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PubMed1992

Genetic variation in resistance to parasitic infection: experimental approaches and practical applications.

Parasitic infections remain a major threat to the successful maintenance of domestic livestock. Control is still centered around management and husbandry, and the use of chemotherapeutic compounds. However, the spread of drug resistance in many important protozoal and helminth infections is placing an increasing emphasis on the development of alternative forms of control. At the present time vaccination is available for only a limited number of parasites, and may never be practical or cost-effective for some of the most important infections. This review examines current views of the mechanisms, control and likely value of genetically determined differences in resistance to parasitic infection. There is an extensive literature dealing with experimental analyses of genetic variation to parasitic infection in both laboratory and domestic species, and a growing interest in the application of this information in the field of practical parasite control.

Animals↗

PubMed2004

TOLL-like receptor 10 genetic variation is associated with asthma in two independent samples.

TOLL-like receptor 10 (TLR10) is the most recently identified human homolog of the Drosophila TOLL protein. In humans, the TOLL-like receptors recognize pathogen-associated molecular patterns (PAMPs) as part of innate immune host defenses. Localized to chromosome 4p14, the specific ligands and functions of TLR10 are currently unknown, although it is expressed in lung and in B-lymphocytes. TLR10 is a potential asthma candidate gene because early life innate immune responses to ubiquitous inhaled allergens and PAMPs may influence asthma susceptibility. Resequencing in 47 subjects revealed a total of 78 single nucleotide polymorphisms (SNPS) (1 SNP per 106 bp) of which only 11 had been previously published. A significant association (p < or = 0.02) between two SNPs (c.+1031G>A, c.+2322A>G) and physician-diagnosed asthma was observed in a case control study (517 cases, 519 control subjects) of European American subjects nested within the Nurses' Health Study cohort. The association for these same two SNPs (p < or = 0.015) replicated in an independent family based cohort, where a measure of airway hyperresponsiveness (PC20) was also associated (p = 0.026 for c.+1031G>A). Consistent association in two independent samples and association with an intermediate phenotype provides strong support for TLR10 genetic variation contributing to asthma risk.

Black or African American↗

PubMed1998

Genetic variation in the amino-terminal part of apolipoprotein B: studies in hyperlipidemic patients.

Hypertriglyceridemia is a heterogeneous lipid disorder often running in families. Variation in the apolipoprotein B (apo B) gene has been associated with serum triglyceride levels. Recently, a role of the amino-terminal end of apo B in binding with lipoprotein lipase (LPL) has been suggested. We screened the 5' end of the apo B gene in 76 Finnish severely hypertriglyceridemic (> 6 mmol/l) patients, using a single-strand conformation polymorphism (SSCP) screening method. We detected a previously unreported polymorphic C2316-->A change, causing a Val703-->Ile substitution. The minor 703 Ile allele frequency was 0.04 in hypercholesterolemic and normolipidemic population samples. This allele was associated with lower serum triglyceride levels in a normolipidemic population sample. Analysis of two previously reported polymorphisms also located in the amino-terminal domain of apo B (Thr71-->Ile and Val591-->Ala) revealed elevating effects on serum apo B concentrations in hypertriglyceridemic individuals. The 591 Ala allele was associated with elevated apo B (P=0.011), and individuals with both minor alleles (apo B 591 Ala + and apo B 71 Ile +) had higher apo B levels compared to subjects homozygous for both common alleles (P=0.004). Although no DNA sequence change seemed to be the cause of hypertriglyceridemia in our patients, genetic variation in the 5' end of the apo B gene may contribute to changes in serum apo B levels in hypertriglyceridemic patients.

Adult↗

PubMed1992

Human GLUT4/muscle-fat glucose-transporter gene. Characterization and genetic variation.

Four overlapping DNA fragments spanning 32 kb containing the human GLUT4 facilitative glucose-transporter gene were isolated and characterized. The sequence of the GLUT4 gene (approximately 6.3 kb) and 2.0 kb of the promoter region was determined. The sequence of the promoter revealed potential binding sites for transcription factors known to regulate gene expression in muscle cells and adipocytes. However, transfection of constructs including 2 kb of the GLUT4 promoter fused to the bacterial CAT gene into 3T3-L1 adipocytes displayed only weak promoter activity. Because insulin resistance plays a prominent role in the development of NIDDM, genetic variation in the sequence of GLUT4 also was evaluated. Oligonucleotide primer pairs were selected that allowed the protein-coding region of the human GLUT4 gene to be amplified by PCR. The sequence of the protein-coding region of the GLUT4 gene and all intron-exon junctions was determined for a single diabetic Pima Indian and was identical to that of the cloned gene and cDNA. SSCP analysis was used to screen patients with diabetes mellitus and normal, healthy nondiabetic individuals for mutations at the GLUT4 locus. In addition to the silent substitution in the codon for Asn130 (AAC or AAT) and a Val383 (GTC)-->Ile(ATC) replacement described previously, two new variants were identified. One was a T-->A substitution in intron 1 that was found in 1 of 36 NIDDM patients who were typed for this variant. The second was a Ile385(ATT)-->Thr(ACT) replacement that occurred in 1 normal individual and was not found in any of 676 other normal and diabetic subjects. A large and racially diverse group of normal and diabetic individuals also was screened for the Ile383 polymorphism. It occurred in both diabetic and nondiabetic subjects. There is no indication from our data that these polymorphisms are associated with NIDDM.

3T3 Cells↗

PubMed2004

Using germ-line genetic variation to investigate and treat cancer.

For many years, there has been spirited debate as to the relative importance of environmental and genetic factors in the pathogenesis of cancer. Current efforts to annotate the human genome for germ-line genetic variants should establish the foundation for dissecting the contribution of genetics to the risk for cancer susceptibility. Population-based studies should be conducted to determine the influence of germline genetic variation on cancer outcomes, including the efficacy of anti-cancer drugs and the risk for life-threatening toxicities. Although we are early in the investigation of the influence of germline genetics on cancer outcomes, it is likely that, in the future, it will be possible to individualize therapeutic interventions. In turn, knowledge of genetic risk factors could afford opportunities for prevention, early intervention and minimization of deleterious toxicities associated with cancer therapy.

Antineoplastic Agents↗

PubMed2006

Genome-wide investigation on the genetic variations of rice disease resistance genes.

Exploitation of plant disease resistance (R) gene in breeding programs has been proven to be the most efficient strategy for coping with the threat of pathogens. An understanding of R-gene variation is the basis for this strategy. Here we report a genome-wide investigation on the variation of NBS-LRR-encoding genes, the common type of R genes, between two sequenced rice genomes, Oryza sativa L. var. Nipponbare and 93-11. We show that the allelic nucleotide diversity in 65.0% of 397 least-divergent pairs is not high (0.344% on average), while the remaining 35% display a greater diversity (5.4% on average). The majority of conserved R genes is single-copy and/or located as a singleton. The clustered, particularly the complex-clustered, R-genes contribute greatly to the rich genetic variation. Surprisingly only 11.2% of R-genes have remarkably high ratios of non-synonymous to synonymous rates, which is much less than the 17.4% observed between Arabidopsis genomes. Noticeable "artificially selective sweeping" could be detected in a large proportion of the conserved R-genes, a scenario described in the "arms race" co-evolutionary model. Based on our study, a variation pattern of R-genes is proposed and confirmed by the analysis of R-genes from other rice lines, indicating that the observed variation pattern may be common in all rice lines.

Genes, Plant↗

PubMed2005

[Epigenetic control, development and natural genetic variation in plants].

Plant life strategies differ radically from those of most animals. Plants are not motile, and can only face stress by developing appropriate physiological responses. In addition, many developmental decisions take place during post-embryonic life in plants, whereas vertebrate and invertebrate development is nearly complete by the time of birth. For instance, while the germ line is typically set aside early during embryogenesis in animals, plants produce gametes from stem cell populations that were previously used for the vegetative growth of shoots. Nevertheless, plants and animals have similar nuclear organization, chromatin constitution and gene content, which raises the question as to whether or not fundamental differences in the use of genetic information underlie their distinct life strategies. More specifically, we would like to know if chromatin and the epigenetically defined, heritable cell fates that it can confer play comparable roles in plants and animals. Here we review our current knowledge on chromatin-mediated epigenetic processes in plants. Based on available evidence, we argue that epigenetic regulation of gene expression plays a relatively minor role in plants compared to mammals. Conversely, plants appear to be more prone than other multicellular organisms to the induction of chromatin-based, epigenetically modified gene activity states that can be transmitted over many generations. These so-called "epimutations" may therefore represent a significant proportion of the natural genetic variation seen in plants. In humans, epimutations are frequently observed in cancers, and given their metastable nature, they could also play an important role in familial disorders that do not demonstrate clear Mendelian inheritance.

Epigenesis, Genetic↗

PubMed1996

Genetic variation in immediate and delayed postictal refractory period in rats.

We determined postictal refractoriness in Sprague-Dawley rats by comparing lengths of two suprathreshold ECS seizures given 15 s to 24 h apart. A bimodal (immediate and delayed) decrease in seizure duration was found, suggesting ECS alters mechanisms of seizure termination. Since adenosine is implicated in seizure termination, we determined immediate (30 s) and delayed (24 h) postictal ECS refractoriness in Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats which vary in adenosine properties and initial ECS seizure length. At 30 s, the decrease in seizures did not differ between WKY (-44%) and SHR (-36%) rats. At 24 h, SHR rats showed no change while the WKY rats showed a 20% decrease in seizure length (P < 0.01). These two strains also differed in the ability of the adenosine antagonist caffeine (50 mg/kg, i.p.) to prolong ECS seizures (no change for WKY, +13% for SHR, P < 0.001). The results suggest immediate and delayed postictal refractoriness are subject to genetic variation and may depend on central adenosine mechanisms.

Adenosine↗

PubMed2006

Genetic variation for the response to ploidy change in Zea mays L.

Polyploidization is an important process in the evolutionary history of most eukaryotic species. It oftentimes causes large-scale genomic reorganizations and is accompanied by a wide variety of phenotypic alterations in morphology, niche preference and fitness characteristics. Despite their importance, the morphological effects of alterations in ploidy are not well understood. We investigated these changes in four diverse maize inbred lines, using monoploid, diploid, triploid and tetraploid derivatives, measuring 13 characters in a randomized field study. Employing several analysis of variance approaches, we find that all characters investigated strongly respond to alterations in ploidy. This response appears to have two sources: one source is shared by all inbred lines and constitutes a common response to ploidy change. The other source is genotype specific and results in a response to ploidy change that varies among inbred lines. This finding demonstrates the existence of genetic variation for the morphological response to ploidy change in Zea mays.

Analysis of Variance↗

PubMed2005

Genetic variation in leptin receptor gene is associated with type 2 diabetes and body weight: The Finnish Diabetes Prevention Study.

OBJECTIVE: Genetic variation in leptin receptor (LEPR) gene has been reported to associate with insulin and glucose metabolism and adiposity in different study settings and various populations. We wanted to evaluate the association between LEPR polymorphisms, diabetes risk and body weight in Finnish subjects with impaired glucose tolerance (IGT). METHODS: We investigated the associations of the three LEPR polymorphisms (Lys109Arg, Gln223Arg, 3'UTR Del/Ins) with the conversion to type 2 diabetes and the changes in body weight in 507 individuals with IGT participating in the Finnish Diabetes Prevention Study. Participants were randomized to either an intensive diet and exercise intervention group or a control group. RESULTS: After 3 years, the odds ratio for the development of type 2 diabetes in individuals in the control group with the Lys109Lys genotype was 2.38-fold higher than in individuals with other genotype combinations (P=0.016). Irrespective of group individuals with the Gln223Gln genotype had higher conversion to type 2 diabetes (OR 2.01 (95% CI 1.03-3.93)) than the Arg223 allele carriers (P=0.042). The risk was more pronounced in the control group than in the intervention group. Individuals having the 3'UTR Del/Del genotype had a slightly higher body weight throughout the study than those with the insertion allele (P=0.020), although no difference in weight change was observed. CONCLUSION: Two polymorphisms (Lys109Arg, Gln223Arg) in the extracellular domain of the leptin receptor predicted the conversion to type 2 diabetes in high-risk individuals with IGT. The Del/Ins polymorphism in the 3'UTR of LEPR was associated with body weight.

Adult↗

PubMed2005

Low genetic variation and inbreeding depression in small isolated populations of the Japanese rosy bitterling, Rhodeus ocellatus kurumeus.

The Japanese rosy bitterling, Rhodeus ocellatus kurumeus, has been affected not only by the invasion of another subspecies, R. o. ocellatus, from China, but also by habitat fragmentation. In this study, the effects of habitat fragmentation on the fitness of R. o. kurumeus were investigated. Owing to exclusion by R. o. ocellatus, R. o. kurumeus in Honshu and Shikoku has disappeared entirely, except for small populations in isolated man-made ponds in Osaka and Kagawa. In Kyushu it still occupies open water systems, into which R. o. ocellatus has only recently invaded. Meristic and genetic data show that the diversity of R. o. kurumeus is significantly lower in the isolated Osaka and Kagawa populations than the non-isolated Fukuoka population. The Osaka population is inferior to the Fukuoka population in terms of viability and growth. The viability of reciprocal inter-population hybrids between the Osaka and Fukuoka populations was, however, as high as that of the Fukuoka population. In addition to the high scores of band sharing index (BSI) in RAPD-PCR analysis, acceptance of transplanted scales among individuals, irrespective of natal pond, indicates that the Osaka population forms a highly inbred line. These results suggest that low genetic variation is associated with inbreeding depression in the small isolated Osaka populations. Consequently, the management of ponds, including the free movement of individuals, in addition to measures to prevent the invasion of R. o. ocellatus, is necessary for the conservation of R. o. kurumeus.

Animals↗

PubMed2006

Genetic variation in N-acetyltransferase 1 (NAT1) and 2 (NAT2) and risk of non-Hodgkin lymphoma.

Animal studies suggest that lymphomagenesis can be induced by exposure to carcinogenic aromatic and heterocyclic amines found in diet, cigarette smoke and the environment, but human epidemiologic investigations of these exogenous exposures have yielded conflicting results. As part of our evaluation of the role of aromatic and heterocyclic amines, which are metabolized by N-acetyltransferase (NAT) enzymes, in the etiology of non-Hodgkin lymphoma (NHL), we examined NHL risk in relation to genetic variation in NAT1 and NAT2 and exposure to cigarette smoke and dietary heterocyclic amines and mutagens. We genotyped 10 common single nucleotide polymorphisms (SNPs) in NAT1 and NAT2 among 1136 cases and 922 controls from a population-based case-control study in four geographical areas of the USA. Relative risk of NHL for NAT1 and NAT2 genotypes, NAT2 acetylation phenotype, and exposure to cigarette smoke and dietary heterocyclic amines and mutagens was estimated using odds ratios (ORs) and 95% confidence intervals (CIs) derived from unconditional logistic regression models. We observed increased risk of NHL among individuals with the NAT1*10/*10 genotype compared with individuals with other NAT1 genotypes (OR = 1.60, 95% CI = 1.04-2.46, P = 0.03). We also observed increased NHL risk in a dose-dependent model among NAT2 intermediate- and rapid-acetylators compared with slow-acetylators, although only the trend was statistically significant (intermediate: OR = 1.18, 95% CI = 0.97-1.44, P = 0.1; rapid: OR = 1.43, 95% CI = 0.97-2.14, P = 0.07; P for linear trend = 0.03). Compared with non-smokers, NHL risk estimates for current cigarette smoking were increased only among NAT2 intermediate/rapid-acetylators (OR = 2.44, 95% CI = 1.15-5.20, P = 0.02). Our data provide evidence that NAT1 and NAT2 genotypes are associated with NHL risk and support a contributory role for carcinogenic aromatic and/or heterocyclic amines in the multi-factorial etiology of NHL.

Adult↗

PubMed1985

Genetic variation in North Amerindian populations: covariance with climate.

Allelic frequencies at seven polymorphic loci in 74 North Amerindian populations are examined relative to patterns of climatic variation. Canonical correlation analysis reveals strong and significant associations of heterozygosity at the ABO, Ss, Duffy, and P loci with climatic variability. Principal component analysis demonstrates that these loci tend to form correlated ensembles. Moreover, canonical correlation analysis of component scores provides support for an association between polymorphism at these loci and environmental variability. The results are concordant with two previous investigations which suggested a relationship between polymorphism for the ABO, Duffy, and Diego systems and climate. It is suggested that the examination of broad geographic patterns of genetic variation at multiple loci is a valuable, but underutilized, method of screening for the effects of long-term systematic pressures.

Climate↗

PubMed2002

Revisiting the question of limited genetic variation within Schistosoma japonicum.

Recent electrophoretic data have indicated that Schistosoma japonicum in mainland China may be a species complex, with the existence of a cryptic species being predicted from the analysis of schistosome populations from Sichuan province. To investigate the Sichuan form of S. japonicum, 4.9 kbp of mitochondrial DNA from each of three samples of the parasite from China (two from Sichuan and one from Hunan) and one from Sorsogon in the Philippines were amplified, sequenced and characterized. The sequence data were compared with those from the related South-east Asian species of S. mekongi (Khong Island, Laos) and S. mlayensis (Baling, Malaysia) and that from S. japonicm from Anhui (China). At both the nucleotide and amino-acid levels, the variation among the five S. japonicum samples was limited (< 1%). This was consistent with the conclusions drawn from previous molecular studies, in which minimal variation among S. japonicum populations was also detected. In contrast, S. mekongi and S. malayensis, species recognized as separate but closely related, differ from each other by about 10%, and each differs by 25%-26% from S. japonicum. Phylogenetic trees provided a graphic representation of these differences, showing all S. japonicum sequences to be very tightly clustered and distant from S. mekongi and S. malayensis, the last two being clearly distinct from each other. The results thus indicate no significant intra-specific genetic variation among S. japonicum samples collected from different geographical areas and do not support the idea of a distinct form in Sichuan.

Amino Acid Sequence↗

PubMed2002

Association between genetic variation in the gene for insulin-like growth factor-I and low birthweight.

Low birthweight is associated with later risk of type 2 diabetes and related disorders. We aimed to show that a polymorphism in the gene for insulin-like growth factor-I, which has proved to raise risk of type 2 diabetes and myocardial infarction, is associated with low birthweight. We recorded birthweight and obtained DNA for 463 adults. Individuals who did not have the wild-type allele of the polymorphism had a 215 g lower birthweight than those homozygous for this allele (95% CI -411 to -10). Our data lend support to the hypothesis that genetic variation affecting fetal growth could account for the association between low birthweight and susceptibility to diabetes and cardiovascular disease in later life.

Adult↗

PubMed2006

Genetic variation of Chinese PRRSV strains based on ORF5 sequence.

Thirteen isolates of porcine reproductive and respiratory syndrome virus (PRRSV) from different provinces of China were studied and compared with several PRRSV isolates from other countries. Phylogenetic analysis shows that all Chinese isolates of PRRSV in this study belong to the American genotype, except for one strain, B13, which clustered as a European genotype. Sequence analysis revealed that PRRSV Chinese isolates of the American genotype were highly similar in the ORF5 sequence and could be classified into two subclades. One contains PRRSV isolates that are more closely related to the American vaccine strain MLV Resp and its parent strain VR-2332, and the other contains ones only distantly related to them. Within the Chinese isolates slight genetic variation occurred, and some strains may originate directly from the vaccine virus.

Amino Acid Sequence↗

PubMed2004

Alpha-1-antitrypsin levels and genetic variation of the alpha-1-antitrypsin gene in Peyronie's disease.

OBJECTIVES: Alpha-1-antitrypsin (alpha1-antitrypsin) is a major protease inhibitor controlling tissue degradation. Reduced alpha1-antitrypsin levels could result in a change of collagen metabolism. Previous studies have described decreased alpha1-antitrypsin levels in patients with Peyronie's disease. However, only a small number of patients were analyzed, and the reason for the decreased alpha1-antitrypsin levels remained unclear. This study investigated prospectively the levels of alpha1-antitrypsin in patients with Peyronie's disease, as well as genetic variation in the coding region of the alpha1-antitrypsin gene. METHODS: Alpha1-antitrypsin levels were determined prospectively in 94 patients with Peyronie's disease and compared to healthy controls. Analysis of the alpha1-antitrypsin gene (S, Z variants; single nucleotid polymorphisms [SNPs]: T-395A, M2, M3, G6118A) was done in 141 Peyronie's patients including 43 patients with investigated alpha1-antitrypsin serum levels and compared to healthy controls. RESULTS: In patients with Peyronie's disease, the alpha1-antitrypsin levels seemed to be decreased significantly compared to healthy controls. However, in the age matched approach no significant differences occurred. Moreover, a significant (p < 0.002) decrease of the alpha1-antitrypsin level with increasing age was observed, explaining the initial differences between the two groups. In confirmation with these findings, no significant association of the alpha1-antitrypsin gene variants with Peyronie's disease was detectable. CONCLUSIONS: The results of this study do not indicate a significant association between Peyronie's disease and decreased alpha1-antitrypsin levels. Low alpha1-antitrypsin levels in Peyronie's patients are, rather, an age-related phenomenon, as revealed by the comparison with aged matched healthy controls. The decrease of the alpha1-antitrypsin serum level with increasing age has not been described before.

Adolescent↗

PubMed2000

Increase of genetic variation over time in a recently founded population of great reed warblers (Acrocephalus arundinaceus) revealed by microsatellites and DNA fingerprinting.

Genetic similarity within pairs of individuals was examined using both 10 polymorphic microsatellite loci and multi-locus DNA fingerprinting profiles in a semi-isolated population of great reed warblers at Lake Kvismaren, south Central Sweden, in 1987-1993. The population was founded by a few individuals in 1978, followed by a gradual increase in numbers until 1988, since when the population has remained relatively stable with about 60 breeding birds. We have previously found that high genetic similarity between pair-mates in the population during the early part of the study period reduced egg hatching success, and hence reproductive success. The measures of pairwise genetic similarity, microsatellite allele sharing and DNA fingerprinting band sharing, were highly correlated with pedigree-based relatedness. Both microsatellite and DNA fingerprinting similarities between pair-mates declined significantly over the study period, and the pattern was most pronounced in the DNA fingerprinting data. Analyses restricted to the microsatellite data showed that the average annual microsatellite similarity between pairwise combinations of individuals, as well as individual homozygosity in males, declined significantly over the study period, and that several immigrants carrying novel alleles entered the population during the study. Hence, the temporal decline in genetic similarity of mates in the population is probably a consequence of increased immigration, facilitated by the recent expansion of the species in the region. These results suggest that the population has now recovered genetically, or is in the process of recovering, from a recent founder event.

Animals↗