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PubMed2000

Sequence heteroplasmy of D-loop and rRNA coding regions in mitochondrial DNA from Holstein cows of independent maternal lineages.

A mitochondrial DNA (mtDNA) fragment containing the D-loop, phenylalanine tRNA, valine tRNA, and 12S and 16 rRNA genes was cloned and sequenced from 36 cows of 18 maternal lineages to identify the polymorphic sites within those regions and to detect the existence of heteroplasmic mtDNA in cows. Seventeen variable sites were observed within the D-loop and rRNA coding regions of bovine mtDNA within a 2.5-kb span. The hypervariable sites in the D-loop and rRNA coding regions were identified at nucleotide positions 169, 216, and 1594. Heteroplasmic mtDNA (variable mtDNA within a tissue) existed extensively in cows and was detected within the above regions in 11 of 36 cows sequenced. The insertion, deletion, and nucleotide transversion polymorphisms were found only in homopolymer regions. Heteroplasmy was observed frequently and seemingly is persistent in cattle. Though heteroplasmy was demonstrated, most lineages and mtDNA sites showed no heteroplasmy.

Animals↗
PubMed2002

Contributions of 18 additional DNA sequence variations in the gene encoding apolipoprotein E to explaining variation in quantitative measures of lipid metabolism.

Apolipoprotein E (ApoE) is a major constituent of many lipoprotein particles. Previous genetic studies have focused on six genotypes defined by three alleles, denoted epsilon2, epsilon3, and epsilon4, encoded by two variable exonic sites that segregate in most populations. We have reported studies of the distribution of alleles of 20 biallelic variable sites in the gene encoding the ApoE molecule within and among samples, ascertained without regard to health, from each of three populations: African Americans from Jackson, Miss.; Europeans from North Karelia, Finland; and non-Hispanic European Americans from Rochester, Minn. Here we ask (1) how much variation in blood levels of ApoE (lnApoE), of total cholesterol (TC), of high-density lipoprotein cholesterol (HDL-C), and of triglyceride (lnTG) is statistically explained by variation among APOE genotypes defined by the epsilon2, epsilon3, and epsilon4 alleles; (2) how much additional variation in these traits is explained by genotypes defined by combining the two variable sites that define these three alleles with one or more additional variable sites; and (3) what are the locations and relative allele frequencies of the sites that define multisite genotypes that significantly improve the statistical explanation of variation beyond that provided by the genotypes defined by the epsilon2, epsilon3, and epsilon4 alleles, separately for each of the six gender-population strata. This study establishes that the use of only genotypes defined by the epsilon2, epsilon3, and epsilon4 alleles gives an incomplete picture of the contribution that the variation in the APOE gene makes to the statistical explanation of interindividual variation in blood measurements of lipid metabolism. The addition of variable sites to the genotype definition significantly improved the ability to explain variation in lnApoE and in TC and resulted in the explanation of variation in HDL-C and in lnTG. The combination of additional sites that explained the greatest amount of trait variation was different for different traits and varied among the six gender-population strata. The role that noncoding variable sites play in the explanation of pleiotropic effects on different measures of lipid metabolism reveals that both regulatory and structural functional variation in the APOE gene influences measures of lipid metabolism. This study demonstrates that resequencing of the complete gene in a sample of >/=20 individuals and an evaluation of all combinations of the identified variable sites, separately for each population and interacting environmental context, may be necessary to fully characterize the impact that a gene has on variation in related traits of a metabolic system.

Alleles↗
PubMed1995

The effect of pulsatile frequency on wall shear in a compliant cast of a human aortic bifurcation.

A realistically compliant flow-through cast of a human aortic bifurcation was perfused with two almost identical physiological flow waves differing in pulsatile frequency. Near-wall fluid velocities were measured with a laser Doppler velocimeter at 14 sites along the flow divider and the lateral walls of the aorta and iliac arteries. The wall position at each site was tracked using a linescan camera. The temporal wall shear rate at each site was then calculated from the near-wall velocity profile and the instantaneous wall position. Increasing the frequency reduced the oscillatory component of shear rate at sites where it was greater than average, and increased it at sites where it was less, effectively reducing its site to site variability. Pulsatile frequency had no significant effect on mean shear rate at most sites. The phase shift between wall shear and radial strain was governed by the phase of the shear, and was linearly related to the extent of site dependent shear reversal. The mean shear rate was inversely related to the extent of shear reversal. If atherosclerotic development depends chiefly on mean shear rate, heart rate would not be expected to affect susceptibility, however, if only the wall sites experiencing the lowest maximum shears are vulnerable, then the effect of increasing the heart rate would seem to be beneficial.

Adult↗
PubMed2000

Phylogeny of 33 ribosomal and six other proteins encoded in an ancient gene cluster that is conserved across prokaryotic genomes: influence of excluding poorly alignable sites from analysis.

Thirty-nine proteins encoded in a large gene cluster that is well-conserved in gene content and gene order across 18 sequenced prokaryotic genomes were extracted, aligned and subjected to phylogenetic analysis. In individual analyses of the alignments, only two probable examples of lateral gene transfer between archaea and eubacteria were detected, involving the genes for ribosomal protein Rpl23 and adenylate kinase. Amino acid sequences for 35 of the 39 proteins were concatenated to yield a data set of 9087 amino acid positions per genome. Many of these proteins, 33 of which are ribosomal proteins, are not highly conserved across distantly related organisms and thus contain many regions that are difficult to align. Phylogenetic analyses were performed with subsets of the concatenated data from which the most highly variable sites had been iteratively removed, using the number of different amino acids that occur at a given site as a criterion of variability. Glycine, which has a strong influence on protein structure, tended to be more frequent at the most conserved (least polymorphic) sites. With most subsets of the data, the proteins from the cyanobacterium Synechocystis tended to branch with their homologues from gram-positive bacteria. The results indicate that excluding only a few percentage of poorly alignable sites from phylogenetic analysis can have a severe impact upon the phylogeny inferred and that bootstrap support for branches can fluctuate substantially, depending upon which sites are excluded.

Adenylate Kinase↗
PubMed1992

Sequence comparison of two highly homologous phycoerythrins differing in bilin composition.

Genes encoding the alpha and beta subunits of class II phycoerythrin from Synechococcus sp. strain WH8103 were cloned and sequenced. The deduced amino acid sequences were compared to class II phycoerythrin from Synechococcus sp. strain WH8020 and found to share 92% identity, yet the proteins differ in the bilin isomer (phycoerythrobilin versus phycourobilin) bound to two of the six chromophore attachment sites. Amino acid residues which might contact the bilin at each of the two variable sites were inferred by sequence alignment with phycocyanins. Putative bilin-contacting residues differing between the two phycoerythrins were identified which may determine bilin specificity.

Amino Acid Sequence↗
PubMed2003

Characterization of the red knot (Calidris canutus) mitochondrial control region.

We sequenced the complete mitochondrial control regions of 11 red knots (Calidris canutus). The control region is 1168 bp in length and is flanked by tRNA glutamate (glu) and the gene ND6 at its 5' end and tRNA phenylalanine (phe) and the gene 12S on its 3' end. The sequence possesses conserved sequence blocks F, E, D, C, CSB-1, and the bird similarity box (BSB), as expected for a mitochondrial copy. Flanking tRNA regions show correct secondary structure, and a relative rate test indicated no significant difference between substitution rates in the sequence we obtained versus the known mitochondrial sequence of turnstones (Charadriiformes: Scolopacidae). These characteristics indicate that the sequence is mitochondrial in origin. To confirm this, we sequenced the control region of a single individual using both purified mitochondrial DNA and genomic DNA. The sequences were identical using both methods. The sequence and methods presented in this paper may now serve as a reference for future studies using knot and other avian control regions. Furthermore, the discovery of five variable sites in 11 knots towards the 3' end of the control region, and the variability of this region in contrast to the more conserved central domain in the alignment between knots and other Charadriiformes, highlights the importance of this area as a source of variation for future studies in knots and other birds.

Animals↗
PubMed1997

Identification of apolipoprotein E polymorphisms using temperature cycled primer oligo base extension and mass spectrometry.

The isothermal Primer Oligo Base Extension (PROBE) reaction combined with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry for diagnostic product detection as recently introduced by our group is modified to incorporate temperature cycling during the primer extension step, resulting in enhanced levels of diagnostic product generation. Utilizing temperature cycled PROBE, the identities of two apolipoprotein E polymorphisms (codons 112 and 158) for differentiation of epsilon 2/epsilon 3, epsilon 3/epsilon 3, epsilon 3/epsilon 4, and epsilon 4/epsilon 4 genotypes were simultaneously determined. Primers specific for each site are extended by a series of bases unique to the identity of that variable site, producing low mass diagnostic products (M(r) < 9000) highly amenable to detection by mass spectrometry. The temperature cycled PROBE method has yielded unambiguous and correct diagnoses for all samples tested thus far. The increased amount of diagnostic product generated per primer by the cycling method makes possible faster spectrum acquisition due to the increased signal intensity, critical for future automated measurement of such samples.

Apolipoproteins E↗
PubMed1985

Influence of assay buffer on dissociation constants of drugs at beta-adrenoceptor subtypes.

The present investigation has assessed the influence of assay buffer (Tris versus Krebs) on the abilities of several beta-adrenoceptor agonists and antagonists to displace the radioligand (-)-[125I]iodocyanopindolol [( 125I]CYP) from beta 1-(left atrial) and beta 2- (uterine) adrenoceptor sites. Saturation studies indicated that the dissociation constant (KD) for [125I]CYP at both beta-receptor sites was approximately 2-fold greater in Krebs as opposed to Tris buffer, and that the maximal density of binding sites (Bmax) in atria (but not uterus) was also reduced 2-fold. In general, the KD values for beta-adrenoceptor agonists were more influenced by the type of buffer used than were KD values for antagonists. Agonist KD values at beta 2-adrenoceptor sites were higher in Krebs than in Tris buffer, while at beta 1-adrenoceptor sites, variable changes resulted. The selective affinity of agonists at beta 1- and beta 2-adrenoceptor sites was therefore markedly influenced by the buffer used and could not be predicted from the established beta 1-/beta 2-adrenoceptor selectivity of the agonists as found in organ bath studies.

Adrenergic beta-Agonists↗
PubMed1999

The period gene: high conservation of the region coding for Thr-Gly dipeptides in the Drosophila nasuta species subgroup.

In this study, the region corresponding to the Thr-Gly region of the period (per) gene in the Drosophila nasuta subgroup of species was sequenced. The results showed that this region was highly conserved in the D. nasuta subgroup. There were only nine variable sites found in this 300-bp-long region, all located in two small regions highly variable among Drosophila species. No length variation was observed either within this subgroup or in the Yunnan (YN) population of D. albomicans. The deduced amino acid sequences were identical for all 14 taxa in the D. nasuta subgroup, and a stretch of alternating Thr-Gly pairs was not observed in this subgroup. A phylogenetic tree was constructed. The clustering of some species was in general agreement with previous works, but it also raised some question on the phylogenetic relationship between the nasuta species. The data did not implicate the Thr-Gly region playing a role in behavioral isolation in this subgroup of Drosophila.

Amino Acid Sequence↗
PubMed1998

Distribution of small intestinal lesions in anaphylaxis of rats.

Hemorrhage and congestion were not uniformly distributed along the small intestine during systemic anaphylaxis in rats. Duodenum had little hemorrhage and congestion and the terminal ileum had even less. Maximum involvement occurred in jejunum of 13% of rats, in ileum of 47%, and in both jejunum and ileum of 40%. Sequential scoring along the entire length of small intestine revealed different patterns of distribution with more than one peak of intensity in some of the rats. Within a lesioned area, banding was common except where hemorrhage and congestion were so severe as to obliterate all patterns. Banding represented a gradient of injury with respect to the vascular supply. The pale stripes (less severe hemorrhage) contained the penetrating vessels derived from the terminal mesenteric arcades. The dark stripes (more severe hemorrhage) did not contain such vessels. In addition, the mesenteric side of the intestine was less affected than the antimesenteric side. This constituted a second gradient that might also be related to the distance from the vascular supply. In both instances, proximity to larger blood vessels had a protective effect. These two gradients and the variable sites and patterns of distribution have not been described previously in intestinal anaphylaxis. Gradients and the variability of the distribution of lesions in intestinal anaphylaxis should be considered in experiments on pathogenesis and altered function.

Anaphylaxis↗
PubMed1992

Significance of ventricular late potentials in patients with myocardial infarction.

Fifty six patients (52 males, 4 females, mean age 53.6 +/- 8 years, range 35-75 years) were studied to determine the influence of clinical variables, site of myocardial infarction, thrombolytic therapy, documented arrhythmias and left ventricular ejection fraction (LVEF) on the incidence of ventricular late potentials (LP's). LP's were detected in 17 (30.3%) patients; in 6 (26%) patients with acute and in 11 (33.3%) patients with old healed myocardial infarction. 87.5% of the patients in whom LPs were detected had low LVEF. The presence of low LVEF correlated significantly with the presence of LP's (p = .02). LP's were also present in all patients with documented sustained ventricular tachycardia. Clinical variables (Killip and NYHA class), site of myocardial infarction, Q wave versus non-Q wave myocardial infarction and thrombolytic therapy did not relate to the presence of LP's (p > 0.5) Patients of myocardial infarction with low LVEF and a history of ventricular tachyarrhythmias should undergo signal averaged electrocardiography for LP detection. LP presence would identify patients at higher risk of future arrhythmic events within this subgroup.

Adult↗
PubMed1994

Variation in mitochondrial DNA and population structure of the Taipei treefrog Rhacophorus taipeianus in Taiwan.

Mitochondrial DNA (mtDNA) from 40 samples of the Taipei treefrog Rhacophorus taipeianus collected from seven populations in Taiwan were sequenced to document the DNA sequence variation in anuran mtDNA and to elucidate the phylogeographic population structure in the Taipei treefrog. Sequences of 722-764 bases in length, including a 108-bp segment of the cytochrome b gene and a 614-656-bp D-loop segment, were obtained by direct sequencing using polymerase chain reaction (PCR). The variation in length was due to a 40-bp region that tandemly repeated four to five times in the D-loop region. The first repeat is the most conserved one among the five repeats because there are no variable sites in this repeat. Besides the 40-bp length variation, 28 positions in the 764-bp sequences are variable and distributed evenly in the cytochrome b gene fragment and D-loop region. Variation in the D-loop of the Taipei treefrog is comparable to those of other vertebrates. Two well-differentiated lineages (northern and central) differing by mean sequence divergence of 1.7% are identified and concordant with their geographic distributions. The two lineages are inferred to have split from a common ancestral population in the early Pleistocene. However, the interpopulation divergence of the northern lineage (< 0.33%) is apparently lower than that of the central lineage (1.11%), implying that the two lineages evolved independently and had different demographic histories after divergence. This study reveals that anuran D-loop has potential as a genetic marker in phylogenetic and population genetic analyses of anurans.

Animals↗
PubMed1995

Characterization and sequence of a novel insertion sequence, IS1162, from Pseudomonas fluorescens.

We have determined the nucleotide sequence of IS1162, a new insertion sequence (IS) isolated from Pseudomonas fluorescens (Pf) strain ST. This IS element is present in two copies on the pEG plasmid harboured by Pf ST and in a single copy on the chromosome, adjacent to the styrene catabolic genes. IS1162 is 2634 bp in length with 12-bp terminal inverted repeats (IR), and could encode four proteins (ORFs), two for each strand. One strand, Pro1 (62,990 Da), showed a helix-turn-helix motif at the N-terminal region, and Pro2 (25,997 Da) was characterized by the presence of the A and B motives of the NTP (ATP/GTP)-binding site. Comparison of IS1162 of Pf with known IS showed a high homology with IS408 of Burkholderia cepacia [Byrne and Lessie, Plasmid 31 (1994) 138-147]. Pro1 and Pro2 were found to be homologous to the corresponding ORFs of IS408, IS21 [Reimmann et al., Mol. Gen. Genet. 215 (1989) 416-424], IS232 [Menou et al., J. Bacteriol. 172 (1990) 6689-6696] and IS5376 [Xu et al., Plasmid 29 (1993) 1-9]. IS1162 transposed at low frequency and no cointegrates were found among the transposition products. The target duplication sites, variable in length, showed the presence of homologous motives, suggesting a certain degree of specificity of the IS1162 insertion site.

Amino Acid Sequence↗
PubMed1998

DNA sequence diversity in a 9.7-kb region of the human lipoprotein lipase gene.

Lipoprotein lipase plays a central role in lipid metabolism and the gene that encodes this enzyme (LPL) is a candidate susceptibility gene for cardiovascular disease. Here we report the complete sequence of a fraction of the LPL gene for 71 individuals (142 chromosomes) from three populations that may have different histories affecting the organization of the sequence variation. Eighty-eight sites in this 9.7 kb vary among individuals from these three populations. Of these, 79 were single nucleotide substitutions and 9 sites involved insertion-deletion variations. The average nucleotide diversity across the region was 0.2% (or on average 1 variable site every 500 bp). At 34 of these sites, the variation was found in only one of the populations, reflecting the differing population and mutational histories. If LPL is a typical human gene, the pattern of sequence variation that exists in introns as well as exons, even for the small number of samples considered here, will present challenges for the identification of sites, or combinations of sites, that influence variation in risk of disease in the population at large.

Base Sequence↗
PubMed1992

Population structure and mitochondrial DNA gene flow in Old World populations of Drosophila subobscura.

An extensive survey of mitochondrial DNA (mtDNA) restriction polymorphism in 156 isofemale lines from 29 different geographic populations of Drosophila subobscura distributed throughout the Old World was carried out. Ten restriction enzymes were used, five of which revealed restriction site polymorphism. Of the 31 restriction sites detected, 13 were found to be polymorphic. Comparisons with the mtDNA map of Drosophila yakuba indicate that the variable sites are mainly concentrated in protein genes, especially those corresponding to the NADH complex. A total of 13 different haplotypes were observed, two of which (haplotypes I and II) are quite frequent and widely distributed throughout the populations, whereas the other 11 with the exception of VIII, which deserves special attention, are each restricted to one population only and occur at low frequencies. The observed distribution of haplotypes, corroborated by a parsimonious unrooted tree, suggests an ancient origin of haplotypes I and II in the continent. In order to compare genetic structure according to mtDNA and allozymes, the 10 populations with higher population sizes were studied for 10 polymorphic allozymes also. One striking result is the high degree of population structure of the mtDNA when compared to that obtained for allozymes. If an island model is assumed, estimates of gene flow give values of 0.013 and 1.89 migrants per generation for mtDNA and allozymes, respectively. What is apparent from these estimates is that Drosophila subobscura populations are effectively subdivided for mtDNA genes at migration rates at which nuclear genes (allozymes) are almost panmictic.

Alleles↗
PubMed2004

Special Supplemental Nutrition Program for Women, Infants, and Children participation and infants' growth and health: a multisite surveillance study.

CONTEXT: The Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) is the largest food supplement program in the United States, serving almost 7 500 000 participants in 2002. Because the program is a grant program, rather than an entitlement program, Congress is not mandated to allocate funds to serve all eligible participants. Little is known about the effects of WIC on infant growth, health, and food security. OBJECTIVE: To examine associations between WIC participation and indicators of underweight, overweight, length, caregiver-perceived health, and household food security among infants < or =12 months of age, at 6 urban hospitals and clinics. DESIGN AND SETTING: A multisite study with cross-sectional surveys administered at urban medical centers in 5 states and Washington, DC, from August 1998 though December 2001. PARTICIPANTS: A total of 5923 WIC-eligible caregivers of infants < or =12 months of age were interviewed at hospital clinics and emergency departments. MAIN OUTCOME MEASURES: Weight-for-age, length-for-age, weight-for-length, caregiver's perception of infant's health, and household food security. RESULTS: Ninety-one percent of WIC-eligible families were receiving WIC assistance. Of the eligible families not receiving WIC assistance, 64% reported access problems and 36% denied a need for WIC. The weight and length of WIC assistance recipients, adjusted for age and gender, were consistent with national normative values. With control for potential confounding family variables (site, housing subsidy, employment status, education, and receipt of food stamps or Temporary Assistance for Needy Families) and infant variables (race/ethnicity, birth weight, months breastfed, and age), infants who did not receive WIC assistance because of access problems were more likely to be underweight (weight-for-age z score = -0.23 vs 0.009), short (length-for-age z score = -0.23 vs -0.02), and perceived as having fair or poor health (adjusted odds ratio: 1.92; 95% confidence interval: 1.29-2.87), compared with WIC assistance recipients. Rates of overweight, based on weight-for-length of >95th percentile, varied from 7% to 9% and did not differ among the 3 groups but were higher than the 5% expected from national growth charts. Rates of food insecurity were consistent with national data for minority households with children. Families that did not receive WIC assistance because of access problems had higher rates of food insecurity (28%) than did WIC participants (23%), although differences were not significant after covariate control. Caregivers who did not perceive a need for WIC services had more economic and personal resources than did WIC participants and were less likely to be food-insecure, but there were no differences in infants' weight-for-age, perceived health, or overweight between families that did not perceive a need for WIC services and those that received WIC assistance. CONCLUSIONS: Infants < or =12 months of age benefit from WIC participation. Health care providers should promote WIC utilization for eligible families and advocate that WIC receive support to reduce waiting lists and eliminate barriers that interfere with access.

Body Height↗
PubMed2006

Candida albicans biofilm development, modeling a host-pathogen interaction.

Medical device-associated infections involve the attachment of cells to a surface, production of an extracellular matrix and development of a mature biofilm. Many Candida albicans disease states involve biofilm growth. These infections have great impact on public health because organisms in biofilms exhibit dramatically reduced susceptibility to antifungal therapy. Progression to a mature biofilm is dependent on cell adhesion, extracellular matrix production and the yeast-to-hyphae transition. Numerous in vitro biofilm model systems have been successfully used to examine biofilm architecture, development, cell phenotypes and drug resistance. Although these studies have included a number of experimental variables to mimic infections in patients, it is difficult to accurately account for the multitude of host and infection-site variables that are probably important in humans. Recent studies have begun to explore C. albicans biofilms using animal biofilm infection models in order to more completely reflect the complexity of this host-fungal interaction.

Animals↗
PubMedDate not supplied

Heterotachy and functional shift in protein evolution.

Study of structure/function relationships constitutes an important field of research, especially for modification of protein function and drug design. However, the fact that rational design (i.e. the modification of amino acid sequences by means of directed mutagenesis, based on knowledge of the three-dimensional structure) appears to be much less efficient than irrational design (i.e. random mutagenesis followed by in vitro selection) clearly indicates that we understand little about the relationships between primary sequence, three-dimensional structure and function. The use of evolutionary approaches and concepts will bring insights to this difficult question. The increasing availability of multigene family sequences that has resulted from genome projects has inspired the creation of novel in silico evolutionary methods to predict details of protein function in duplicated (paralogous) proteins. The underlying principle of all such approaches is to compare the evolutionary properties of homologous sequence positions in paralogs. It has been proposed that the positions that show switches in substitution rate over time--i.e., 'heterotachous sites'--are good indicators of functional divergence. However, it appears that heterotachy is a much more general process, since most variable sites of homologous proteins with no evidence of functional shift are heterotachous. Similarly, it appears that switches in substitution rate are as frequent when paralogous sequences are compared as when orthologous sequences are compared. Heterotachy, instead of being indicative of functional shift, may more generally reflect a less specific process related to the many intra- and inter-molecular interactions compatible with a range of more or less equally viable protein conformations. These interactions will lead to different constraints on the nature of the primary sequences, consistently with theories suggesting the non-independence of substitutions in proteins. However, a specific type of amino acid variation might constitute a good indicator of functional divergence: substitutions occurring at positions that are generally slowly evolving. Such substitutions at constrained sites are indeed much more frequent soon after gene duplication. The identification and analysis of these sites by complementing structural information with evolutionary data may represent a promising direction to future studies dealing with the functional characterization of an ever increasing number of multi-gene families identified by complete genome analysis.

Amino Acid Substitution↗