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W S Davidson

Publications and source records attributed to W S Davidson.

At least 19 recordsLinked to original sources
PubMed2006

Identification of the sex-determining locus of Atlantic salmon (Salmo salar) on chromosome 2.

We have integrated data from linkage mapping, physical mapping and karyotyping to gain a better understanding of the sex-determining locus, SEX, in Atlantic salmon (Salmo salar). SEX has been mapped to Atlantic salmon linkage group 1 (ASL1) and is associated with several microsatellite markers. We have used probes designed from the flanking regions of these sex-linked microsatellite markers to screen a bacterial artificial chromosome (BAC) library, representing an 11.7x coverage of the Atlantic salmon genome, which has been HindIII fingerprinted and assembled into contigs. BACs containing sex-linked microsatellites and their related contigs have been identified and representative BACs have been placed on the Atlantic salmon chromosomes by fluorescent in situ hybridization (FISH). This identified chromosome 2, a large metacentric, as the sex chromosome. By positioning several BACs on this chromosome by FISH, it was possible to orient ASL1 with respect to chromosome 2. The region containing SEX appears to lie on the long arm between marker Ssa202DU and a region of heterochromatin identified by DAPI staining. BAC end-sequencing of clones within sex-linked contigs revealed five hitherto unmapped genes along the sex chromosome. We are using an in silico approach coupled with physical probing of the BAC library to extend the BAC contigs to provide a physical map of ASL1, with a view to sequencing chromosome 2 and, in the process, identifying the sex-determining gene.

Animals↗
PubMed2004

Bardet-Biedl syndrome 1 genotype and obesity in the Newfoundland population.

BACKGROUND AND OBJECTIVES: Obesity is one of the primary clinical features of Bardet-Biedl Syndrome (BBS), a genetically heterogeneous disorder that is usually inherited as an autosomal recessive trait. It has been suggested that heterozygous carriers of BBS are predisposed to obesity. We set out to identify the common mutation in BBS1 families from southwest Newfoundland and to examine the relationship between this mutation and obesity in the general population. METHODS AND SUBJECTS: We genotyped BBS1 families from Newfoundland to determine the nature of the mutation causing BBS in this population. We then screened 200 obese individuals (average body mass index (BMI)=37.9 kg/m2; average waist to hip ratio=0.935; average waist=113.8 cm) and 200 ethnically matched, unrelated, controls (average BMI=25.0 kg/m2; average waist to hip ratio=0.896; average waist=86.9 cm) from the same geographic region for the presence of this mutation. RESULTS: All affected members of the six Newfoundland BBS1 families were homozygous for the most common BBS1 mutation (M390R). This mutation was found in the heterozygous state in three of the 200 obese individuals and also in three of the 200 matched controls. CONCLUSIONS: The high frequency of BBS1 in Newfoundland appears to be the result of a founder event. Our data do not support the hypothesis that the M390R BBS1 mutation plays a significant role in the frequency of obesity in the general public in Newfoundland.

Adult↗
PubMed2004

A genetic linkage map for Arctic char (Salvelinus alpinus): evidence for higher recombination rates and segregation distortion in hybrid versus pure strain mapping parents.

We constructed a genetic linkage map for Arctic char (Salvelinus alpinus) using two backcrosses between genetically divergent strains. Forty-six linkage groups (expected = 39-41) and 19 homeologous affinities (expected = 25) were identified using 184 microsatellites, 129 amplified fragment length polymorphisms (AFLPs), 13 type I gene markers, and one phenotypic marker, SEX. Twenty-six markers remain unlinked. Female map distance (9.92 Morgans) was substantially higher than male map distance (3.90 Morgans) based on the most complete parental information (i.e., the F1 hybrids). Female recombination rates were often significantly higher than those of males across all pairwise comparisons within homologous chromosomal segments (average female to male ratios within families was 1.69:1). The female hybrid parent had significantly higher recombination rates than the pure strain female parent. Segregation distortion was detected in four linkage groups (4, 8, 13, 20) for both families. In family 3, only the largest fish were sampled for genotyping, suggesting that segregation distortion may represent regions possessing influences on growth. In family 2, almost all cases showing segregation distortion involved markers in the female hybrid parent.

Animals↗
PubMed2001

Triallelic inheritance in Bardet-Biedl syndrome, a Mendelian recessive disorder.

Bardet-Biedl syndrome (BBS) is a genetically heterogeneous disorder characterized by multiple clinical features that include pigmentary retinal dystrophy, polydactyly, obesity, developmental delay, and renal defects. BBS is considered an autosomal recessive disorder, and recent positional cloning efforts have identified two BBS genes (BBS2 and BBS6). We screened our cohort of 163 BBS families for mutations in both BBS2 and BBS6 and report the presence of three mutant alleles in affected individuals in four pedigrees. In addition, we detected unaffected individuals in two pedigrees who carry two BBS2 mutations but not a BBS6 mutation. We therefore propose that BBS may not be a single-gene recessive disease but a complex trait requiring three mutant alleles to manifest the phenotype. This triallelic model of disease transmission may be important in the study of both Mendelian and multifactorial disorders.

Alleles↗
PubMed2001

Apolipoprotein A-I adopts a belt-like orientation in reconstituted high density lipoproteins.

Apolipoprotein A-I (apoA-I) is the major protein associated with high density lipoprotein (HDL), and its plasma levels have been correlated with protection against atherosclerosis. Unfortunately, the structural basis of this phenomenon is not fully understood. Over 25 years of study have produced two general models of apoA-I structure in discoidal HDL complexes. The "belt" model states that the amphipathic helices of apoA-I are aligned perpendicular to the acyl chains of the lipid bilayer, whereas the "picket fence" model argues that the helices are aligned parallel with the acyl chains. To distinguish between the two models, various single tryptophan mutants of apoA-I were analyzed in reconstituted, discoidal HDL particles composed of phospholipids containing nitroxide spin labels at various positions along the acyl chain. We have previously used this technique to show that the orientation of helix 4 of apoA-I is most consistent with the belt model. In this study, we performed additional control experiments on helix 4, and we extended the results by performing the same analysis on the remaining 22-mer helices (helices 1, 2, 5, 6, 7, 8, and 10) of human apoA-I. For each helix, two different mutants were produced that each contained a probe Trp occurring two helical turns apart. In the belt model, the two Trp residues in each helix should exhibit maximal quenching at the same nitroxide group position on the lipid acyl chains. For the picket fence model, maximal quenching should occur at two different levels in the bilayer. The results show that the majority of the helices are in an orientation that is consistent with a belt model, because most Trp residues localized to a position about 5 A from the center of the bilayer. This study corroborates a belt hypothesis for the majority of the helices of apoA-I in phospholipid discs.

Apolipoprotein A-I↗
PubMed2001

Genetic and mutational analyses of a large multiethnic Bardet-Biedl cohort reveal a minor involvement of BBS6 and delineate the critical intervals of other loci.

Bardet-Biedl syndrome (BBS) is a rare autosomal recessive disorder characterized primarily by obesity, polydactyly, retinal dystrophy, and renal disease. The significant genetic and clinical heterogeneity of this condition have substantially hindered efforts to positionally clone the numerous BBS genes, because the majority of available pedigrees are small and the disorder cannot be assigned to any of the six known BBS loci. Consequently, the delineation of critical BBS intervals, which would accelerate the discovery of the underlying genetic defect(s), becomes difficult, especially for loci with minor contributions to the syndrome. We have collected a cohort of 163 pedigrees from diverse ethnic backgrounds and have evaluated them for mutations in the recently discovered BBS6 gene (MKKS) on chromosome 20 and for potential assignment of the disorder to any of the other known BBS loci in the human genome. Using a combination of mutational and haplotype analysis, we describe the spectrum of BBS6 alterations that are likely to be pathogenic; propose substantially reduced critical intervals for BBS2, BBS3, and BBS5; and present evidence for the existence of at least one more BBS locus. Our data also suggest that BBS6 is a minor contributor to the syndrome and that some BBS6 alleles may act in conjunction with mutations at other BBS loci to cause or modify the BBS phenotype.

Alleles↗
PubMed2001

A proteolytic method for distinguishing between lipid-free and lipid-bound apolipoprotein A-I.

Recent studies indicate that certain lipid-poor forms of apolipoprotein (apo)A-I may be particularly important in promoting cholesterol release from overburdened cells in the periphery. However, a detailed understanding of the physiological relevance of these species has been hampered by the difficulty in measuring them. As part of a search for a rapid assay for these forms of apoA-I, we have observed that the protease enteropeptidase can specifically cleave human lipid-free apoA-I but not its lipid-bound form. Enteropeptidase cleaved lipid-free apoA-I at a single site at amino acid 188, resulting in an N-terminal fragment of 22 kDa. However, apoA-I was not susceptible to enteropeptidase when present in reconstituted high-density lipoprotein (rHDL) particles as small as 6 nm in diameter or in human HDL(3) particles, even at extremely high enzyme-to-protein ratios and extended reaction times. We capitalized on this observation to develop an assay for the measurement of lipid-poor apoA-I in in vitro systems. Densitometry was used to generate a standard curve from sodium dodecyl sulfate polyacrylamide gels to determine the amounts of the N-terminal proteolytic fragment in unknown samples treated with enteropeptidase. This system could accurately quantify apoA-I that had been displaced from rHDL particles and human HDL(3) with purified apoA-II. On the basis of the results, a system of nomenclature is proposed for "lipid-free," "lipid-poor," and "lipid bound" apoA-I. The reported method distinguishes forms of apoA-I by a conformational parameter without previous separation of the species. This simple and inexpensive method will be useful for understanding the characteristics of plasma HDL that are favorable for the dissociation of apoA-I.

Apolipoprotein A-I↗
PubMed2000

The orientation of helix 4 in apolipoprotein A-I-containing reconstituted high density lipoproteins.

The three-dimensional structure of the high density lipoprotein (HDL) component apolipoprotein (apo) A-I and the molecular basis for its protection against coronary artery disease are unknown. In terms of discoidal HDL particles, there has been a debate as to the orientation of the apoA-I alpha-helices around the disc edge. The "picket fence" model states that the alpha-helical repeats, separated by turns, are arranged parallel to the phospholipid acyl chains of the enclosed lipid bilayer. On the other hand, the "belt" model states that the helical segments run perpendicular to the acyl chains. To distinguish between these models, we used nitroxide spin labels present at various depths in the bilayer of reconstituted HDL (rHDL) to measure the position of Trp residues in single Trp mutants of human proapoA-I. Two mutants were studied; the first contained a Trp at position 108, which was located near the center of helix 4. The second contained a Trp at position 115, two turns along the same helix. The picket fence model predicts that these Trp residues should be at different depths in the bilayer, whereas the belt model predicts that they should be at similar depths. Different sized rHDL particles were produced that contained 2, 3, and >4 molecules of proapoA-I per complex. In each case, parallax analysis indicated that Trp-108 and Trp-115 were present at similar depths of about 6 A from the center of the bilayer, consistent with helix 4 being oriented perpendicular to the acyl chains (in agreement with the belt model). Similar experiments showed that control transmembrane peptides were oriented parallel to the acyl chains in vesicles, demonstrating that the method was capable of distinguishing between the two models. This study provides one of the first experimental measurements of the location of an apoA-I helix with respect to the bilayer edge.

Amino Acid Sequence↗
PubMed2000

Longitudinal effects of integrated treatment on alcohol use for persons with serious mental illness and substance use disorders.

A randomized experimental design was used to assign participants to an integrated mental health and substance use treatment program or to standard hospital treatment. A multilevel, nonlinear model was used to estimate hospital treatment effects on days of alcohol use for persons with serious mental illness and substance use disorders over 18 months. The integrated treatment program had a significant effect on the rate of alcohol use at 2 months postdischarge, reducing the rate of use by 54%. Motivation for sobriety at hospital discharge, posttreatment self-help attendance, and social support for sobriety were also found to reduce the rate of use during the follow-up period. Implications for mental health treatment and aftercare support are discussed.

Adult↗
PubMed2000

Mutations in MKKS cause obesity, retinal dystrophy and renal malformations associated with Bardet-Biedl syndrome.

Bardet-Biedl syndrome (BBS) is an autosomal recessive disorder predominantly characterized by obesity, retinal dystrophy, polydactyly, learning difficulties, hypogenitalism and renal malformations, with secondary features that include diabetes mellitus, endocrinological dysfunction and behavioural abnormalities. Despite an initial expectation of genetic homogeneity due to relative clinical uniformity, five BBS loci have been reported, with evidence for additional loci in the human genome; however, no genes for BBS have yet been identified. We performed a genome screen with BBS families from Newfoundland that were excluded from BBS1-5 and identified linkage with D20S189. Fine-mapping reduced the critical interval to 1.9 cM between D20S851 and D20S189, encompassing a chaperonin-like gene. Mutations in this gene were recently reported to be associated with McKusick-Kaufman syndrome (MKKS; ref. 8). Given both the mapping position and clinical similarities of these two syndromes, we screened MKKS and identified mutations in five Newfoundland and two European-American BBS pedigrees. Most are frameshift alleles that are likely to result in a non-functional protein. Our data suggest that a complete loss of function of the MKKS product, and thus an inability to fold a range of target proteins, is responsible for the clinical manifestations of BBS.

Alleles↗
PubMed2000

Predictors of participation in health care at menopause.

Patient participation in health care is widely advocated but little is known about the factors influencing patients' active participation. To learn whether attitudes and beliefs helped predict patient participation, 252 midlife women completed measures of self-efficacy, perceived barriers to participation, attitudes, subjective norms, and intentions following a decision to support intervention on menopause. Two months following the intervention, 63 women who had visited a health care provider returned questionnaires by mail regarding self-reported participation in the health care encounter and satisfaction with the decision about estrogen replacement therapy. The results were that self-efficacy (beta = .19; p < .05) significantly predicted intention to participate in the next health care encounter. Both patient intentions (beta = .40;p < .05) and perceived barriers (beta = -.27; p < .05) were significant predictors of self-reported participation. Active participation (beta = .42;p < .05) and attitude (beta =.25;p < .05) were associated with increased satisfaction with decision. Participation resulted in increased self-efficacy (beta = .30;p < .05). The conclusions were that midlife women who express more confidence in their ability to participate in their health care have greater intentions to participate. Women who experience fewer barriers to participation and have more intention to participate are more likely to report actively participating in a health care encounter, and self-reported participation and more positive attitudes toward participation are associated with greater satisfaction with decisions.

Adult↗
PubMed1999

The complete mitochondrial DNA sequence of the Atlantic salmon, Salmo salar.

The complete sequence of the Atlantic salmon (Salmo salar) mitochondrial genome has been determined. The entire sequence is 16665 base pairs (bp) in length, with a gene content (13 protein-coding, two ribosomal RNA [rRNA] and 22 transfer RNA [tRNA] genes) and order conforming to that observed in most other vertebrates. Base composition and codon usage have been detailed. Nucleotide and derived amino acid sequences of the 13 protein-coding genes from Atlantic salmon have been compared with their counterparts in rainbow trout. A putative structure for the origin of L-strand replication (O(L)) is proposed, and sequence features of the control region (D-loop) are described.

Animals↗
PubMed1999

Structural organization of the N-terminal domain of apolipoprotein A-I: studies of tryptophan mutants.

Site-directed mutagenesis and detailed fluorescence studies were used to study the structure and dynamics of recombinant human proapolipoprotein (proapo) A-I in the lipid free state and in reconstituted high-density lipoprotein (rHDL) particles. Five different mutants of proapoA-I, each containing a single tryptophan residue, were produced in bacteria corresponding to each of the naturally occurring Trp residues (position -3 in the pro-segment, 8, 50, 72, and 108) in the N-terminal half of the protein. Structural analyses indicated that the conservative Phe-Trp substitutions did not perturb the conformation of the mutants with respect to the wild-type protein. Steady-state fluorescence studies indicated that all of the Trp residues exist in nonpolar environments that are highly protected from solvent in both the lipid-free and lipid-bound forms. Time-resolved lifetime and anisotropy studies indicated that the shape of the monomeric form of proapoA-I is a prolate ellipsoid with an axial ratio of about 6:1. In addition, the region surrounding Trp 108 appears to be more mobile than the rest of the protein in the lipid-free state. However, in rHDL particles, no significant domain motion was detected for any of the Trp residues. The results presented in this work are consistent with a model for monomeric lipid-free proapoA-I in which the N-terminal half of the molecule is organized into a bundle of helices.

Amino Acid Substitution↗
PubMed1999

Genetic heterogeneity of Bardet-Biedl syndrome in a distinct Canadian population: evidence for a fifth locus.

Bardet-Biedl syndrome (BBS) is a rare, autosomal recessive disease characterized by retinal dystrophy, renal structural abnormalities, obesity, dysmorphic extremities, and hypogenitalism in males. BBS is genetically heterogeneous with four known loci: BBS1 (11q), BBS2 (16q), BBS3 (3p), and BBS4 (15q). The prevalence of BBS in Newfoundland is approximately 10-fold greater than in Switzerland (1:160,000) and similar to the prevalence among the Bedouin of Kuwait (1:13,500). A population-based genetic survey was performed on 17 BBS families from the island portion of the province of Newfoundland, a comparatively isolated region of Canada. The families in the study had a total of 36 well-documented, affected individuals with 12 families having 2 or more affected individuals. Linkage at each of the four known loci was tested with two-point linkage and haplotype analysis. Three of the 17 kindreds showed linkage to 11q, 1 to 16q, and 1 to 3p. The latter is the first BBS3 family identified in a population of northern European descent. Six families remain undetermined because of poor pedigree structure or inconclusive haplotype analyses. Six families were excluded from all four known BBS loci, indicating that there is at least a fifth BBS locus (BBS5).

Abnormalities, Multiple↗
PubMed1999

Population genetic structure and the effect of founder events on the genetic variability of moose, Alces alces, in Canada.

Moose, Alces alces, occur naturally throughout most of Canada but successful introductions of known numbers of animals have been made to the islands of Newfoundland and Cape Breton. Five microsatellite loci were used to investigate the population genetic structure and any change in genetic variability due to founder events of moose in Canada. Comparisons of allele frequencies for moose from 11 regions of the country suggested that there are at least seven genetically distinct populations (P < 0.05) in North America, namely Alberta, eastern Ontario, New Brunswick, Cape Breton, Labrador, western Newfoundland, and the Avalon Peninsula of Newfoundland. The average population heterozygosity was approximately 33% (range from 22 to 41%). UPGMA analysis of Nei's genetic distances produced phenograms similar to what would be expected when geographical location and population history are considered. The loss of heterozygosity due to a single founder event (n = 3; two introductions and a natural colonization) ranged from 14 to 30%, and the cumulative loss of heterozygosity due to two successive founder events (an introduction followed by a natural colonization) was 46%. In these examples loss of genetic variability has not been associated with any known phenotypic deviances, suggesting that populations may be established from a small number of founders. However, the viability of these founded populations over evolutionary timescales cannot be determined and is highly dependent upon chance.

Alleles↗
PubMed1999

A founder effect in the newfoundland population reduces the Bardet-Biedl syndrome I (BBS1) interval to 1 cM.

Bardet-Biedl syndrome (BBS) is a rare, autosomal recessive disorder; major phenotypic findings include dysmorphic extremities, retinal dystrophy, obesity, male hypogenitalism, and renal anomalies. In the majority of northern European families with BBS, the syndrome is linked to a 26-cM region on chromosome 11q13. However, the finding, so far, of five distinct BBS loci (BBS1, 1q; BBS2, 16q; BBS3, 3p; BBS4, 15q; BBS5, 2q) has hampered the positional cloning of these genes. We use linkage disequilibrium (LD) mapping in an isolated founder population in Newfoundland to significantly reduce the BBS1 critical region. Extensive haplotyping in several unrelated BBS families of English descent revealed that the affected members were homozygous for overlapping portions of a rare, disease-associated ancestral haplotype on chromosome 11q13. The LD data suggest that the BBS1 gene lies in a 1-Mb, sequence-ready region on chromosome 11q13, which should enable its identification.

Alleles↗