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PubMed1974

Genetic variation in natural populations of five Drosophila species and the hypothesis of the selective neutrality of protein polymorphisms.

We have studied genetic variation at 30-32 loci coding for enzymes in natural populations of five species of Drosophila. The average proportion of heterozygous loci per individual is 17.7 +/- 0.4%. The average proportion of polymorphic loci per population is 69.2 +/- 2.6% or 49.8 +/- 2.2%, depending on what criterion of polymorphism is used. The following generalizations are advanced: (1) The amount of genetic polymorphism varies considerably from locus to locus. (2) At a given locus, populations of the same species are very similar in the amount and pattern of genetic variation. (3) However, at some loci large differences sometimes occur between local populations of the same species. (4) The amount of variation at a given locus is approximately the same in all five species. (5) When different species are compared, the pattern of the variation is either essentially identical or totally different at a majority of loci. We have tested the hypothesis that protein polymorphisms are selectively neutral by examining four predictions derived from the hypothesis. Our results are at variance with every one of the predictions. We have measured the amount of genetic differentiation, D, between taxa of various degrees of evolutionary divergence. The average value of D is 0.033 for local populations, 0.228 for subspecies, 0.226 for semispecies, 0.538 for sibling species, and 1.214 for morphologically distinguishable species. Our results indicate that a substantial degree of genetic differentiation (22.8 allelic substitutions for every 100 loci) occurs between allopatric populations that have diverged to the point where they might become different species if they were to become sympatric. However, very little additional genetic change is required for the development of complete reproductive isolation. After the speciation process is completed, species continue to diverge genetically from each other.

Alleles↗
PubMed2004

Systematic evaluation of genetic variation at the androgen receptor locus and risk of prostate cancer in a multiethnic cohort study.

Repeat length of the CAG microsatellite polymorphism in exon 1 of the androgen receptor (AR) gene has been associated with risk of prostate cancer in humans. This association has been the focus of >20 primary epidemiological publications and multiple review articles, but a consistent and reproducible association has yet to be confirmed. We systematically addressed possible causes of false-negative and false-positive association in >4,000 individuals from a multiethnic, prospective cohort study of prostate cancer, comprehensively studying genetic variation by microsatellite genotyping, direct resequencing of exons in advanced cancer cases, and haplotype analysis across the 180-kb AR genomic locus. These data failed to confirm that common genetic variation in the AR gene locus influences risk of prostate cancer. A systematic approach that assesses both coding and noncoding genetic variation in large and diverse patient samples can help clarify hypotheses about association between genetic variants and disease.

Aged↗
PubMed1976

Genetic variation of pancreatic esterase isozyme in Japanese quail.

A genetic variation was found in pancreatic esterases of Japanese quail which appeared to be arylesterase. It was found on the cathode side in the agar gel electrophoresis. Three phenotypes, A,B and AB, were observed. These phenotypes were shown to be controlled by one autosomal locus, designated as Es-4, with co-dominant alleles Es-4A and Es-4B. Es-4 esterase isozymes were detected in all the individuals from about 4 days of age, but the activity was very weak. However, it gradually increased to reach a level almost the same as that of a mature quail from about 15 days of age.

Age Factors↗
PubMed1999

Genetic variation at 9 autosomal microsatellite loci in Asian and Pacific populations.

Genetic variation at 9 autosomal microsatellite loci (CFS1R, TH01, PLA2A, F13A1, CYP19, LPL, D20S481, D20S473, and D20S604) has been characterized in 16 Asian and Oceanic populations, mostly from mainland and insular Southeast Asia. The neighbor-joining tree and the principal coordinates analysis of the genetic relationships of these populations show a clear separation of Papua New Guinea Highlanders and, to a lesser extent, Malayan aborigines (Orang Asli or Semai) from the rest of the populations. Although the number of markers used in this study appears to be inadequate for clarifying the patterns of genetic relationships among the studied populations, in the principal coordinates analysis a geographic trend is observed in the mainland and insular Southeast Asian populations. Furthermore, in an attempt to contrast the extent of variation between autosomal and Y-chromosome-specific microsatellite loci and to reveal potential differences in the patterns of male and female migrations, we have also compared genetic variation at these 9 autosomal loci with variation observed at 5 Y-chromosome-specific microsatellites in a common set of 14 Asian populations.

Asia↗
PubMed2001

Cambridge Healthtech Institute's Third Annual Conference on human genetic variation. 16-18 October 2000, Philadelphia, Pennsylvania, USA.

A major goal of pharmacogenomics is to identify the human genetic variation that influences susceptibility to complex diseases. Recently, theoretical statistical analyses have suggested that genes for complex diseases may be found by linkage disequilibrium (i.e., association). Single nucleotide polymorphism (SNP) susceptibility alleles for common diseases can occur at high frequencies in various populations and, thus, have a major impact on morbidity and mortality. To be successful, SNP mapping studies require successful teamwork, integrating clinicians, epidemiologists, molecular genetics experts, laboratory automation engineers, bioinformatics and database experts. New statistical methods are also developing rapidly and promise to further increase the power of these studies. A recent conference on human genetic variation provided an opportunity for experts in all of these disciplines to exchange ideas. At present, great technological challenges need to be overcome in order to increase the throughput greatly while lowering cost and still maintaining high accuracy for SNP genotyping. Although this approach is relatively new (at least on the scale now being contemplated), the large payoffs anticipated to accrue from the successful mapping of SNPs in disease genes has led the area to be very strongly supported by both public and private funding sources. The potential payoff for improving disease diagnosis and therapeutic efficacy, with better avoidance of adverse events based on SNP associations, is providing a tremendous incentive to move this effort forward at an ever-accelerating pace.

Genetic Predisposition to Disease↗
PubMed2005

Genetic variation in pro-inflammatory cytokines (interleukin-1beta, interleukin-1alpha and interleukin-6) associated with the aggressive forms, survival, and relapse prediction of breast carcinoma.

OBJECTIVES: Interleukin-1 (IL-1) and interleukin-6 (IL-6) are determining factors in the immune and inflammatory responses to tumors cells. Experimental data suggest that interleukin-1 and interleukin-6 play important roles in the development and progression of breast cancer. We designed a broad study to investigate the susceptibility and prognostic implications of the genetic variation in IL-1alpha, IL-1beta and IL-6 in breast carcinoma. EXPERIMENTAL DESIGN: We used the polymerase chain reaction and restriction enzyme digestion to characterize the genetic variation of IL-1alpha, IL-1beta and IL-6 in 305, unrelated Tunisian patients with breast carcinoma and 200 healthy control subjects. Associations between the genetic markers and the clinicopathological parameters, the specific overall survival rate (OVS) of breast carcinoma and the disease free-survival rate (DFS) were assessed using univariate and multivariate analyses. RESULTS: Both IL-6 (-597) GA and IL-6 (-174) GC heterozygous genotypes were found to be significantly associated with breast carcinoma (OR = 1.59, p = 0.024 and OR = 1.61, p = 0.022 respectively). A highly significant association was found between the (+3954) T allele of IL1-B gene and the aggressive phenotype of breast carcinoma as defined by the high histological grade, axillary lymph node metastasis and large tumor size. The IL-1alpha (-889) TT homozygous genotype showed a significant association with reduced disease-free survival and/or overall survival rate. The IL-1beta (+3954) TT, IL-6 (-597) GG and IL-6 (-174) GG homozygous genotypes were found to be associated with reduced DFS but not with overall survival. CONCLUSIONS: The polymorphisms in the promoter region of the IL-6 gene may represent a marker for the increased risk of breast carcinoma. Genetic variations in IL-1alpha, IL-1beta and IL-6 may predict the clinical outcome of breast carcinoma.

Adult↗
PubMed2005

Genetic variation in male and female reproductive characters associated with sexual conflict in Drosophila melanogaster.

Recent studies have shown that elevated mating, courtship and seminal substances affect female fitness negatively in Drosophila melanogaster. It has also been shown that males vary with respect to these characters and that male harm to females correlates positively with components of male fitness. These results suggest that there is sexual conflict over the effect of such male characters. An important component of this scenario is that females have evolved counteradaptations to male harm, but so far there is limited evidence for this. Here I define female resistance as the ability to withstand an increased exposure to males. Across 10 genetically differentiated lines of D. melanogaster, I found genetic variation among females in the reduction of lifespan that followed from exposure to males of different durations. There was also genetic variation among males with regards to the degree to which they decrease the lifespan of their mates. These results suggest that genetic variation for female ability to endure male sexually antagonistic adaptations exists and may play an important role in male-female coevolution.

Adaptation, Physiological↗
PubMed2006

Genetic variation and haplotype structure of the ABC transporter gene ABCG2 in a Japanese population.

The ATP-binding cassette transporter, ABCG2, which is expressed at high levels in the intestine and liver, functions as an efflux transporter for many drugs, including clinically used anticancer agents such as topotecan and the active metabolite of irinotecan (SN-38). In this study, to elucidate the linkage disequilibrium (LD) profiles and haplotype structures of ABCG2, we have comprehensively searched for genetic variations in the putative promoter region, all the exons, and their flanking introns of ABCG2 from 177 Japanese cancer patients treated with irinotecan. Forty-three genetic variations, including 11 novel ones, were found: 5 in the 5'-flanking region, 13 in the coding exons, and 25 in the introns. In addition to 9 previously reported nonsynonymous single nucleotide polymorphisms (SNPs), 2 novel nonsynonymous SNPs, 38C>T (Ser13Leu) and 1060G>A (Gly354Arg), were found with minor allele frequencies of 0.3%. Based on the LD profiles between the SNPs and the estimated past recombination events, the region analyzed was divided into three blocks (Block -1, 1, and 2), each of which spans at least 0.2 kb, 46 kb, and 13 kb and contains 2, 24, and 17 variations, respectively. The two, eight, and five common haplotypes detected in 10 or more patients accounted for most (>90%) of the haplotypes inferred in Block -1, Block 1, and Block 2, respectively. The SNP and haplotype distributions in Japanese were different from those reported previously in Caucasians. This study provides fundamental information for the pharmacogenetic studies investigating the relationship between the genetic variations in ABCG2 and pharmacokinetic/pharmacodynamic parameters.

ATP Binding Cassette Transporter, Subfamily G, Mem↗
PubMed2004

Genetic variations that regulate bone morphology in the male mouse skeleton do not define its susceptibility to mechanical unloading.

Genetics can substantially influence bone morphology and may define the skeleton's response to mechanical unloading. Recent data indicated that disuse produces different site-specific responses in the skeleton of genetically distinct adult female C3H/HeJ (C3H) and BALB/cByJ (BALB) mice; while disuse BALB mice had significantly less bone than age-matched controls in the distal and diaphyseal femur, the removal of weight bearing had a much smaller influence in C3H. Using adult male mice from these two inbred strains, the hypothesis was tested that interactions between genetic variations and anatomic location define bone morphology and its susceptibility to unloading. Four-month-old male BALB and C3H mice were either subjected to 21 days of hindlimb unloading or served as controls. Multiple cortical and trabecular regions within the distal and diaphyseal femur were analyzed by micro-computed tomography. C3H controls had significantly greater diaphyseal and metaphyseal cortical bone area (45% and 32%) and greater metaphyseal trabecular bone volume fraction (67%) than BALB controls, but epiphyseal trabecular bone volume fraction was similar between the two strains. Despite these substantial, site-specific differences in bone morphology, disuse induced similar changes in bone morphology in these two strains. Compared to controls, disuse BALB and C3H had significantly less metaphyseal (17% and 19%) and epiphyseal (10% and 13%) trabecular bone, while diaphyseal and metaphyseal cortical bone geometry was unaffected. These data indicate that the genetic variations that caused spatially nonuniform differences in trabecular and cortical bone morphology between the two strains had little influence on the susceptibility of a specific site to unloading. Cross-gender comparisons with previous data from female BALB and C3H mice further suggest strong interactions by which gender, genotype, and anatomical location define the response of the skeleton to the removal of weight bearing.

Animals↗
PubMedDate not supplied

Genetic variation in homothallic and hyphal swelling isolates of Pythium ultimum var. ultimum and P. utlimum var. sporangiferum.

Genetic variation in a collection of 22 Pythium ultimum isolates was analyzed using restriction fragment length polymorphisms (RFLPs), random amplified polymorphic DNA (RAPD), and sequence characterized amplified regions (SCARs) as genetic markers. Qualitative evidence for the occurrence of sexual outcrossing in the field, asexual mechanisms affecting variation, and differences in aggressiveness between isolates was found. Codominant SCAR and RFLP markers detected multiple alleles in several isolates. Genetic analysis of F1 progeny from a cross indicates that heterozygosity is one cause of multiple alleles and contributes to genetic variation. Segregation analysis of F2 progeny fit diploid expectations and supported the use of the molecular markers for phenetic analysis. One isolate contained three alleles at one locus suggesting that polyploidy, aneuploidy or heterokaryosis may also contribute to genetic variation. Phenetic analysis using UPGMA clustering of Nei's distance calculated from RFLP data, UPGMA clustering of similarity matrixes calculated from RAPD data, and principle component analysis of RAPD data revealed no clustering of the three morphological types of Pythium ultimum (var. ultimum, var. sporangiferum, and group HS). Our results suggest that the three morphological variants of this homothallic oomycete are not genetically distinct.

Base Sequence↗
PubMed2004

Haplotype diversity and SNP frequency dependence in the description of genetic variation.

Haplotype diversity is controlled by a variety of processes, including mutation, recombination, marker ascertainment and demography. Understanding the extent to which genetic variation at physically linked loci is co-inherited is crucial for the design of the HapMap project and the correct interpretation of the resulting data. In the absence of an analytical theory extensive coalescent simulations are used to disentangle the influence of all of these factors on haplotype diversity. In addition to these qualitative insights, this study also demonstrates (i) that marker spacing and frequency profoundly influence observed levels of haplotype diversity; (ii) that the spectrum of haplotypes contains information about how exhaustively genetic variation in a region is described by a given marker set; and (iii) that so-called haplotype blocks can be generated due by the stochasticity inherent in the recombination process without having to assume variation in the recombination rate.

Computer Simulation↗
PubMed2000

High genetic variation in leopards indicates large and long-term stable effective population size.

In this paper we employ recently developed statistical and molecular tools to analyse the population history of the Tanzanian leopard (Panthera pardus), a large solitary felid. Because of their solitary lifestyle little is known of their past or present population dynamics. Eighty-one individuals were scored at 18 microsatellite loci. Overall, levels of heterozygosity were high (0.77 +/- 0.03), with a small heterozygote deficiency (0.06 +/- 0.03). Effective population size (Ne) was calculated to be 38 000-48 000. A Ne:N ratio of 0.42 (average from four cat studies) gives a present population size of about 100 000 leopards in Tanzania. Four different bottleneck tests indicated that this population has been large and stable for a minimum of several thousand years. FST values were low and no significant genetic structuring of the population could be detected. This concurs well with the large migration values (Nm) obtained (>3.3 individuals/generation). Our analysis reveals that ecological factors (e.g. disease), which are known to have had major impact on other carnivore populations, are unlikely to have impacted strongly on the population dynamics of Tanzanian leopards. The explanation may be found in their solitary life-style, their often nonconfrontational behaviour toward interspecific competitors, or that any bottlenecks have been of limited size, localized, or too short to have affected genetic variation to any measurable degree. Since the genetic structuring is weak, gene flow is not restricted to within protected areas. Local loss of genetic variation is therefore not of immediate concern.

Alleles↗
PubMed2004

Deciphering genetic variations of proteome responses to water deficit in maize leaves.

The proteome of the basal part of growing Zea mays leaves was analyzed from 4 to 14 d after stopping watering and in well watered controls. The relative quantity of 46 proteins was found to increase in leaves of plants submitted to water deficit. Different types of responses were observed, some proteins showing a constant increase during water deficit, while others showed stabilization after a first increase or a transient increase. Isoforms encoded by the same gene showed different responses. The response to water deficit showed genetic variation. Some increased proteins were induced specifically in one of the two studied genotypes (e.g. ASR1) while others were significantly induced in both genotypes but to a different level or with different kinetics. Analyses of relations between protein quantities, relative water content (RWC) and abscisic acid (ABA) concentration allowed us to show that the quantitative variation of some proteins (e.g. ABA45 and OSR40 proteins) was linked to differences in ABA accumulation between the genotypes. Other proteins showed genetic variations that were not related to differences in water status or ABA concentration (e.g. a cystatin). Data obtained from these experiments, together with data from other experiments, contribute to the characterization of maize proteome response to drought in different conditions and in different genotypes. This characterization allows the search for candidate proteins, i.e. for protein whose genetic variation of expression could be partly responsible for the variability of plant responses to drought.

Dehydration↗
PubMed2003

Geographic and genetic variation in feeding preference for chemically defended seaweeds.

Genetic variation in tolerance for seaweed chemical defenses among populations of marine herbivores is poorly described, either because few marine studies have addressed the issue or because the feeding preferences of populations of marine herbivores rarely differentiate. We address this using the polyphagous amphipod Ampithoe longimana (Crustacea), which commonly consumes, and lives on, terpene-rich brown seaweeds in the tropical genus Dictyota. Previous work demonstrated that in areas where the amphipod and seaweeds overlap geographically, these chemically deterrent seaweeds provide the amphipod with spatial refuges from predation by omnivorous fishes that avoid consuming Dictyota. However, the amphipod's distribution extends northward of the seaweed's distribution, making this benefit of association unavailable to more northerly populations of amphipods. On average, populations sympatric with Dictyota have stronger feeding preference for Dictyota species and greater fitness when raised on Dictyota than do populations that are outside Dictyota's geographic endpoint. These results are consistent with the hypothesis that in areas where the amphipods co-exist with Dictyota, selection favors amphipods that tolerate Dictyota's chemical defenses and thereby access its enemy-free space. Amphipods allopatric with Dictyota are unable to tolerate Dictyota's chemical defenses, either because of selection, drift, or some mix of both forces. A trade-off between preference for Dictyota and for the chemically distinct seaweed Hypnea musciformis is suggested by the finding that populations with high preference for Dictyota tended to have lower preference for Hypnea. However, this population-level pattern appears to be the result of independent evolution and not a genetic trade-off: an analysis of full-sib families within a single population detected heritable variation in preferences for Dictyota and suggested this for Hypnea (although the latter was not statistically significant), yet no family-level covariation was detected. Phylogeographic analysis of mitocondrial DNA and nuclear sequences indicates a strong historical break between populations sympatric with Dictyota and populations more than 500 km beyond Dictyota's geographic endpoint. The historical separation of these most northerly populations could have allowed a random accumulation of alleles to effectively degrade tolerance for Dictyota, although selection may also be responsible for the degradation.

Amphipoda↗
PubMed2005

Genetic variation for expression of the sex determination pathway genes in Drosophila melanogaster.

Sequence polymorphisms result in phenotypic variation through the pathways of interacting genes and their products. We focused on transcript-level variation in the splicing pathway for sex determination - a model network defining downstream morphological characters that are dimorphic between males and females. Expression of Sex lethal, transformer, transformer2, doublesex, intersex and hermaphrodite was assayed with quantitative RT-PCR in 0- to 1-day-old adult males and females of 36 Drosophila melanogaster inbred lines. Abundant genetic variation in the transcript levels was found for all genes. Sex-specific splices had high concentrations in the appropriate sex. In the other sex, low but detectable concentrations were also observed. Abundances of splices strongly co-varied between sexes among genotypes, with little genetic variation strictly limited to one sex. The level of sexually dimorphic Yolk protein1 expression - an immediate downstream target of the pathway - was modelled as the target phenotype of the upstream sex determination pathway. Substantial genetic variation in this phenotype in males was explained by leaky splicing of female-specific transcripts. If higher transcript levels of the appropriate isoform of sex determination genes are beneficial in a sex, then stronger leakiness of the inappropriate transcript might be deleterious, perhaps contributing to the fitness trade-offs previously observed between the sexes.

Alternative Splicing↗
PubMed2005

The influence of genetic variation in oxidative stress genes on human noise susceptibility.

Noise induced hearing loss (NIHL) is a complex disease caused by an interaction between genetic and environmental factors. Damage in the cochlea as a result of noise exposure appears to be mediated by reactive oxygen species (ROS). To investigate whether genetic variation in the human protective antioxidant system is associated with high or low susceptibility to NIHL, genetic polymorphisms derived from genes involved in the oxidative stress response were analysed in the 10% most susceptible and 10% most resistant extremes of 1200 Swedish noise-exposed workers. The genetic polymorphisms included 2 deletion polymorphisms for the GSTM1 and GSTT1 gene, and 14 SNPs derived from the CAT, SOD, GPX, GSR and GSTP1 genes. No significant differences were found between susceptible and resistant groups, providing no support for a major role of genetic variation of antioxidant enzymes in the susceptibility to NIHL.

Audiometry↗
PubMed2005

Genetic variations in the pgm locus among natural isolates of Yersinia pestis.

A PCR-based screening method was used to study the genetic variations of the pgm locus among natural isolates of Yersinia pestis from China. Our results indicate that genetic variations in the pgm locus are well correlated with biovars of Y. pestis and plague foci, suggesting that the pgm locus plays a role in Y. pestis adaptation to its environment. The gene encoding two-component regulatory system sensor kinase became a pseudogene in all strains of biovar Orientalis due to a thymidine deletion, while it is intact in all the strains of the other biovars. Only strains from Foci H and L are the same as Yersinia pseudotuberculosis in that they have an intact transmembrane helix in the sensor kinase protein, which is lost in all the other strains because of the 18 bp in-frame deletion. The IS100 element that flanks the 39 terminus of the pgm locus was inserted into the chromosome during the within-species microevolution of Y. pestis, which is absent in strains from Foci G, H and L and also in Y. pseudotuberculosis. This fact indicates that the strains from these three foci are of an older lineage of Chinese Y. pestis. It is this IS100 element's absence that maintained high stability of the pgm locus in the Y. pestis strains from these three foci. The IS285 element insertion in the pigmentation segment and the IS100 element insertion in the downstream flanking region of the pgm locus are only present in strains from Foci H and L. The flanking region outside the 59 terminus of the upstream IS100 element is identical in the strains from these two foci, which is different in the other strains. All of these unique characteristics suggest that they are of a special lineage of Chinese Y. pestis.

Alleles↗