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PubMed1995

HIV population dynamics in vivo: implications for genetic variation, pathogenesis, and therapy.

Several recent reports indicate that the long, clinically latent phase that characterizes human immunodeficiency virus (HIV) infection of humans is not a period of viral inactivity, but an active process in which cells are being infected and dying at a high rate and in large numbers. These results lead to a simple steady-state model in which infection, cell death, and cell replacement are in balance, and imply that the unique feature of HIV is the extraordinarily large number of replication cycles that occur during infection of a single individual. This turnover drives both the pathogenic process and (even more than mutation rate) the development of genetic variation. This variation includes the inevitable and, in principle, predictable accumulation of mutations such as those conferring resistance to antiviral drugs whose presence before therapy must be considered in the design of therapeutic strategies.

Acquired Immunodeficiency Syndrome↗
PubMed2005

Genetic variation among epizootic hemorrhagic disease viruses in the southeastern United States: 1978-2001.

The epizootic hemorrhagic disease (EHD) viruses, which are endemic in the southeastern United States, are the causative agents of an important clinical disease in wild and captive ruminants. In order to elucidate the molecular epidemiology of EHD serotype 2, the sequences of portions of the S10 and L2 gene segments (which encode the NS3 viral egress protein and the VP2 surface protein, respectively) of viral isolates made from white-tailed deer over 23 years(1978-2001) were determined and compared using phylogenetic analyses. Both loci demonstrated very little genetic variation among isolates, with a 94-100% nucleotide identity among isolates at the S10 locus (98-100% amino acid conservation), and an 89.1-100% identity among isolates at the L2 locus (87.6-100% amino acid conservation). The grouping of isolates within the resulting cladograms appeared nearly random with respect to time of isolation and geographic origin. One exception to this was a distinctive grouping of some isolates from 1996 to 1997, which formed a separate subclade in both the S10 and L2 cladograms.

Animals↗
PubMed2006

Effect of genetic variation on human cytochrome p450 reductase-mediated paraquat cytotoxicity.

Paraquat (1,1'-dimethyl-4,4'-bipyridylium dichloride) is a widely used herbicide and is highly toxic to human and animals. The mechanisms of paraquat toxicity involve the generation of superoxide anion through the process of redox cycling. NADPH-cytochrome P450 oxidoreductase (POR) has been reported to be a major enzyme for one-electron reduction of paraquat that initiates the redox cycling. Recently, a total of six missense variants of human POR have been identified in patients with discorded steroidogenesis. However, the effect of these genetic variations on POR-mediated paraquat toxicity is not known. Using the Flp-In Chinese hamster ovary (CHO) cells stably expressing either mouse or human POR and the cells with POR knockdown by siRNA, we confirmed that POR is responsible for paraquat-induced cytotoxicity. We further used this validated system to compare paraquat-induced toxicity among the cells that stably expressed wild-type human POR and its natural variants. While there was no difference in paraquat-induced toxicity between the cells expressing wild-type human POR and the Cys569Tyr variant, the toxicity in cells expressing all the other variants (Tyr181Asp, Ala287Pro, Arg457His, Val492Glu, and Val608Phe) was significantly decreased. Our results provide further evidence on the important role of POR in paraquat-induced toxicity and suggest that individuals carrying the functional variant POR alleles may have an altered susceptibility to paraquat exposure.

Alleles↗
PubMed2006

Molecular phylogeny of VP1, 2A, and 2B genes of echovirus isolates: epidemiological linkage and observations on genetic variation.

Phylogenetic relationships between 37 echovirus clinical isolates, most of them originating from an aseptic meningitis outbreak during 2001 in Greece, were investigated by RT-PCR and sequencing. The generic primers 292 and 222 were used to amplify about 300 bp of the 5' end of VP1 while primers EUG3a, 3b, 3c, and EUC2 amplified the entire coding sequence of the 2A and 2B genes. Phylogenetic trees were constructed for each genomic region using the clinical isolates' sequences and those of the prototype echoviruses in order to investigate the correlation of part of VP1 with the serotype as well as the genetic variation of the echovirus genome in 2A and 2B. The phylogenetic grouping pattern of the clinical isolates revealed that there is a correlation of serotype and genotype in the part of VP1 that was investigated, while this pattern is disrupted in the adjacent genomic regions that were sequenced. Sequence analysis of the adjacent 2A and 2B genes provided a different pattern of phylogenetic relationships and strong evidence of epidemiological linkage of most of the clinical isolates.

Amino Acid Sequence↗
PubMed2005

Reduced genetic variation occurs among genes of the highly clonal plant pathogen Xanthomonas axonopodis pv. vesicatoria, including the effector gene avrBs2.

The bacterial plant pathogen Xanthomonas axonopodis pv. vesicatoria, also known as Xanthomonas campestris pv. vesicatoria group A, is the causal agent of bacterial spot in pepper and tomato. In order to test different models that may explain the coevolution of avrBs2 with its host plants, we sequenced avrBs2 and six chromosomal loci (total of 5.5 kb per strain) from a global sample of 55 X. axonopodis pv. vesicatoria strains collected from diseased peppers. We found an extreme lack of genetic variation among all X. axonopodis pv. vesicatoria genomic loci (average nucleotide diversity, pi = 9.1 x 10(-5)), including avrBs2. This lack of diversity is consistent with X. axonopodis pv. vesicatoria having undergone a recent population bottleneck and/or selective sweep followed by population expansion. Coalescent analysis determined that approximately 1.4 x 10(4) to 7.16 x 10(4) bacterial generations have passed since the most recent common ancestor (MRCA) of the current X. axonopodis pv. vesicatoria population. Assuming a range of 50 to 500 bacterial generations per year, only 28 to 1,432 years have passed since the MRCA. This time frame coincides with human intervention with the pathogen's host plants, from domestication to modern agricultural practices. Examination of 19 mutated (loss-of-function) avrBs2 alleles detected nine classes of mutations. All mutations affected protein coding, while no synonymous changes were found. The nature of at least one of the avrBs2 mutations suggests that it may be possible to observe one stage of an evolutionary arms race as X. axonopodis pv. vesicatoria responds to selection pressure to alter avrBs2 to escape host plant resistance.

Alleles↗
PubMed2002

Temporal modulation of pyrrolizidine alkaloid intake and genetic variation in performance of Utetheisa ornatrix caterpillars.

Foraging on a variety of different food items allows individuals to balance nutrient intake, but it also may dilute toxins present in single items of the diet. The distinction between nutrient balancing and toxin dilution becomes less clear, however, for organisms that sequester potentially toxic compounds for their own benefit. Additionally, specific dietary components chosen may or may not affect metabolic rate, growth, and other measures of fitness. Using the arctiid moth Utetheisa ornatrix, we (1) evaluated the temporal pattem of larval feeding behavior when presented with diet enriched with the pyrrolizidine alkaloid (PA), monocrotaline, (2) estimated the cost of ingesting PAs by measuring larval nutritional performance on diets containing different amounts of usaramine, and (3) investigated the magnitude of genetic effects on the performance of families raised on diets of different usaramine concentrations. We demonstrate that an herbivorous insect can temporally vary its intake of sequestered allelochemical. Individuals combined a preference for intermediate amounts of monocrotaline with temporal modulation of the specific amount of PA ingested on a given day. Using usaramine, we found little evidence for a cost of ingesting PAs, except among some family groups. Measures of digestive and metabolic efficiency showed no consistent reduction in performance on higher alkaloid diets. Only when larvae in family groups were fed a single concentration of PA over more than one instar was there any evidence for a cost of ingestion. Additionally, there were large genetic components to both growth and an individual's growth response to dietary alkaloid. These results suggest that while genetic variation in performance on alkaloid-rich diets exists, modulation of intake rate by caterpillars may be an important mechanism to reduce effects on the growth and fitness of individuals.

Animals↗
PubMed1998

Molecular genetic variation in Emmonsia crescens and Emmonsia parva, etiologic agents of adiaspiromycosis, and their phylogenetic relationship to Blastomyces dermatitidis (Ajellomyces dermatitidis) and other systemic fungal pathogens.

Emmonsia crescens, an agent of adiaspiromycosis, Blastomyces dermatitidis, the agent of blastomycosis, and Histoplasma capsulatum, the agent of histoplasmosis, are known to form meiotic (sexual) stages in the ascomycete genus Ajellomyces (Onygenaceae, Onygenales), but no sexual stage is known for E. parva, the type species of the genus Emmonsia. To evaluate relationships among members of the putative Ajellomyces clade, large-subunit ribosomal and internal transcribed spacer region DNA sequences were determined from PCR-amplified DNA fragments. Sequences were analyzed phylogenetically to evaluate the genetic variation within the genus Emmonsia and evolutionary relationships to other taxa. E. crescens and E. parva are distinct species. E. crescens isolates are placed into two groups that correlate with their continents of origin. Considerable variation occurred among isolates previously classified as E. parva. Most isolates are placed into two closely related groups, but the remaining isolates, including some from human sources, are phylogenetically distinct and represent undescribed species. Strains of B. dermatitidis are a sister species of E. parva. Paracoccidioides brasiliensis and Histoplasma capsulatum are ancestral to most Emmonsia isolates, and P. brasiliensis, which has no known teleomorph, falls within the Ajellomyces clade.

Blastomyces↗
PubMed2004

Heat and cold-induced male sterility in Drosophila buzzatii: genetic variation among populations for the duration of sterility.

Here we studied three phenotypic traits in Drosophila buzzatii that are strongly effected by temperature, and are expected to be closely associated with fitness in nature. The traits measured were thermal threshold of male sterility, time for males to gain fertility when reared at a sterility-inducing temperature and transferred to 25 degrees C on eclosion and survival after development. The last two traits were measured under four temperature regimes, constant 12 degrees C, 25 degrees C, 31 degrees C, and fluctuating 25 degrees C (18 h) and 38 degrees C (6 h). We looked for genetic variation in these traits and relations among them in four lines of D. buzzatii originating from Argentina and Tenerife. The thermal threshold of heat-induced male sterility was found to lie within the range of 30.0-31.0 degrees C. When measuring the time for males to gain fertility, males reared at a nonstressful temperature (25 degrees C) were fertile 58-67 h after emergence with only minor differences among lines. When reared constant 31 degrees C, males were fertile 174-225 h after hatching. The Argentinean lines were significantly faster in recovering from sterility than were the lines from Tenerife. When reared in a fluctuating temperature regime, differences among lines increased, dividing the lines into three significantly different groups, with a sterility period of 135-215 h. When reared at 12 degrees C from the pupal stage, males were fertile after 106-130 h with significant difference in the variance but not in the mean duration of sterility. Significant differences in viability were found among development temperatures, but not among lines, and viability and the duration of sterility seem to be genetically independent.

Adaptation, Physiological↗
PubMed1999

Genetic variation at the porcine MYF-5 gene locus. Lack Of association with meat production traits.

The number of muscle fibers at birth appears to determine the maximal lean meat growth capacity in pigs and in cattle. Development of muscle fibers is regulated by the MyoD gene family consisting of MyoD1, myf-5, myf-6, and myogenin. Myf-5 is expressed in proliferating myoblasts. Here we report the genomic sequence of the porcine myf-5 gene with three microsatellites and two RFLPs located close to the coding sequences. Two of the microsatellites are located in the promoter region. The allelic distribution differs between breeds and selection lines. In two GY selection lines, 1216 pigs of two-generation families were genotyped for the HinfI RFLP, which was segregating in the GY breed. The other polymorphic loci are physically linked to this RFLP locus, and therefore the results can be extrapolated to these loci. Statistical analysis revealed no association with birth weight, growth rate, weight at slaughter age, carcass meat weight, and backfat thickness. Thus, in this study myf-5 did not explain genetic variation in meat (muscle) development in pigs.

Animals↗
PubMed2005

CYP1A1 polymorphisms and risk of lung cancer in non-smoking Chinese women: influence of environmental tobacco smoke exposure and GSTM1/T1 genetic variation.

OBJECTIVE: We examined whether polymorphisms of CYP1A1, which plays a role in the metabolic activation of polycyclic aromatic hydrocarbons (PAHs), confer an increased risk of lung cancer in lifetime non-smoking Chinese women. METHODS: A total of 126 incident lung cancer cases, of which 87.7 were pathologically confirmed, and 162 age-matched hospital controls were included. CYP1A1 MspI and Ile(462)Val polymorphisms were genotyped and tested for association with this disease. RESULTS: An elevated risk of lung cancer was observed among individuals with the MspI CC (OR=1.7, 95 CI=0.9-3.3) and Ile(462)Val ValVal genotypes (OR=2.8, 95 CI=1.1-7.6). After stratifying by environmental tobacco smoke (ETS) exposure, the risk of lung cancer associated with both polymorphisms was higher among individuals with lower exposure to ETS, compared with those who reported at least weekly exposure. Individuals with the MspI CC genotype showed a two-fold higher risk of lung cancer if they were also null for either GSTM1 or T1 (OR=2.3, 95CI=1.0-5.0 and OR=2.7, 95 CI=1.1-6.9, respectively, compared to other genotype combinations combined). CONCLUSIONS: CYP1A1 is a susceptibility gene for lung cancer among non-smoking Asian women and this association can be influenced by ETS exposure and genetic variation at GST genes.

Adult↗
PubMed2005

Genetic variation in pure lines and crosses of large-bodied turkeys. 4. Body shape and carcass traits.

An experimental line (F) of turkeys selected long-term for increased 16-wk BW was reciprocally crossed with a primary breeding sire line (C) from a major international turkey breeder to study the inheritance of carcass traits and body shape. The birds were weighed and killed at 16 wk of age, and various measurements of muscling, leg bones, and body shape were made. The BW of males were 16.0 and 15.1 kg, respectively, in the C and F lines. The respective BW for females were 12.2 and 11.2 kg. Additive genetic variation, as indicated by differences between the F and C line, was a more important source of variation for measurements of muscling than for measurements of leg bones. The anterior and posterior depth of the body and the ratio of these measurements differed between the F and C lines. Body cavity volume index (length x width x height) differed between lines in females and sexes combined. The weights of some internal organs (gizzard, heart, liver, pancreas, and spleen), but not others (proventriculus and lungs), differed between lines, and the total weight of these organs was greater in the C line than in the F line. However, the ratio of total demand organs (muscles and bones) to the total weight of the supply organs was less in the F line than in the C line. Heterosis was a more important source of variation in body weight and weights of the pectoralis major and pectoralis minor muscle weights in males than in females. Heterosis for some body shape measurements (keel length, body depth 1, body depth 2, body depth ratio, body cavity height, and body cavity volume index) was significant in some comparisons. Heterosis (range = 3.64 to 3.99%) for leg muscle measurements (thigh muscles, drumstick muscles, and total leg muscles) was highly significant (P < or = 0.01) based on the analysis for both sexes. Differences between the reciprocal crosses of the F and C lines were more frequent in the present study than in previous studies in which the F line was reciprocally crossed with sire lines from 2 other commercial breeders. However, when the data from the previous studies and the current study were summarized, it appeared that the only reciprocal effect that was consistent was for the weight of the drumstick muscles, indicating sex linkage or maternal effects may influence the weight of these muscles.

Animals↗
PubMed2004

Probing genetic variation and glycoform distribution in lectins of the Erythrina genus by mass spectrometry.

Six leguminous lectins from the seeds of plants of the Erythrina genus, namely E. caffra (ECafL), E. cristagalli (ECL), E. flabelliformis (EFL), E. lysistemon (ELysL), E. rubrinerva (ERL), and E. vespertilio (EVL), were examined to establish their sequence homology and to determine the structure and sites of attachment of their glycans. Tryptic digests of these lectins were analyzed by capillary electrophoresis coupled to electrospray mass spectrometry (CE-ESMS). Assignments were made by comparing the molecular masses of the observed tryptic peptides with those of Erythrina corallodendron lectin (ECorL), the sequence of which had been established previously. Glycan structure and genetic variations in the amino acid sequence were probed by tandem mass spectrometry. Small differences were found between the sequences of the various lectins examined and all of them exhibited C-terminal processing resulting in proteins with a C-terminal Asn residue. The major glycan of these glycoproteins was shown to be the heptasaccharide Man(3)XylFucGlcNAc(2), consistent with previous investigations on ECL and ECorL. A minor glycan heterogeneity was observed for most lectins examined except for that of ECafL and ECorL where an extra hexose residue was observed on the reducing GlcNAc residue of the heptasaccharide.

Amino Acid Sequence↗
PubMed2005

Common genetic variation at the endothelial nitric oxide synthase locus and relations to brachial artery vasodilator function in the community.

BACKGROUND: Sequence variants at the endothelial nitric oxide synthase (NOS3) locus have been associated with endothelial function measures, but replication has been limited. METHODS AND RESULTS: In reference pedigrees, we characterized linkage disequilibrium structure at the NOS3 locus using 33 common single nucleotide polymorphisms (SNPs). Eighteen SNPs that capture underlying common variation were genotyped in unrelated Framingham Heart Study participants (49.5% women; mean age, 62 years) with measured brachial artery flow-mediated dilation (n=1446) or hyperemic flow velocity (n=1043). Within 3 defined blocks of strong linkage disequilibrium that spanned NOS3, 11 SNPs captured >80% of common haplotypic variation. Among men, there were nominally significant associations between 8 NOS3 SNPs (minimum P=0.002) and between haplotypes (minimum P=0.002) and either flow-mediated dilation or hyperemic flow velocity. In women, we did not observe significant associations between NOS3 SNPs or haplotypes and endothelial function measures. To correct for multiple testing, we constructed 1000 bootstrapped null data sets and found that empirical probability values exceeded 0.05 for both phenotypes. CONCLUSIONS: A parsimonious set of SNPs captures common genetic variation at the NOS3 locus. A conservative interpretation of our results is that, accounting for multiple testing, we did not observe statistically significant relations between NOS3 sequence variants and endothelial function measures in either sex. The nominal associations of select NOS3 variants with endothelial function in men (unadjusted for multiple testing) should be viewed as hypothesis-generating observations and may merit testing in other cohorts and experimental designs.

Aged↗
PubMed2007

Genetic variation in the base excision repair pathway and bladder cancer risk.

Genetic polymorphisms in DNA repair genes may impact individual variation in DNA repair capacity and alter cancer risk. In order to examine the association of common genetic variation in the base-excision repair (BER) pathway with bladder cancer risk, we analyzed 43 single nucleotide polymorphisms (SNPs) in 12 BER genes (OGG1, MUTYH, APEX1, PARP1, PARP3, PARP4, XRCC1, POLB, POLD1, PCNA, LIG1, and LIG3). Using genotype data from 1,150 cases of urinary bladder transitional cell carcinomas and 1,149 controls from the Spanish Bladder Cancer Study we estimated odds ratios (ORs) and 95% confidence intervals (CIs) adjusting for age, gender, region and smoking status. SNPs in three genes showed significant associations with bladder cancer risk: the 8-oxoG DNA glycosylase gene (OGG1), the Poly (ADP-ribose) polymerase family member 1 (PARP1) and the major gap filling polymerase-beta (POLB). Subjects who were heterozygous or homozygous variant for an OGG1 SNP in the promoter region (rs125701) had significantly decreased bladder cancer risk compared to common homozygous: OR (95%CI) 0.78 (0.63-0.96). Heterozygous or homozygous individuals for the functional SNP PARP1 rs1136410 (V762A) or for the intronic SNP POLB rs3136717 were at increased risk compared to those homozygous for the common alleles: 1.24 (1.02-1.51) and 1.30 (1.04-1.62), respectively. In summary, data from this large case-control study suggested bladder cancer risk associations with selected BER SNPs, which need to be confirmed in other study populations.

Adult↗
PubMed2005

Novel genetic variations of the p53R2 gene in patients with colorectal adenoma and controls.

AIM: p53-inducible ribonucleotide reductase small subunit 2 (p53R2) encodes a 351-amino-acid peptide, which catalyzes conversion of ribonucleoside diphosphates to the corresponding deoxyribonucleotides required for DNA replication and repair. A recent study reported that a point mutation (G/T) in the p53 binding sequence in a colon cancer cell line completely impaired p53R2 protein activity. METHODS: We screened the p53R2 gene coding regions and a regulatory region which contains a p53 binding sequence in 100 patients with colorectal adenoma and 100 control subjects using PCR, cold SSCP, and direct DNA sequencing. RESULTS: Although we did not identify genetic variation in all nine exons, four regulatory-region variants were found, of which three were single nucleotide polymorphisms (SNPs) (nt 1 789 C/G, nt 1 928 A/G, 1 933 T/C), and one was 20 bp insertion which replaced a ATTTT between nt 1831 and 1835. Additionally, we determined the frequency of these p53R2 variants in a recently concluded case-control study of incident sporadic colorectal adenomas (163 cases and 210 controls). CONCLUSION: Although more detailed functional characterizations of these polymorphisms remain to be undertaken, these polymorphic sites may be useful for identifying alleles associated with mis-splicing, additional transcript factors and, more generally, in cancer-susceptibility association studies.

Adenoma↗
PubMed2003

The influence of the Miocene Mediterranean desiccation on the geographical expansion and genetic variation of Androcymbium gramineum (Cav.) McBride (Colchicaceae).

Chloroplast DNA (cpDNA) restriction site and isozyme data were combined to explore the spatial-temporal influence of the Messinian desiccation in the Mediterranean on the disjunct distribution of Androcymbium gramineum in Almería and Morocco (north and south of the straits of Gibraltar, respectively). Lack of evidence for different selective pressures, divergence time estimates based on the calibration of the isozyme molecular clock with the cpDNA data, the basal position of Almerian populations in the A. gramineum clade, and the much higher isozyme polymorphism in Almería suggest that (i) only a southern European range of A. gramineum existed before the Messinian [ approximately 11.2 million years ago (Ma), in the middle Miocene] and (ii) the desiccation of the Mediterranean basin about 5.5-4.5 Ma induced the migration of A. gramineum from Almería to Morocco (between 4.9 and 4.6 Ma, according to our time estimates). After the split into two allopatric units following the refilling of the Mediterranean, the major influence of drift associated with Plio-Pleistocene recurrent glaciation cycles and range expansions/contractions probably fostered the substantial interpopulation genetic differentiation observed within Almería (CGST = 0.41, average DNei = 0.185) and, to a lesser extent, within Morocco (CGST = 0.24, average DNei = 0.089), but did not hinder the maintenance of considerable levels of genetic variation in either geographical area (A = 2.14, HE = 0.230 and A = 1.90, HE = 0.213, respectively).

Climate↗