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PubMed1998

Genetic variation in functionally important domains of the bovine mtDNA control region.

DNA sequences of the mitochondrial control region (CR) of 32 unrelated Austrian cattle were analysed in order to determine the extent of variability in functionally important domains. Using sequencing of PCR products, allele-specific PCR (AS-PCR) and primer introduced restriction analysis (PIRA), 43 differences were observed. They included 33 transitions, five transversions, one deletion and four differences in the number of consecutive cytosines. Twenty-three of these polymorphisms have not been reported before. In addition, we analysed all available European cattle sequences for this region. The transcriptional start sites, the conserved sequence block CSB 1 and both binding sites for the mitochondrial transcription factor mtTFA were highly conserved. We found a transition in each of the inter-specifically conserved Mt4 and Mt5 elements, three nucleotide substitutions in the termination-associated sequence TAS-A and six polymorphisms in the conserved sequence block CSB 2+3, a region which has been implicated in mitochondrial RNA processing.

Animals↗
PubMedDate not supplied

Genetic variation associated with preterm birth: a HuGE review.

Preterm birth (PTB) is a major public health concern because of its high prevalence, associated mortality and morbidity, and expense from both short-term hospitalization and long-term disability. In 2002, 11.9% of U.S. births occurred before 37 weeks gestation. Epidemiologic studies have identified many demographic, behavioral, and medical characteristics associated with PTB risk. In addition, recent evidence indicates a role for genetic susceptibility. We reviewed 18 studies published before June 1, 2004, that examined associations between polymorphisms in the maternal or fetal genome and PTB risk. Studies of a polymorphism in tumor necrosis factor-alpha, a proinflammatory cytokine, showed the most consistent increase in the risk of PTB. Environmental factors such as infection, stress, and obesity, which activate inflammatory pathways, have been associated with PTB, suggesting that environmental and genetic risk factors might operate and interact through related pathways. This review highlights maternal and fetal genetic susceptibilities to PTB, the potential relationships with environmental risk factors, and the need for additional well-designed studies of this critical public health problem.

Environmental Exposure↗
PubMed1995

Quantitative and qualitative genetic variation in two-dimensional DNA gels of human lymphocytoid cell lines.

There is a continuing need for more efficient methods to examine human (and other) populations for altered germinal and somatic cell mutation rates. To this end, we have explored the potential usefulness of two-dimensional (2-D) electrophoresis of human DNA fragments obtained from restriction-enzyme-digested genomic DNA, using samples from father/mother/child trios. On a single 2-D DNA preparation, approximately 2000 DNA fragments varying in size from 1.0 to 5.0 kbp in the first dimension and 0.3 to 2.0 kbp in the second dimension are visualized. To enter into a genetic analysis of quantitative variation, these fragments must exhibit positional and quantitative stability. With respect to the latter, if spots that are the product of two homologous DNA fragments are to be distinguished with the requisite accuracy from spots that are the product of only one fragment, the coefficient of variation of spot intensity should be approximately < or = 0.12. At present, 482 of the spots in our preparations meet these standards. In an examination of preparations based on three Japanese mother/father/child trios, 43 of these 482 spots were found to exhibit variations that segregated within families according to Mendelian principles. Additionally, of the 2000 spots, 1114 (of which the aforementioned 482 are a subset) were deemed appropriate for the study of qualitative variation. A total of 142 variable spots were identified; the heterozygosity index for these DNA fragments was 4.4%. The genetic nature of the additional variants was again established by their segregation according to Mendelian principles. We have established the feasibility of cloning fragments from such gels and determining their nucleotide sequence. This technology should be highly efficient in monitoring for mutation resulting in loss/gain/rearrangement events in DNA fragments distributed throughout the genome.

Autoradiography↗
PubMed2004

Genetic variation of the dihydrofolate reductase gene in Plasmodium vivax in Snoul, northeastern Cambodia.

In Plasmodium vivax, pyrimethamine resistance is associated with amino acid substitutions Ser117Asn and Ser58Arg in dihydrofolate reductase (DHFR), which correspond to Ser108Asn and Cys59Arg in the Plasmodium falciparum homolog, respectively. Sequence variations within the DHFR domain of 32 P. vivax isolates from Snoul, Cambodia, were analyzed by direct sequencing of polymerase chain reaction (PCR) products. Sequence polymorphisms within the entire DHFR domain were limited to codons 58 and 117 and GGDN tandem repeat units. A large majority (30 of 32) of isolates were characterized to be double mutants (Arg-58 and Asn-117) and associated with the presence of two GGDN repeat units. Only one isolate was of wild-type with three GGDN repeat units, and an additional isolate was of mixed type. Our data suggest that most Cambodian P. vivax isolates display double dhfr mutations associated with pyrimethamine resistance, as in the neighboring countries in Southeast Asia. Further molecular characterization of P. vivax isolates from different endemic areas may be a useful alternative approach to establish the epidemiology of drug-resistant malaria.

Animals↗
PubMedDate not supplied

Human genetic variation in the Sierra de Gredos mountain (central Spain): study of several polymorphisms.

The variation in the third component of human complement (C3) and orosomucoid (ORM1) serum proteins, and 6-phosphogluconate dehydrogenase (6PGD), adenosine deaminase (ADA), esterase D (ESD), and acid phosphatase (ACP1) red cell enzymes was examined in two samples from autochthonous populations living on either side of the Sierra de Gredos range in Central Spain. These results support only a moderate differentiation between Gredos subpopulations, which is discussed in relation to other Iberian Peninsula groups. Allele frequencies in Gredos show a remarkable heterogeneity as contrasted with other Iberian populations for most of the markers examined; relatively high C3*S, ORM1*F, ADA*1, ESD*2, and ACP1*C gene frequencies are characteristics of Gredos samples. This differentiation was more marked for the Northern Gredos population and could be related to the geographical peculiarities of this region.

Acid Phosphatase↗
PubMed1997

The phenotypic plasticity of wing size in Drosophila melanogaster: the cellular basis of its genetic variation.

The reaction norms in Drosophila melanogaster of thorax length, wing length and cell size were determined for 28 isofemale lines from three populations to investigate the role of cell size in determining the response of body size to temperature during the preimaginal stages. Both overall level and plasticity of the reaction norms of thorax length and wing length are highly correlated, leading to a relatively constant wing-thorax ratio between lines. Genetic differences in overall level of wing size reaction norms are mainly caused by differences in cell number. The response of wing size to temperature consists of changes in cell size and, to a lesser extent, cell number. The cellular basis of genetic differences in plasticity shows a transition point at an intermediate level. In steeper reaction norms, genetic differences in plasticity result from differences in the plasticity of cell size, whereas less steep reaction norms only differ in the plasticity of cell number. A significant partial correlation between wing length plasticity and cell size plasticity, correcting for thorax length plasticity, indicates a role of cell size in determining the wing-thorax ratio.

Animals↗
PubMed2005

A functional genetic variation of adenosine deaminase affects the duration and intensity of deep sleep in humans.

Slow, rhythmic oscillations (<5 Hz) in the sleep electroencephalogram may be a sign of synaptic plasticity occurring during sleep. The oscillations, referred to as slow-wave activity (SWA), reflect sleep need and sleep intensity. The amount of SWA is homeostatically regulated. It is enhanced after sleep loss and declines during sleep. Animal studies suggested that sleep need is genetically controlled, yet the physiological mechanisms remain unknown. Here we show in humans that a genetic variant of adenosine deaminase, which is associated with the reduced metabolism of adenosine to inosine, specifically enhances deep sleep and SWA during sleep. In contrast, a distinct polymorphism of the adenosine A(2A) receptor gene, which was associated with interindividual differences in anxiety symptoms after caffeine intake in healthy volunteers, affects the electroencephalogram during sleep and wakefulness in a non-state-specific manner. Our findings indicate a direct role of adenosine in human sleep homeostasis. Moreover, our data suggest that genetic variability in the adenosinergic system contributes to the interindividual variability in brain electrical activity during sleep and wakefulness.

Adenosine Deaminase↗
PubMed2003

Impact of genetic variation on metabolic response of bone to diet.

There is compelling evidence to suggest that both the development of bone to peak bone mass at maturity and subsequent loss depend on the interaction between genetic, hormonal, environmental and nutritional factors. The major part (< or = 80%) of the age-specific variation in bone turnover and bone density is genetically determined. However, the notion of genetic determinant is of little value unless the specific genes that are involved can be identified. Most work in this area of osteoporosis research has focused on the candidate gene approach, which has identified several candidate genes for osteoporosis, including genes encoding the vitamin D receptor (VDR), oestrogen receptors (alpha and beta), apolipoprotein E, collagen type I alpha 1 and methylenetetrahydrofolate reductase, amongst many others. However, in general, findings from numerous studies of the association between such genes and various bone variables have been inconsistent. In addition to possible gene-gene interactions it is likely that there are interactions between these genes and certain environmental factors, especially nutrition, that may mediate expression of bone-related phenotypes. While these potential interactions add a level of complexity to our understanding of these apparent genetic effects on bone, identification of a role for genetic factors without knowledge of their interaction with nutrients can do little to advance prevention and treatment of osteoporosis. This information is especially important because, unlike genotype, diet and nutrition can be modified. The aim of the present review is to critically evaluate current knowledge relating to candidate genes for osteoporosis, with particular emphasis on their interaction with nutrients and dietary factors in determining bone health.

Bone Density↗
PubMed1980

Genetic variation during persistent reovirus infection: presence of extragenically suppressed temperature-sensitive lesions in wild-type virus isolated from persistently infected L cells.

Persistent reovirus infection of L cells was established with a serially passaged stock of temperature-sensitive (ts) mutant C(447) containing greater than 90% defective interfering particles. Within a month after establishment of the carrier culture, the ts mutant was replaced by virus that expressed the wild-type (ts(+)) temperature phenotype (R. Ahmed and A. F. Graham, J. Virol. 23:250-262, 1977). To determine whether the ts(+) phenotype of the virus was due to intragenic reversion or to the presence of an extragenic mutation suppressing the original ts defect, several clones were backcrossed to wild-type reovirus, and the progeny of each cross were screened for temperature sensitivity. The results indicated that the original tsC lesion had reverted. However, in two of the seven clones examined, new ts lesions were found. These new ts lesions appeared phenotypically as ts(+) due to the presence of extragenic suppressor mutations. Temperature-sensitive mutants representing three different groups were rescued from one suppressed clone, indicating that this ts(+) clone contained multiple ts lesions. Among the ts mutants rescued were the initial isolates of a new recombination group which we have designated H. Some of the ts mutants rescued from the suppressed clones are capable of interfering with the growth of wild-type reovirus and may play a role in maintaining the carrier state. The results of this study show that persistently infected L cells contain a genetically heterogeneous population of reovirus even though all virus clones express the ts(+) phenotype. It is thus critical to distinguish between genotype and phenotype when analyzing viruses that emerge during persistent infection.

Animals↗
PubMed1995

Prevalence and geographic genetic variation of hantaviruses of New World harvest mice (Reithrodontomys): identification of a divergent genotype from a Costa Rican Reithrodontomys mexicanus.

We recently described a novel hantavirus (HMV-1) of the western harvest mouse Reithrodontomys megalotis. Screening of 181 additional specimens of Reithrodontomys from the United States and Mexico, including samples of R. mexicanus, R. sumichrasti, and R. gracilis of Costa Rica, for antibodies to hantavirus nucleocapsid protein revealed a widespread enzootic of hantavirus infection. Genetic analyses of 7 S genomes of Reithrodontomys-associated hantaviruses demonstrated that the enzootic of HMV-1 extends from central Mexico into the southwestern United States. A presumed deer mouse hantavirus was found in an R. megalotis animal in Mexico. A highly divergent HMV-1-like virus, tentatively called HMV-2, was identified in a Costa Rican R. mexicanus. These data suggest a longstanding radiation of hantaviruses among New World harvest mice. We identify possible opportunities for genetic exchange among hantaviruses of related rodent hosts.

Animals↗
PubMed2002

Characterization of apolipoprotein E genetic variations in Taiwanese: association with coronary heart disease and plasma lipid levels.

Apolipoprotein E (apoE, protein; APOE, gene) is important in lipoprotein metabolism. Three isoforms, apoE2 (Cys112 Cys158), apoE3 (Cys112 Arg158), and apoE4 (Arg112 Arg158), are present in the general population. This report investigates the frequency distribution of apoE isoforms and the association of APOE genotypes with plasma lipid profile and coronary heart disease (CHD) in a population of Taiwan. ApoE isoforms were determined genetically by polymerase chain reaction and HhaI restriction enzyme digestion in control and coronary heart disease (CHD) patients. Plasma lipid and lipoprotein concentrations were also determined. The control group exhibited frequencies of 84.6% APOE3, 7.9% APOE4, 7.5% APOE2, 70.6% APOE3E3, 14.4% APOE3E4, 13.6% APOE2E3, and 1.4% APOE2E4. Comparable frequencies were observed in the CHD group. In both APOE2 carrier and APOE3E3 groups, the CHD patients expressed abnormal lipid profiles while the control group expressed normal lipid profiles. The APOE4 carriers, however, expressed abnormal lipid profiles in both normal control and CHD groups. Extremely high apoE levels in the hypertriglyceridemic group (TG > 400 mg/dL) seemed to be undesirable and were often observed in CHD patients.

Adult↗
PubMed2006

Examining the role of common genetic variation in the gamma2 subunit of the GABA(A) receptor in epilepsy using tagging SNPs.

INTRODUCTION: Mutations in the gamma2 subunit gene of the GABA(A) receptor, GABRG2, have been shown to cause generalised epilepsy syndromes in rare familial cases. Here we set out to examine whether common variation in GABRG2 predisposes to the development of common, complex forms of epilepsy in two large independent cohorts. METHODS: We have applied a tagging single nucleotide polymorphism (tSNP) technique allowing us to satisfactorily represent common variation in the gene. However, to ensure maximal representation of functional variation and in particular in cases of low minor allele frequency (MAF), we have identified and forced known functional variation as tagging SNPs. We examined the association between tagging SNPs and subtypes of epilepsy in two independent cohorts; the first consisted of 677 cases and 384 healthy controls, the second of 684 cases and 277 healthy controls. RESULTS: We failed to detect any variation that conferred an increased risk of disease development in both cohorts. DISCUSSION: Our results suggest that common variants of strong effect in GABRG2 do not appear to play a role in the development of common, complex forms of epilepsy. This report illustrates a number of important features of study design in genetic association studies, including the simultaneous use of map and sequence-based techniques and the necessity of replication before robust conclusions can be drawn from results.

Alleles↗
PubMed2026

The Role of Genetic Variation in Phenotypic Variability in Loeys-Dietz Syndrome.

BACKGROUND: Loeys-Dietz syndrome (LDS) is a heritable connective tissue disorder caused by pathogenic variants in genes of the transforming growth factor-&#x3b2; (TGF-&#x3b2;) signaling pathway. Although genotype-phenotype correlations have been suggested, comprehensive comparative data across LDS subtypes remain limited. Improved understanding of these correlations is essential to guide individualized surveillance and management strategies. METHODS: We conducted a retrospective cohort study of adults with genetically confirmed LDS evaluated between 2018 and 2024 across Mayo Clinic sites. Patients with pathogenic, likely pathogenic, or suspicious variants in TGFBR1, TGFBR2, or SMAD3 were included. Clinical characteristics, physical examination findings, cardiovascular and noncardiovascular manifestations, surgical interventions, and mortality were compared across genotypes. Categorical variables were analyzed using chi-square tests and continuous variables using parametric or nonparametric methods as appropriate. RESULTS: A total of 93 patients were included (29 TGFBR1, 33 TGFBR2, 31 SMAD3). Demographics and mortality did not differ significantly between groups. Patients with TGFBR1 and TGFBR2 demonstrated trends toward higher rates of ascending aortic aneurysm and aortic dissection compared with SMAD3 patients, though these differences were not statistically significant. Renal artery aneurysms were significantly more common in TGFBR1 patients (13.8%, p = 0.010). SMAD3 patients had significantly higher rates of mitral regurgitation (54.8%, p = 0.04), peripheral neuropathy (29.0%, p = 0.018), and trends toward increased atrial fibrillation and osteoarthritis. A novel association was identified between TGFBR1 variants and migraine, which was significantly more prevalent in this group (62.1%, p = 0.017). The rates of major cardiovascular surgical interventions were high and comparable across all genotypes. CONCLUSION: Distinct genotype-phenotype associations exist among LDS subtypes. TGFBR1 and TGFBR2 variants are associated with a greater burden of aggressive vascular disease, whereas SMAD3 variants are linked to mitral valve disease, peripheral neuropathy, and osteoarthritis. We also identified a novel association between TGFBR1 genotype and migraine. These findings reinforce the importance of comprehensive genetic testing to inform personalized surveillance and management strategies in LDS.

Humans↗
PubMed1979

Amylase genetic variation of serum in Holstein cattle.

Three amylase phenotypes, AmIB, AmIC, and AmIBC, were detected by electrophoresis of blood serum from 329 Holstein cattle. These phenotypes appear to be controlled by two alleles AmIB and AmIC at the amylase I locus (AmI). Frequencies were .518 and .482 for alleles B and C. The numbers of phenotypes corresponded closely to expectations of Hardy-Weinberg equilibrium. No evidence of linkage between the AmI locus and other genetic marker loci of blood and milk was detected.

Amylases↗
PubMed1987

Genetic variation between woodchuck populations with high and low prevalence rates of woodchuck hepatitis virus infection.

Woodchuck hepatitis virus (WHV) infection is known to be endemic in areas of the mid-Atlantic states but is apparently absent from populations in New York and much of New England. Blood samples of 40 woodchucks (Marmota monax) from New York and from Delaware were examined by starch gel electrophoresis, and 18 monomorphic and six polymorphic protein-coding genetic systems were identified. Mendelian inheritance of variants of the six polymorphic systems was confirmed in 52 laboratory offspring of the original samples. Average heterozygosity of 0.066 in New York woodchucks and 0.039 in Delaware woodchucks were high values for mammals, although similar to those of other sciurids. Significant heterogeneity between samples from New York and Delaware woodchucks was observed at two loci (peptidase with glycyl leucine-4 and phosphogluconate dehydrogenase), suggesting that these populations were genetically distinct. Whether there are genetically determined differences in response to WHV infection remains to be determined experimentally.

Alleles↗