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PubMed2006

Integrating genetic and gene expression data: application to cardiovascular and metabolic traits in mice.

The millions of common DNA variations that occur in the human population, or among inbred strains of mice and rats, perturb the expression (transcript levels) of a large fraction of the genes expressed in a particular tissue. The hundreds or thousands of common cis-acting variations that occur in the population may in turn affect the expression of thousands of other genes by affecting transcription factors, signaling molecules, RNA processing, and other processes that act in trans. The levels of transcripts are conveniently quantitated using expression arrays, and the cis- and trans-acting loci can be mapped using quantitative trait locus (QTL) analysis, in the same manner as loci for physiologic or clinical traits. Thousands of such expression QTL (eQTL) have been mapped in various crosses in mice, as well as other experimental organisms, and less detailed maps have been produced in studies of cells from human pedigrees. Such an integrative genetics approach (sometimes referred to as "genetical genomics") is proving useful for identifying genes and pathways that contribute to complex clinical traits. The coincidence of clinical trait QTL and eQTL can help in the prioritization of positional candidate genes. More importantly, mathematical modeling of correlations between levels of transcripts and clinical traits in genetic crosses can allow prediction of causal interactions and the identification of "key driver" genes. An important objective of such studies will be to model biological networks in physiologic processes. When combined with high-density single nucleotide polymorphism (SNP) mapping, it should be feasible to identify genes that contribute to transcript levels using association analysis in outbred populations. In this review we discuss the basic concepts and applications of this integrative genomic approach to cardiovascular and metabolic diseases.

Animals↗
PubMed1992

A study of the basis of virulence variation of bovine rotaviruses.

Rotaviruses are enteric pathogens of cattle but sub-clinical infections are common. Virulence variation has been identified with bovine rotaviruses and some rotaviruses replicated without clinical signs in non-immune calves. The rotavirus genome is composed of eleven segments of double-stranded RNA and the fourth largest segment codes for a non-glycosylated surface protein, VP4, which has been linked with virulence. In the present study the biological basis of rotavirus virulence variation was studied in vivo and compared with the known properties of the fourth gene. Calves were inoculated orally with a virulent rotavirus or a rotavirus of low virulence which multiplied but failed to cause diarrhoea. They were taken for necropsy at intervals of 2 days after inoculation. Clinical signs, virus in faeces and the percentage of infected small intestinal epithelium were determined. Damage to the small intestine was assessed by measurement of villus heights and crypt-cell production rates. Virulence was associated with a greater level of colonization of the small intestinal epithelium, greater enterocyte damage and preferential infection of the upper small intestine. The fourth gene determines the ability of rotaviruses to spread in vitro and the finding that virulence was associated with greater colonization in vivo raises the possibility that this gene may have an important role in rotavirus virulence.

Animals↗
PubMed1991

Genetic factors in neurotoxicology and neuropharmacology: a critical evaluation of the use of genetics as a research tool.

Animals have evolved a detoxication system to enable them to survive in a hostile chemical environment in which foods contain many non-nutrient chemicals. Detoxication depends on enzymes which are often genetically polymorphic. As a result, inter-individual variation is common, and in humans several Mendelian loci have been identified. However, most variation in response is probably due to the action of several genes. Genetic variation in response to the neurotoxin MPTP and to chemically and physically-induced seizures is reviewed. In the former case, differences between pigmented and white mouse strains have been noted which are consistent with the hypothesis that humans are more sensitive than mice or rats because of the presence of melanin in human brains. However, variation in sensitivity probably also depends on other genes. In the case of audiogenic seizures, a single locus has been identified and mapped, but its relationship with seizures induced by other agents is not clear. Genetic variation in response to alcohol is also discussed. The failure of most toxicologists to consider genetic variation as a potentially confounding variable, and as a powerful research tool, is discussed critically in relation to non-repeatability of research on the neurotoxic effects of lead, and in relation to the genetic variation in MPTP, seizures, and alcohol response already noted. It seems clear that genetic methods provide a powerful research tool which is largely being ignored by toxicologists.

Animals↗
PubMed1998

Genetic variation in paraoxonase-1 and paraoxonase-2 is associated with variation in plasma lipoproteins in Alberta Hutterites.

In a sample taken from the genetically isolated Alberta Hutterites, we previously found that PON1 variation was associated with variation in plasma lipoprotein traits, including LDL and HDL cholesterol. With the recent cloning of the PON1-related gene PON2, we undertook studies of the association between genetic variation in PON2 and variation in plasma quantitative traits variation in a sample of 745 Alberta Hutterites. We found novel genetic associations between PON2 variation and variation in fasting plasma concentrations of total cholesterol and apolipoprotein AI. We confirmed our previously observed significant associations in this study sample between PON1 genetic variation and variation in plasma apo B-related traits, such as LDL, non-HDL and HDL cholesterol and apo B itself. Furthermore, there was almost complete linkage disequilibrium between PON2 alleles G148 and C311. We found no association between PON2 variation and plasma glucose or insulin. Taken together, our results suggest that common genetic variation on chromosome 7q21.3-22.1 in both PON1 and PON2 that affects the amino acid sequence of the respective gene products is associated with significant variation in intermediate traits in plasma lipoprotein metabolism.

Alberta↗
PubMed2005

Polymorphisms within the C-reactive protein (CRP) promoter region are associated with plasma CRP levels.

Elevated plasma levels of C-reactive protein (CRP), an inflammation-sensitive marker, have emerged as an important predictor of future cardiovascular disease and metabolic abnormalities in apparently healthy men and women. Here, we performed a systematic survey of common nucleotide variation across the genomic region encompassing the CRP gene locus. Of the common single-nucleotide polymorphisms (SNPs) identified, several in the CRP promoter region are strongly associated with CRP levels in a large cohort study of cardiovascular risk in European American and African American young adults. We also demonstrate the functional importance of these SNPs in vitro.

Adolescent↗
PubMed2006

Relationship of BMPR2 mutations to vasoreactivity in pulmonary arterial hypertension.

BACKGROUND: Vasoreactivity tests are fundamental in evaluating pulmonary arterial hypertension (PAH). Mutations of the transforming growth factor-beta type II receptor gene, BMPR2, predispose to the development of pulmonary hypertension and may alter the response to vasodilators. Previous investigations have not examined the relationship of BMPR2 mutations to vasoreactivity. METHODS AND RESULTS: We identified 133 consecutive unrelated patients with either idiopathic or familial PAH. Sixty-six patients were excluded because we lacked either DNA samples (n=18) or complete data from a vasoreactivity test (n=48). The remaining 67 patients were screened for BMPR2 DNA sequence variations, and specific variations were confirmed by gene sequencing. The vasoreactivity of patients with nonsynonymous BMPR2 variations was compared with that of patients without nonsynonymous BMPR2 variations. We found nonsynonymous BMPR2 variations in 27 of 67 patients with idiopathic (n=16 of 52) or familial (n=11 of 15) PAH. Vasoreactivity was identified in 3.7% of 27 patients with nonsynonymous BMPR2 variations and in 35% of 40 patients without nonsynonymous BMPR2 variations (P=0.003). Five of the 27 nonsynonymous variations occur commonly in healthy individuals. None of the remaining 22 patients with BMPR2 variations demonstrated vasoreactivity, and the analysis remained unchanged when we assumed that nonsynonymous BMPR2 variations were present in all 15 patients with familial PAH. CONCLUSIONS: Patients with familial or idiopathic PAH and nonsynonymous BMPR2 variations are unlikely to demonstrate vasoreactivity. Further trials are required to determine whether long-term therapy can be directed by tests for BMPR2 variations.

Adolescent↗
PubMed1997

Developmental variation in lumbosacropelvic anatomy of thoroughbred racehorses.

OBJECTIVE: To describe the incidence and types of gross osseous developmental variations and ages of physeal closure in the caudal portion of the thoracic and lumbosacral spine and the pelvis in a sample of Thoroughbred racehorses. ANIMALS: Thoroughbred racehorses (n = 36) that died or were euthanatized at California racetracks between October 1993 and July 1994. PROCEDURE: Lumbosacropelvic specimens were collected, and all soft tissues were removed. The osseous specimens were visually examined. RESULTS: Only 22 (61%) specimens had the expected number of 6 lumbar and 5 sacral vertebrae. Eight (22%) specimens had thoracolumbar transitional vertebrae, and 13 (36%) had sacrocaudal transitional vertebrae. Articular process asymmetries were present at 1 or more vertebral segments in 30 (83%) specimens. Intertransverse joints (2 to 4 pairs/specimen) were bilaterally distributed in the caudal portion of the lumbar spine and the lumbosacral joint in 31 (86%) specimens. Five (14%) specimens had asymmetric distribution of the intertransverse joints. Intertransverse joint ankylosis was found in 10 (28%) specimens. Lumbosacral vertebral body physeal closure occurred between 4.9 and 6.7 years of age; pelvic physeal closure occurred between 5.2 and 5.8 years of age. Iliac crest and ischial arch epiphyseal formation was evaluated, using a grading system, and fusion to the underlying bone occurred at 7.2 years and 5.4 years of age, respectively. CONCLUSIONS: Numerous vertebral anatomic variations were commonly found in a sample of Thoroughbred racehorses. CLINICAL RELEVANCE: Normal anatomic variations and ages of skeletal maturity need to be considered in clinical evaluation of the equine spine and pelvis for differentiation from pathologic findings.

Aging↗
PubMed2004

The effects of scale: variation in the APOA1/C3/A4/A5 gene cluster.

While there is considerable appeal to the idea of selecting a few SNPs to represent all, or much, of the DNA sequence variability in a local chromosomal region, it is also important to quantify what detail is lost in adopting such an approach. To address this issue, we compared high- and low-resolution depictions of sequence diversity for the same genomic region, the APOA1/C3/A4/A5 gene cluster on chromosome 11. First, extensive re-sequencing identified all nucleotide and sequence haplotype variation of the linked apolipoprotein genes in 72 individuals from three populations: African-Americans from Jackson, Miss., Europeans from North Karelia, Finland, and European-Americans from Rochester, Minn. We identified 124 SNPs in 17.7 kb and significant differences in variation among genes. APOC3 gene diversity was particularly distinctive at high resolution, showing large allele frequency differences ( F(ST) values >0.250) between Jackson and the other two samples, and divergent population-specific haplotype lineages. Next, we selected haplotype-tagging SNPs (htSNPs) for each gene, at a density of approximately one SNP per kb, using an algorithm suggested by Stram et al. (2003). The 17 htSNPs identified were then used to reconstruct low-resolution haplotypes, from which inferences about the structure of variation were also drawn. This comparison showed that while the htSNPs successfully tagged common haplotype variation, they also left much underlying sequence diversity undetected and failed, in some cases, to co-classify groups of closely related haplotypes. The implications of these findings for other haplotype-based descriptions of human variation are discussed.

Apolipoprotein C-III↗
PubMed1982

A successful gestational outcome in the presence of genitourinary abnormalities and severe medical complications of pregnancy.

Müllerian duct dysgenesis may result in various genitourinary abnormalities and a high incidence of associated gestational losses. The bicornuate uterus (with either one or two cervices) and a single vagina are the most common genital variations, whereas an ectopic pelvic kidney and unilateral renal agenesis are the most common associated renal malformations. Inspite of the high incidence of fetal wastage resulting from pregnancies associated with congenital uterine abnormalities, aggressive perinatal and neonatal therapy may improve the gestational outcome.

Adolescent↗
PubMed1987

Structural variants of human T200 glycoprotein (leukocyte-common antigen).

Structural variation in the primary structure of human T200 glycoprotein has been detected. Three cDNA variants have been characterized each of which encode T200 molecules that differ in size as a result of sequence differences in their amino-terminal regions. The largest form of the molecule is distinguished from the smallest by an insert of 161 amino acids, after the first eight amino-terminal residues. The other variant has an insert at the same location of 47 amino acids identical to residues 75-121 in the larger insert. Both extra domains are rich in serine and threonine residues and are likely to display multiple O-linked oligosaccharides. These structural variants which probably arise by cell-type-specific alternative splicing provide a molecular basis for the previously observed structural and antigenic heterogeneity of T200 glycoprotein. In addition to the variable amino-terminal region, the external domain of human T200 glycoprotein consists of a second cysteine-rich region of about 400 amino acids, a single transmembrane-spanning region and a large cytoplasmic domain of 707 amino acids shared by all of the structural variants and highly conserved between species. The gene encoding human T200 is located on the long arm of chromosome 1.

Amino Acid Sequence↗
PubMed2002

Major histocompatibility complex variation in red wolves: evidence for common ancestry with coyotes and balancing selection.

We examined variation at a class II major histocompatibility complex (MHC) gene (DRB1) in the captive red wolf population and samples of coyotes from Texas and North Carolina. We found 4 alleles in the 48 red wolves, 8 alleles in the 10 coyotes from Texas and 15 alleles in the 29 coyotes from North Carolina. Two of the four alleles found in red wolves, Caru-2 and Caru-4, were found in both the Texas and North Carolina coyote samples. Allele Caru-1, previously found in gray wolves, was also found in the North Carolina sample. The most frequent red wolf allele, Caru-3, was not found in any of the coyote samples. However, an allele found in both the Texas and North Carolina coyote samples is only one nucleotide (one amino acid) different from this red wolf allele. Overall, it appears from examination of this MHC gene that red wolves are more closely related to coyotes than to gray wolves. There were a number of different types of evidence supporting the action of balancing selection in red wolves. Namely, there was: (i) an excess of heterozygotes compared with expectations; (ii) a higher rate of nonsynonymous than synonymous substitution for the functionally important antigen-binding site positions; (iii) an eight times higher average heterozygosity of individual amino acids at the positions identified as part of the antigen-binding site than those not associated with it; (iv) the amino acid divergence of four red wolf alleles was greater than that expected from a simulation of genetic drift; and (v) the distribution of alleles, and the distributions of amino acids at many positions were more even than expected from neutrality. Examination of the level and pattern of linkage disequilibria between pairs of sites suggest that the heterozygosity, substitution and frequencies at individual amino acids are not highly dependent upon each other.

Adaptation, Physiological↗
PubMed2005

Genetic susceptibility and single-nucleotide polymorphisms.

The completion of the Human Genome Project has provided insight into human genetic variation, most commonly represented by single-nucleotide polymorphisms. There is presently a great deal of interest in linking genetic and phenotypic variation in the form of severity of, and susceptibility to, common multifactorial diseases. This article provides a background to recent advances in genetics, focusing on the application to common neonatal disorders and the practical difficulties of genetic association studies, as well as highlighting the potential impact on clinical practice.

Genetic Predisposition to Disease↗
PubMed1966

Immunoglobulin kappa-chains. Comparative sequences in selected stretches of Bence-Jones proteins.

Three type K Bence-Jones proteins have been fully reduced and carboxymethylated with high-specific-activity iodo[(14)C]acetate. A tryptic digest and a chymotryptic digest of each protein were fractionated on a Sephadex column and the radioactive peptides were purified by paper electrophoresis. All the proteins studied had five unique carboxymethylated cysteine sequences. Three of these were identical with the exception of a single substitution, and two had some variations. The common peptides could be placed in the C-terminal half of the molecule. The variations around the other two half-cysteine residues provided information about the nature of the variability of the primary sequence of immunoglobulin kappa-chains. The results are consistent with the hypothesis that the chains derive from a common ancestor by somatic mutation of a small number of genes or by gene doubling and selection in the course of evolution. The isolation of the N-terminal peptide in methionine-containing Bence-Jones proteins is also described.

Amino Acid Sequence↗
PubMed2004

Chloroplast DNA variation and postglacial recolonization of common ash (Fraxinus excelsior L.) in Europe.

We used chloroplast polymerase chain reaction-restriction-fragment length polymorphism (PCR-RFLP) and chloroplast microsatellites to assess the structure of genetic variation and postglacial history across the entire natural range of the common ash (Fraxinus excelsior L.), a broad-leaved wind-pollinated and wind-dispersed European forest tree. A low level of polymorphism was observed, with only 12 haplotypes at four polymorphic microsatellites in 201 populations, and two PCR-RFLP haplotypes in a subset of 62 populations. The clear geographical pattern displayed by the five most common haplotypes was in agreement with glacial refugia for ash being located in Iberia, Italy, the eastern Alps and the Balkan Peninsula, as had been suggested from fossil pollen data. A low chloroplast DNA mutation rate, a low effective population size in glacial refugia related to ash's life history traits, as well as features of postglacial expansion were put forward to explain the low level of polymorphism. Differentiation among populations was high (GST= 0.89), reflecting poor mixing among recolonizing lineages. Therefore, the responsible factor for the highly homogeneous genetic pattern previously identified at nuclear microsatellites throughout western and central Europe (Heuertz et al. 2004) must have been efficient postglacial pollen flow. Further comparison of variation patterns at both marker systems revealed that nuclear microsatellites identified complex differentiation patterns in south-eastern Europe which remained undetected with chloroplast microsatellites. The results suggest that data from different markers should be combined in order to capture the most important genetic patterns in a species.

DNA, Chloroplast↗
PubMed2002

Polymorphic G-protein-coupled receptors and associated diseases.

Polymorphisms are quite common in the human population. Most likely every gene could be polymorphic. Most of these variations are common and have no functional consequence. However, as we learn more about the function of G-protein-coupled receptors (GPCRs) and how amino acid differences can modulate the function enough to measure, especially in a compromised physical state, the importance of characterizing these variations becomes substantial. This review will focus on polymorphisms in receptors that bind biogenic amines, calcium, opioids, endothelin, and those that also regulate taste, skin pigmentation, and oogenesis that have been suggested to cause variations of physiology.

GTP-Binding Proteins↗
PubMed2002

Variation of mood and empathy during internship.

CONTEXT: Internship is a time of great transition, during which mood disturbances are common. However, variations in mood and empathy levels throughout the internship year have not been investigated. OBJECTIVE: To examine mood patterns and changes in empathy among internal medicine residents over the course of the internship year. DESIGN: Cohort study of interns involving completion of survey instruments at 4 points: time 1 (June 2000; Profile of Mood States [POMS] and Interpersonal Reactivity Index [IRI]), times 2 and 3 (November 2000 and February 2001; POMS), and time 4 (June 2001; POMS and IRI). SETTING: Internal medicine residency program at a university-based medical center. PARTICIPANTS: Sixty-one interns. MAIN OUTCOME MEASURES: Baseline scores of mood states and empathy; trends in mood states and empathy over the internship year. RESULTS: Response rates for time 1 were 98%; for time 2, 72%; for time 3, 79%; and for time 4, 79%. Results of the POMS revealed that physicians starting their internship exhibit less tension, depression, anger, fatigue, and confusion and have more vigor than general adult and college student populations (P<.001 for all). Results of the IRI showed better baseline scores for perspective taking (P<.001) and empathic concern (P =.007) and lower scores for personal distress (P<.001) among interns compared with norms. Five months into internship, however, POMS scores revealed significant increases in the depression-dejection (P<.001), anger-hostility (P<.001), and fatigue-inertia (P<.001) scales, as well as an increase in IRI personal distress level (P<.001). These increases corresponded with decreases in the POMS vigor-activity scores (P<.001) and IRI empathic concern measures (P =.005). Changes persisted throughout the internship period. CONCLUSIONS: We found that, in this sample, enthusiasm at the beginning of internship soon gave way to depression, anger, and fatigue. Future research should be aimed at determining whether these changes persist beyond internship.

Adult↗
PubMed1997

Human hepatic microsomal epoxide hydrolase: comparative analysis of polymorphic expression.

Interindividual variation in the expression of human microsomal epoxide hydrolase (mEH) may be an important risk factor for chemically induced toxicities, including cancer and teratogenesis. In this study, phenotypic variability and mEH genetic polymorphisms were examined in a bank of 40 transplant-quality human liver samples. Immunochemically determined protein content, enzymatic activities, polymorphic amino acids, as well as mEH RNA levels were evaluated in parallel. Enzymatic activity was assessed using (+/-)-benzo[a]pyrene-4,5-epoxide at 2 substrate concentrations. The relative hydrolyzing activities obtained using saturating substrate levels were highly correlated (r = 0.85) with results derived from limiting substrate concentrations and exhibit approximately an 8-fold range in activity levels across the panel of 40 liver samples. mEH enzyme activity also demonstrated strong correlation (r > or = 0.74) with an 8.4-fold variation determined for mEH protein content within the same samples. However, these protein/activity measurements were poorly correlated (r < or = 0.23) with mEH RNA levels, which exhibited a 49-fold variation. Two common polymorphic amino acid loci in the mEH protein did not exclusively account for variation in enzymatic activity, although this conclusion is confounded by heterozygousity in the samples. These data demonstrate the extent of hepatic mEH functional variability in well-preserved human tissues and suggest that polymorphism of mEH protein expression is regulated in part by posttranscriptional controls, which may include nonstructural regulatory regions of the mEH transcript.

Adolescent↗
PubMed2005

Population structure within lineages of Wheat streak mosaic virus derived from a common founding event exhibits stochastic variation inconsistent with the deterministic quasi-species model.

Structure of Wheat streak mosaic virus (WSMV) populations derived from a common founding event and subjected to serial passage at high multiplicity of infection (MOI) was evaluated. The founding population was generated by limiting dilution inoculation. Lineages of known pedigree were sampled at passage 9 (two populations) and at passage 15, with (three populations) or without mixing (four populations) of lineages at passage 10. Polymorphism within each population was assessed by sequencing 17-21 clones containing a 1371 nt region (WSMV-Sidney 81 nts 8001-9371) encompassing the entire coat protein cistron and flanking regions. Mutation frequency averaged approximately 5.0 x 10(-4)/nt across all populations and ranged from 2.4 to 11.6 x 10(-4)/nt within populations, but did not consistently increase or decrease with the number of passages removed from the founding population. Shared substitutions (19 nonsynonymous, 10 synonymous, and 3 noncoding) occurred at 32 sites among 44 haplotypes. Only four substitutions became fixed (frequency = 100%) within a population and nearly one third (10/32) never achieved a frequency of 10% or greater in any sampled population. Shared substitutions were randomly distributed with respect to genome position, with transitions outnumbering transversions 5.4:1 and a clear bias for A to G and U to C substitutions. Haplotype composition of each population was unique with complexity of each population varying unpredictably, in that the number and frequency of haplotypes within a lineage were not correlated with number of passages removed from the founding population or whether the population was derived from a single or mixed lineage. The simplest explanation is that plant virus lineages, even those propagated at high MOI, are subject to frequent, narrow genetic bottlenecks during systemic movement that result in low effective population size and stochastic changes in population structure upon serial passage.

Base Sequence↗