Genetic Disequilibrium Research Articles

Comparison of natural populations of Mycosphaerella graminicola from single fields in Kansas and California

Kansas and California wheat-growing regions differ dramatically in soils, climate, wheat cultivars, crop rotation patterns, and cultural practices, which could select for different fungal populations of Mycosphaerella graminicola. Our objective in this study was to use amplified fragment length polymorphism (AFLP) loci to assess the genetic diversity of M. graminicola populations within single fields in two widely separated, and geographically isolated sites in Kansas and California. Three primer-pair combinations were used to resolve polymorphism at 177 loci in 67 and 63 isolates from Kansas and California, respectively. Genotypic variability was high, which is consistent with a genetically diverse initial inoculum. There was no evidence of genetic disequilibrium in either population, with only 4.6% of the locus pairs in Kansas, and 5.4% of the locus pairs in California in detectable disequilibrium. The migration rate calculated between the two sites was as low as 1.8 individuals per generation, and significant differences in allele frequencies were observed. Therefore, these two populations do not represent mere subsamples of a larger, randomly mating population. This is a rare report of isolation by distance occurring between two North American populations of M. graminicola, indicating that at least some of these populations may be differentiating. Although genetic isolation by distance may occur, we cannot exclude movement of new gene combinations such as fungicide resistance or virulence between these two locations.

Human apolipoprotein C-I expression in mice impairs learning and memory functions

The H2 allele of APOC1, giving rise to increased gene expression of apolipoprotein C-I (apoC-I), is in genetic disequilibrium with the APOE4 allele and may provide a major risk factor for Alzheimer's disease (AD). We found that apoC-I protein is present in astrocytes and endothelial cells within hippocampal regions in both human control and AD brains. Interestingly, apoC-I colocalized with beta-amyloid (Abeta) in plaques in AD brains, and in vitro experiments revealed that aggregation of Abeta was delayed in the presence of apoC-I. Moreover, apoC-I was found to exacerbate the soluble Abeta oligomer-induced neuronal death. To establish a potential role for apoC-I in cognitive functions, we used human (h) APOC1(+/0) transgenic mice that express APOC1 mRNA throughout their brains and apoC-I protein in astrocytes and endothelial cells. The hAPOC1(+/0) mice displayed impaired hippocampal-dependent learning and memory functions compared with their wild-type littermates, as judged from their performance in the object recognition task (P = 0.012) and in the Morris water maze task (P = 0.010). ApoC-I may affect learning as a result of its inhibitory properties toward apoE-dependent lipid metabolism. However, no differences in brain mRNA or protein levels of endogenous apoE were detected between transgenic and wild-type mice. In conclusion, human apoC-I expression impairs cognitive functions in mice independent of apoE expression, which supports the potential of a modulatory role for apoC-I during the development of AD.

Sequence variation and linkage disequilibrium in the GABA transporter-1 gene (SLC6A1) in five populations: implications for pharmacogenetic research

BackgroundGABA transporter-1 (GAT-1; genetic locus SLC6A1) is emerging as a novel target for treatment of neuropsychiatric disorders. To understand how population differences might influence strategies for pharmacogenetic studies, we identified patterns of genetic variation and linkage disequilibrium (LD) in SLC6A1 in five populations representing three continental groups.ResultsWe resequenced 12.4 kb of SLC6A1, including the promoters, exons and flanking intronic regions in African-American, Thai, Hmong, Finnish, and European-American subjects (total n = 40). LD in SLC6A1 was examined by genotyping 16 SNPs in larger samples. Sixty-three variants were identified through resequencing. Common population-specific variants were found in African-Americans, including a novel 21-bp promoter region variable number tandem repeat (VNTR), but no such variants were found in any of the other populations studied. Low levels of LD and the absence of major LD blocks were characteristic of all five populations. African-Americans had the highest genetic diversity. European-Americans and Finns did not differ in genetic diversity or LD patterns. Although the Hmong had the highest level of LD, our results suggest that a strategy based on the use of tag SNPs would not translate to a major improvement in genotyping efficiency.ConclusionOwing to the low level of LD and presence of recombination hotspots, SLC6A1 may be an example of a problematic gene for association and haplotype tagging-based genetic studies. The 21-bp promoter region VNTR polymorphism is a putatively functional candidate allele for studies focusing on variation in GAT-1 function in the African-American population.

Examining Emergence of Functional Gene Clustering in a Simulated Evolution

Recent research suggests that rather than being random, gene order may be coupled with gene functionality. These findings may be explained by mechanisms that require physical proximity such as co-expression and co-regulation. Alternatively, they may be due to evolutionary-dynamics forces, as expressed in genetic drift or linkage disequilibrium. This paper proposes a biologically plausible model for evolutionary development. Using the model, which includes natural selection and the development of gene networks and cellular organisms, the co-evolution of recombination rate and gene functionality is examined. The results presented here are compatible with previous biological findings showing that functionally related genes are clustered. These results imply that evolutionary pressure in a complex environment is sufficient for the emergence of gene order that is coupled with functionality. They shed further light on the mechanisms that may cause such gene clusters.

Mapping of a disease susceptibility locus in the HLA region for Primary Biliary Cirrhosis in Japan

Primary biliary cirrhosis (PBC) is a chronic progressive cholestatic disease of unknown pathogenesis. However, several reports have demonstrated the involvement of genetic backgrounds in this syndrome. The aim of this study is to examine the genetic disequilibrium in the HLA region in Japanese patients using six microsatellite markers. Genomic DNAs were obtained from 73 patients with PBC (patient cohort) and 186 healthy volunteers (control cohort). Genetic polymorphisms at six microsatellite markers (D6S1568, DQ.CAR, D6S273, TNF-d, C1-2-A, C3-2-11) were determined using fluorescence-labeled polymerase chain reaction (PCR) genetic analyzer. Allele frequencies were estimated by direct counting and the genotypic differentiation test was performed by the Markov chain method using Genepop software. Among these six microsatellite markers, four markers in the patients significantly (P < 0.05) deviated from the Hardy-Weinberg equilibrium: DQ.CAR (P = 0.0278), D6S273 (P = 0.0168), TNF-d (P = 0.0089) and C1-2-A (P = 0.0005). Genotypic differentiation test between the patients and controls demonstrated that DQ.CAR (P = 0.0111), TNF-d (P = 0.0051) and C1-2-A (P = 0.0371) were significant. Finally, allelic association test revealed before correction for multiple testing demonstrated allele125 of TNF-d (P = 0.00065, Pc = 0.0052) and allele246 of C1-2-A (P = 0.0026 Pc = 0.033) had significant association after Bonferroni's correction. Disequilibrium mapping using microsatellite markers was a useful method to narrow a disease susceptibility locus. The possible susceptibility gene in the HLA region is thought to be localized around or in the TNF gene. Further studies seem feasible using more closely distributed microsatellite markers or single nucleotide polymorphisms (SNPs) to narrow the susceptibility locus in PBC in Japanese populations.

Molecular characterization of bulgarian livestock genetic resources, II: Microsatelite variation within and among Bulgarian cattle breeds

This study was undertaken to determine the genetic structure and the diversity among 2 local cattle breeds from Bulgaria, the Rhodope Shorthorn and Grey cattle. A panel of 11 microsatellites was used for the evaluation. For these loci, allele frequencies, heterozygosity, HWE, genetic disequilibrium, genic differentiation were determined. Both populations displayed a relatively high level of genetic variation as estimated by allelic diversity and heterozygosity. Heterozygosities ranged from 0.5424 /SPS 115/ to 0.8983 /TGLA 227/ for the Rhodope population and 0.6333 /TGLA 53/ to 0.9333 /TGLA227/ for Grey cattle, with similar average values for the two groups - 0.7858 and 0.7757. These results clearly suggest that these breeds are suitable to preserve as a genetic resources.

Analysis of genetic co-adaptability of structural loci in Hu sheep

Using the method of multiloci electrophoresis, genetic co-adaptability of Hu Sheep was analyzed according to allele frequencies in 14 structural loci. The results showed that no co-adaptability existed in the dominance-dominance model, while co-adaptability was observed in X-p-Cat combination locus of dominance-codominance model and in Po-CA, Po-Cat combination locus of codominance-codominance model. The findings demonstrated that co-adaptability occurred among neutral structural loci and played a key role in maintaining genetic situation, equilibrium or disequilibrium.

Genetic co-adaptability among structural genes under the condition of genetic disequilibrium

Genetic co-adaptability of colony gene bank is formed in the process of system evolvement, and it is a part of the attribute of gene bank, just as the gene frequency of every locus. With the genetic co-adaptability of loci combination under the condition of genetic disequilibrium, the genesis evolution and the system status of colony could be analyzed; through the study of genetic co-adaptability, the veracity of the economy character mark could be improved. We summarized about the concept, the basic and the actuality of genetic co-adaptability.

Gene expression patterns in isolated keloid fibroblasts

Keloid scars after skin trauma are a significant clinical problem, especially in black populations, in which the incidence of keloids has been estimated at 4-16%. Keloids are abnormal dermal proliferative scars secondary to dysregulated wound healing. Despite several biochemical studies on the role of extracellular matrix proteins and growth factors during keloid formation, we still do not know what molecules and signals induce this change. Fibroblasts are thought to be the major inductive cell for keloid scar formation. The aim of this study was to identify gene expression patterns that characterize keloid fibroblasts; identifying such genetic disequilibrium may shed light on the molecular signaling events responsible for keloid formation. In this study, we performed gene expression analysis of fibroblasts isolated from keloid lesions from three individuals in comparison with the fibroblasts isolated from normal skin using the Affymetrix U133a chip (22,284 genes and expression sequence tags). We found through J5 test score expression analysis that among 22,284 genes, there were 43 genes that were overexpressed and five genes were underexpressed in keloid fibroblasts when compared with dermal fibroblasts from persons without keloids. The overexpression of three genes not previously reported as being up-regulated in keloids (annexin A2, Transgelin, and RPS18) was confirmed by real-time polymerase chain reaction. Certain overexpressed genes were similar to previous biochemical observations on the protein levels of these overexpressed genes during keloid formation. We also report for the first time that a few tumor-related genes are overexpressed in keloid fibroblasts.

Pharmacogenetic Screening for Polymorphisms in Drug-Metabolizing Enzymes and Drug Transporters in a Dutch Population

A possible explanation for the wide interindividual variability in toxicity and efficacy of drug therapy is variation in genes encoding drug-metabolizing enzymes and drug transporters. The allelic frequency of these genetic variants, linkage disequilibrium (LD), and haplotype of these polymorphisms are important parameters in determining the genetic differences between patients. The aim of this study was to explore the frequencies of polymorphisms in drug-metabolizing enzymes (CYP1A1, CYP2C9, CYP2C19, CYP3A4, CYP2D6, CYP3A5, DPYD, UGT1A1, GSTM1, GSTP1, GSTT1) and drug transporters (ABCB1[MDR1] and ABCC2[MRP2]), and to investigate the LD and perform haplotype analysis of these polymorphisms in a Dutch population. Blood samples were obtained from 100 healthy volunteers and genomic DNA was isolated and amplified by PCR. The amplification products were sequenced and analyzed for the presence of polymorphisms by sequence alignment. In the study population, we identified 13 new single nucleotide polymorphisms (SNPs) in Caucasians and three new SNPs in non-Caucasians, in addition to previously recognized SNPs. Three of the new SNPs were found within exons, of which two resulted in amino acid changes (A428T in CYP2C9 resulting in the amino acid substitution D143V; and C4461T in ABCC2 in a non-Caucasian producing the amino acid change T1476M). Several LDs and haplotypes were found in the Caucasian individuals. In this Dutch population, the frequencies of 16 new SNPs and those of previously recognized SNPs were determined in genes coding for drug-metabolizing enzymes and drug transporters. Several LDs and haplotypes were also inferred. These data are important for further research to help explain the interindividual pharmacokinetic and pharmacodynamic variability in response to drug therapy.

Study on genetic coadaptability of wild quail populations in China

Genetic coadaptability of wild Japanese quail, wild Common quail and Domestic quail populations in China was studied using 7 microsatellite DNA markers and Monte Carlo method to test genetic disequilibrium. The molecular effects of genetic coadaptability were analyzed through a new statistical model of neutral site. The results showed that genetic coadaptability dominated the genetic disequilibrium of the three quail populations, and totally 16.67%, 9.66% and 10.05% of non-allelic combinations were in the genetic disequilibrium in wild Japanese quail, wild Common quail and Domestic quail populations, respectively. Genetic coadaptability existed at almost all the tested sites. In the molecular point of view, genetic coadaptability plays an important role of keeping lots of polymorphisms in natural populations. Therefore, it is another key factor to the genetic disequilibrium in the population except for linkage. The results enrich the conceptions and connotations of genetic disequilibrium, and help us know more about genetic coadaptability and its effects, and lay a foundation of evaluation and protection of wild quail genetic resources in China.

LEI0258 microsatellite variability and its relationship to B-F haplotypes in Brazilian (blue-egg Caipira) chickens

A total of 149 chickens from two different sources (one non-commercial, the other commercial) was tested for variability of the LEI0258 microsatellite. Fifty- three genotypes, explainable by 15 alleles, were found. There are clear allele and heterozygosity differences between the two samples. One of them was simultaneously studied for the MHC B-F haplotypes. Strong genetic disequilibrium was observed between the variants of the two systems, therefore providing a cheap alternative for MHC genotyping.

Phylogeography and population genetics of the endangered Amazonian manatee, Trichechus inunguis Natterer, 1883 (Mammalia, Sirenia)

We used mitochondrial DNA control region sequences to examine phylogeography and population differentiation of the endangered Amazonian manatee Trichechus inunguis. We observe lack of molecular differentiation among localities and we find weak association between geographical and genetic distances. However, nested clade analysis supports restricted gene flow and/or dispersal with some long-distance dispersal. Although this species has a history of extensive hunting, genetic diversity and effective population sizes are relatively high when compared to the West Indian manatee Trichechus manatus. Patterns of mtDNA haplotype diversity in T. inunguis suggest a genetic disequilibrium most likely explained by demographic expansion resulting from secession of hunting and enforcement of conservation and protective measures. Phylogenetic analysis of T. manatus and T. inunguis haplotypes suggests that T. inunguis is nested within T. manatus, effectively making T. manatus a paraphyletic entity. Paraphyly of T. manatus and recent divergence times of T. inunguis and the three main T. manatus lineages suggest a possible need for a taxonomic re-evaluation of the western Atlantic Trichechus.

Mapping of the HLA Class II Susceptibility Haplotype for Multiple Sclerosis in Finland

We analyzed the four class II loci DPB1, DQB1, DQA1 and DRB1 and two microsatellites located close to the TAP1 (25530.5, 26610.3) and TNFα (IR2/4) loci in a Finnish patient cohort comprising twenty-one Finnish multiplex families with 2–6 affected individuals per pedigree. Association analyses, parametric linkage analyses and TDT analyses all suggest that a MS susceptibility locus is to be found in the class II DQ, rather than the DP and DR, subregions. The particular locus involved in the DQ region could not be pinpointed, either due to the strong genetic disequilibrium among loci or the involvement of either of several alternative loci in disease development.

Analysis of 12 STR loci in Antioquia (Colombia) population sample

In this study, the validation of 12 short tandem repeated (STRs) systems is presented in a sample of the population from Antioquia, central region of Colombia. The DNA for the analyses of PCR was obtained of 244 to 546 unrelated individuals. PCR amplification was performed according to the manufacturer's recommendations, using PowerPlex 1.2 System and FFFL Multiplex (Promega). Amplificated fragments were separated by capillary electrophoresis using the ABI Prism 310 Genetic Analyzer (PE Applied Biosystems). Allele frequencies, Hardy-Weinberg equilibrium, observed and expected heterozygosity and genetic disequilibrium were calculated using GENEPOP ver. 3.3 and GDA ver. 1.1 software. Forensic parameters were calculated using the PowerStat ver. 1.2 software (Promega). The 12 of the loci met Hardy-Weinberg expectations and they reached a combined power discrimination higher than 0.999999999999 and a combined power exclusion similar to 0.9999, showing to be a powerful tool for paternity testing, individual identification and forensic applications in Antioquia population.

Population differentiation and recombination in wheat scab populations of Gibberella zeae from the United States

In limited previous studies of the Ascomycete fungus Gibberella zeae in North America, the populations examined were genetically and phenotypically diverse and could be viewed as subsamples of a larger population. Our objective in this study was to test the hypothesis that a homogeneous, randomly mating population of G. zeae is contiguous throughout the central and eastern United States across a span of several years. We analysed presence/absence alleles based on amplified fragment length polymorphisms (AFLPs) at 30 loci, 24 of which are defined genetically on a linkage map of G. zeae, from > 500 isolates in eight field populations from seven states collected during the 1998, 1999 and 2000 cropping seasons. All these strains had AFLP profiles similar to those of standard isolates of G. zeae phylogenetic lineage 7. All the populations are genetically similar, have high genotypic diversity and little or no detectable genetic disequilibrium, and show evidence of extensive interpopulation genetic exchange. Allele frequencies in some of the populations examined are not statistically different from one another, but others are. Thus, the populations examined are not mere subsamples from a single, large, randomly mating population. Geographic distance and genetic distance between populations are correlated significantly. The observed differences are relatively small, however, indicating that while genetic isolation by distance may occur, genetic exchange has occurred at a relatively high frequency among US populations of G. zeae. We think that these differences reflect the time required for the alleles to diffuse across the distances that separate them, because relatively little linkage disequilibrium is detected either in the population as a whole or in any of the individual subpopulations.

Linkage disequilibrium assessment via log-linear modeling of SNP haplotype frequencies.

Analyses of high-density single-nucleotide polymorphism (SNP) data, such as genetic mapping and linkage disequilibrium (LD) studies, require phase-known haplotypes to allow for the correlation between tightly linked loci. However, current SNP genotyping technology cannot determine phase, which must be inferred statistically. In this paper, we present a new Bayesian Markov chain Monte Carlo (MCMC) algorithm for population haplotype frequency estimation, particularly in the context of LD assessment. The novel feature of the method is the incorporation of a log-linear prior model for population haplotype frequencies. We present simulations to suggest that 1) the log-linear prior model is more appropriate than the standard coalescent process in the presence of recombination (>0.02 cM between adjacent loci), and 2) there is substantial inflation in measures of LD obtained by a "two-stage" approach to the analysis by treating the "best" haplotype configuration as correct, without regard to uncertainty in the recombination process.

Quantitative genetic variation in Daphnia: temporal changes in genetic architecture.

Nonadditive genetic variation and genetic disequilibrium are two important factors that influence the evolutionary trajectory of natural populations. We assayed quantitative genetic variation in a temporary-pond-dwelling population of Daphnia pulex over a full season to examine the role of nonadditive genetic variation and genetic disequilibrium in determining the short-term evolutionary trajectory of a cyclic parthenogen. Quantitative traits were influenced by three factors: (1) clonal selection significantly changed the population mean phenotype during the course of the growing season; (2) sexual reproduction and recombination led to significant changes in life-history trait means and the levels of expressed genetic variation, implying the presence of substantial nonadditive genetic variation and genetic disequilibrium; and (3) Egg-bank effects were found to be an important component of the realized year-to-year change. Additionally, we examined the impact of genetic disequilibria induced by clonal selection on the genetic (co)variance structure with a common principal components model. Clonal selection caused significant changes in the (co)variance structure that were eliminated by a single bout of random mating, suggesting that a build-up of disequilibria was the primary source of changes in the (co)variance structure. The results of this study highlight the complexity of natural selection operating on populations that undergo alternating phases of sexual and asexual reproduction.

QUANTITATIVE GENETIC VARIATION IN DAPHNIA: TEMPORAL CHANGES IN GENETIC ARCHITECTURE

Nonadditive genetic variation and genetic disequilibrium are two important factors that influence the evolutionary trajectory of natural populations. We assayed quantitative genetic variation in a temporary-pond-dwelling population of Daphnia pulex over a full season to examine the role of nonadditive genetic variation and genetic disequilibrium in determining the short-term evolutionary trajectory of a cyclic parthenogen. Quantitative traits were influenced by three factors: (1) clonal selection significantly changed the population mean phenotype during the course of the growing season; (2) sexual reproduction and recombination led to significant changes in life-history trait means and the levels of expressed genetic variation, implying the presence of substantial nonadditive genetic variation and genetic disequilibrium; and (3) Egg-bank effects were found to be an important component of the realized year-to-year change. Additionally, we examined the impact of genetic disequilibria induced by clonal selection on the genetic (co)variance structure with a common principal components model. Clonal selection caused significant changes in the (co)variance structure that were eliminated by a single bout of random mating, suggesting that a build-up of disequilibria was the primary source of changes in the (co)variance structure. The results of this study highlight the complexity of natural selection operating on populations that undergo alternating phases of sexual and asexual reproduction.Corresponding Editor: D. Waller

Genetic variation within Phaeoacremonium aleophilum and P. chlamydosporum in Italy

Genetic variation among isolates of Phaeoacremonium chlamydosporum (Pch) and P. aleophilum (Pal), two hyphomycetous fungi involved in the development of symptoms of esca and in a decline of young grapevines, was studied in eight Italian grapevine growing regions. Genetic variation was estimated by analysis of amplification profiles obtained in RAPD- and RAMS-PCR experiments (RAPD = Random Amplified Polymorphic DNA; RAMS = Random Amplified Micro- or Mini-Satellites). The genetic divergence between the two species suggests their assignment to two different genera. Within each species, a low level of polymorphism was found; however a higher degree of genetic variation was found with RAPD than with RAMS experiments, and more with Pal than with Pch isolates. No relationship was found for either species between the clustering of isolates in statistically defined groups and the geographic origin of those isolates. A low level of genetic disequilibrium was found in Pch and Pal, suggesting that sexual reproduction may occur in both fungi.