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PubMed2006

24-h ambulatory blood pressure is linked to chromosome 18q21-22 and genetic variation of NEDD4L associates with cross-sectional and longitudinal blood pressure in Swedes.

Numerous linkage studies have indicated chromosome 18q21-22 as a locus of importance for blood pressure regulation. This locus harbors the neural precursor cell expressed developmentally downregulated 4-like (NEDD4L) gene, which is instrumental for the regulation of the amiloride-sensitive epithelial sodium channel (ENaC). In a linkage study of 16 markers (including two single nucleotide polymorphism markers located within the NEDD4L gene) on chromosome 18 between 70-104 cM and ambulatory blood pressure (ABP), in 118 families, the strongest evidence of linkage was found for 24 h and day-time systolic ABP at the NEDD4L locus (82.25 cM) (P=0.0014). In a large population sample (n=4001), we subsequently showed that a NEDD4L gene variant (rs4149601), which by alternative splicing leads to varying expression of a functionally crucial C2 domain, was associated with diastolic blood pressure (DBP) (P=0.03) and DBP progression over time (P=0.04). A genotype combination of the rs4149601 and an intronic NEDD4L marker (rs2288774) was associated with systolic blood pressure (SBP) (P=0.01), DBP (P=0.04), and progression of both SBP (P=0.03) and DBP (P=0.05) over time. A quantitative transmission disequilibrium test in the family material of the rs4149601 supported this NEDD4L variant as being at least partially causative of the linkage result. In conclusion, our findings suggest that the chromosome 18 linkage peak at 82.25 cM is explained by genetic NEDD4L variation affecting cross-sectional and longitudinal blood pressure, possibly as a consequence of altered NEDD4L interaction with ENaC.

Adult↗
PubMed2000

Genetic variation and population structure in the endangered greater horseshoe bat Rhinolophus ferrumequinum.

Following a dramatic decline last century, the British population of the endangered greater horseshoe bat Rhinolophus ferrumequinum is highly fragmented. To examine the consequences of fragmentation and limited dispersal on patterns of genetic structure and variation, we used microsatellite markers to screen bats from around 50% of the known maternity colonies in Britain, and two areas from continental Europe. Analyses revealed that Welsh and English colonies were genetically isolated. This, and lower variability in Britain than north France, may result from either genetic drift, or the species' colonization history. Gene flow among most neighbouring colonies was not generally restricted, with one exception. These findings have important implications for the ongoing conservation management of this species.

Animals↗
PubMed2003

Impact of selection, mutation rate and genetic drift on human genetic variation.

The accumulation of genome-wide information on single nucleotide polymorphisms in humans provides an unprecedented opportunity to detect the evolutionary forces responsible for heterogeneity of the level of genetic variability across loci. Previous studies have shown that history of recombination events has produced long haplotype blocks in the human genome, which contribute to this heterogeneity. Other factors, however, such as natural selection or the heterogeneity of mutation rates across loci, may also lead to heterogeneity of genetic variability. We compared synonymous and non-synonymous variability within human genes with their divergence from murine orthologs. We separately analyzed the non-synonymous variants predicted to damage protein structure or function and the variants predicted to be functionally benign. The predictions were based on comparative sequence analysis and, in some cases, on the analysis of protein structure. A strong correlation between non-synonymous, benign variability and non-synonymous human-mouse divergence suggests that selection played an important role in shaping the pattern of variability in coding regions of human genes. However, the lack of correlation between deleterious variability and evolutionary divergence shows that a substantial proportion of the observed non-synonymous single-nucleotide polymorphisms reduces fitness and never reaches fixation. Evolutionary and medical implications of the impact of selection on human polymorphisms are discussed.

Animals↗
PubMed2005

Genetic variations of tubular sodium reabsorption leading to "primary" hypertension: from gene polymorphism to clinical symptoms.

The definition of the most appropriate strategy to demonstrate causation of a given genetic-molecular mechanism in a complex multifactorial polygenic disease like hypertension is hampered by the underestimation of the complexity arising from the genetic and environmental interactions. To disentangle this complexity, we developed a strategy based on six steps: 1) isolation of a rodent model of hypertension (Milan hypertensive strain and Milan normotensive strain) that shares some pathophysiological abnormalities with human primary hypertension; 2) definition in the model of the sequence of events linking these abnormalities to a genetic molecular mechanism; 3) determination of the polymorphism of the three adducin genes discovered in the model both in rats and in humans; 4) comparison at biochemical and physiological levels between the rodent models and the hypertensive carriers of the "mutated" gene variants; 5) evaluation of the impact of the adducin genes in hypertension and its organ complications with association and linkage studies in humans, also considering the genetic and environmental interactions; and 6) development of a pharmacogenomic approach aimed at establishing the therapeutic benefit of a drug interfering with the sequence of events triggered by adducin and their effect's size. The bulk of data obtained demonstrates the importance of a multidisciplinary approach considering a variety of genetic and environmental interactions. Adducin functions within the cells as a heterodimer composed of a combination of three subunits. Each of these subunits is coded by genes mapping to different chromosomes. Therefore, the interaction among these genes, taken together with the interactions with other modulatory genes or with the environment, is indispensable to establish the adducin clinical impact. The hypothesis that adducin polymorphism favors the development of hypertension via an increased tubular sodium reabsorption is well supported by a series of consistent experimental and clinical data. Many mechanistic aspects, underlying the link between these genes and clinical symptoms, need to be clarified. The clinical effect size of adducin must be established also with the contribution of pharmacogenomics with a drug that selectively interferes with the sequence of events triggered by the mutated adducin.

Animals↗
PubMed1991

Rapid identification of genetic variation and pathotype of Leptosphaeria maculans by random amplified polymorphic DNA assay.

Canadian isolates of Leptosphaeria maculans, the causal agent of blackleg of crucifers, were examined for genetic relatedness by the random amplified polymorphic DNA assay. DNA polymorphisms amplified with random decamer primers were used to distinguish three groups of isolates. Group 1 contained all isolates of the virulent pathotype, group 2 contained isolates of the avirulent pathotype from western Canada, and group 3 contained avirulent pathotype isolates from Ontario. These results agreed with other reports which showed many genetic differences between pathotypes and were consistent with the hypothesis that the virulent pathotype was recently introduced into Canada and has diverged relatively little. In contrast, the avirulent pathotype has probably been present in Canada for a longer time and has diverged with geographic isolation. In addition to establishing genetic relationships, DNA fingerprints generated by the random amplified polymorphic DNA assay have potential applications in pathotype identification and blackleg disease management.

Ascomycota↗
PubMed2001

Genetic variation in the promoter region of the beta2 bradykinin receptor gene is associated with essential hypertension in a Chinese Han population.

The present study examined whether a genetic variant (-58T/C) in the promoter region of the human beta2 bradykinin receptor gene was genetically involved in essential hypertension. Chinese hypertensive subjects (n = 120) and normotensive controls (n = 98; sex- and age-matched with hypertensives) were recruited from the outpatients of Fu Wai hospital. Distribution of the -58T/C polymorphism was determined in patients and controls by means of PCR, SSCP, cloning and sequencing. The allelic frequencies were 0.56 for the C allele and 0.44 for the T allele in hypertensive subjects, and 0.46 for the C allele and 0.54 for the T allele in normotensive subjects. The allelic frequencies were in Hardy-Weinberg equilibrium. Significant differences between hypertensive and normotensive subjects were seen in the genotypes distribution (p = 0.045) and allelic frequencies (p = 0.033). These results suggested that -58C allele of the human beta2 bradykinin receptor gene may be an independent risk factor for essential hypertension in the Chinese Han population.

Aged↗
PubMed1988

Genetic variation within a linguistic group: Apalai-Wayana and other Carib tribes.

A total of 136 individuals were studied in relation to 31 genetic systems, and the results were compared with South American Indian averages and previous surveys on the Wayana of French Guiana and Surinam. The information was afterwards integrated with data from other Carib groups, and two types of genetic distances (Nei's and Edwards') were calculated a) between five groups, considering ten systems; and b) between nine groups, using five systems. The two measures of genetic distances correlated well (Spearman's correlation coefficient around 0.70), and there was good agreement between the geographical and genetic distances. All analyses indicated a peripheral position for the Apalai-Wayana and their distinctiveness from the Wayana of French Guiana and Surinam, suggesting that intertribal fusions may play an important role in the genetic differentiation of these populations.

Anthropology, Physical↗
PubMed2003

Used leucodepletion filters as a source of large quantities of DNA suitable for the study of genetic variations in human populations.

UNLABELLED: A simple technique for developing large control panels with large quantities of DNA suitable for studies in population genetics was established. BACKGROUND AND OBJECTIVES: Both a lack of suitable controls and insufficient quantities of DNA for repeated analysis of the same control group often hamper the investigation of genetic markers for disease. MATERIALS AND METHODS: Using a waste product from routine blood donation, we describe a simple method that allows the investigator to extract large amounts of DNA. RESULTS: A mean of 1520 microg of DNA per sample was obtained. The DNA obtained remains suitable for polymerase chain reaction and sequencing techniques after 2 years of storage at both 4 degrees C and -40 degrees C. CONCLUSION: This technique allows the development of a large panel of controls with sufficient quantities of genomic DNA for thousands of tests.

Blood Donors↗
PubMed2003

Genetic variation in oocyte phenotype revealed through parthenogenesis and cloning: correlation with differences in pronuclear epigenetic modification.

Previous studies revealed that oocytes of different genetic strains (e.g, C57BL/6 and DBA/2) modify maternal and paternal pronuclei differently, affecting early preimplantation development. To determine whether these strain-dependent effects would also apply to oocyte modifications of somatic cell nuclei introduced during cloning procedures, we compared the efficiency of development of parthenogenetic and cloned embryos made with DBA/2, C57BL/6, and (B6D2)F1 oocytes. Our results reveal significant differences in the ability of oocytes of different genetic backgrounds to support parthenogenetic development in different culture media. Additionally, our results reveal oocyte strain-dependent differences in the ability to support cloned embryo development beyond what can be accounted for on the basis of differences in parthenogenesis. Thus, the previously documented differences in oocyte-directed parental genome modification are accompanied in the same strains by differences in the ability of oocytes to modify somatic cell nuclei and support clonal development, raising the possibility that these oocyte functions may be mediated by related mechanisms. These results provide a genetic basis for further studies seeking to identify specific genes that determine oocyte phenotype, as well as genes that determine the success of nuclear reprogramming and clonal development.

Animals↗
PubMed1997

HIV-2 genetic variation and DNA load in asymptomatic carriers and AIDS cases in Guinea-Bissau.

The purpose of this study was to document which genetic subtypes of HIV-2 are present in Guinea-Bissau and to investigate whether asymptomatic HIV-2 carriers and AIDS patients carry distinct genetic variants. A secondary aim was to correlate proviral DNA load to clinical and immunologic status of the patients. Thirty-eight asymptomatic HIV-2 carriers and 11 AIDS patients from Bissau, Guinea-Bissau were included in a cross-sectional study in which HIV-2 env V3 sequences, HIV-2 DNA load, and CD4-positive (CD4+) lymphocyte counts were determined. Phylogenetic analyses showed that all investigated subjects carried subtype A HIV-2 variants and that the sequences from AIDS patients and asymptomatic carriers did not form distinct subclusters in the tree. As expected, patients with AIDS had significantly higher median HIV-2 DNA load than did asymptomatic carriers (4.6 vs. 2.0 log10 HIV-2 DNA copies/10(6) CD4+ lymphocytes). Our study indicates that the HIV-2 epidemic in Guinea-Bissau is almost exclusively caused by subtype A HIV-2 variants and that the HIV-2 infections among the asymptomatic carriers and AIDS cases included in the study do not have distinct epidemiologic histories.

Acquired Immunodeficiency Syndrome↗
PubMed2006

How much genetic variation is stored in the seed bank? A study of Atriplex tatarica (Chenopodiaceae).

We investigated to what extent the soil seed bank differed genetically and spatially in comparison to three consecutive life history stages (seedlings, mature plants, and fruiting plants) in a natural population of Atriplex tatarica. Representatives of particular life history stages from twenty subunits within a large population were randomly collected and subjected to allozyme analysis. Comparison of population polymorphism among various life history stages showed significant differences in observed heterozygosity (H(O)) and F statistics (F(IS) and F(ST)), but nonsignificant ones in the cases of number of alleles per polymorphic locus (A) and gene diversity (H(S)). These results indicate an increasing number of heterozygotes, a decreasing level of inbreeding and an increase of the partitioning genetic diversity among populations with increasing population age. Spatial autocorrelation was used to calculate f, the average co-ancestry coefficient between individuals within distance intervals of two meters along a 39 m long transect. Significant positive fine scale genetic structure was detected in mature and fruiting plants but not in soil seeds and seedlings stages. The results of the presented study on A. tatarica indicated that significant differences exist in genetic differentiation, differentiation in allele frequencies and spatial autocorrelation among early (soil seeds and seedlings) and late (mature and fruiting plants) life history stages but not within early and late ones. This pattern suggests that, rather than storing genetic variability in the soil or germination and establishment success, self-thinning might be the major microselective force in populations of A. tatarica.

Alleles↗