and short-term phenotypic selective breeding. We present here results from a third experimental method-that of marker-based genotypic selection--in evaluation of two nominated QTLs for alcohol acceptance in mice.

Alcohol Drinking↗