Evaluation of the ELAC2 Ser217Leu and Ala541Thr Polymorphisms in the Patients with Prostate Cancer

Introduction: Prostate cancer is the fifth most common cancer in the world and the second leading cause of cancer death among men. The ELAC2 gene (HPC2 locus) on chromosome 17p11 has been identified as hereditary tumor suppressor genes in prostate cancer. Some evidence showed that ELAC2 Ser217Leu and Ala541Thr polymorphisms were associated with prostate cancer risk. The aim of this study was to investigate the ELAC2 Ser217Leu and Ala541Thr polymorphisms in the patients with prostate cancer. Methods: In this study, blood samples were collected from 64 persons of a family, which suspected to of having prostate cancer. The genomic DNA was extracted using Commercialthe commercial DNA extraction kit. ELAC2 Ser217Leu and Ala541Thr target regions were PCR amplified with specific primers. PCR products were then sequenced to determine mutations. The final analysis was performed using Rest 2009 software. AlsoFurthermore, SPSS software version 16 and Kolmogorov-Smirnov statistical test were used to evaluate the normality of the data and T test was used to evaluate the expression of ELAC2 gene and its relationship with T and N factors. Results: The results of gene sequencing for Ser217Leu mutation showed that 18.75% were mutant homozygote (Leu/Leu), 40.62% were heterozygote (Leu/Ser) and 40.62% were normal homozygote (Ser/Ser). In addition, for Ala541Thr, the Ala/Thr heterozygosity and Ala/Ala normal homozygosity were determined in 18.75% and 81.25%, respectively. There was not observed any mutant homozygosity (Thr/Thr) in these samples. Conclusion: The results of this study showed that Ser217Leu and Ala541Thr polymorphisms were associated with prostate cancer and might be used as susceptibility markers of prostate cancer. In addition, PCR and gene sequencing are very useful for screening the mutations of prostate cancer in clinical trials and diagnosis.

Connection of TF and TCF4 Gene Polymorphisms with ASD

Though the prevalence of autism spectrum disorder (ASD) is increasing day by day, there is still a lack of a proper way to diagnose or prevent ASD. There is no study carried out in the Bangladeshi children with ASD to evaluate the association of Transferrin (TF) and Transcription Factor 4 (TCF4) genetic polymorphisms. This genetic association study was designed to explore the association of rs1867503 polymorphism of TF and rs9951150 polymorphism of TCF4 genes with ASD. We collected blood from 96 children with ASD and 118 healthy children of very similar age differences. Genotyping of these SNPs was performed by the PCR-RFLP method. SPSS (version 16) was used to estimate the odds ratio (OR) and their 95% confidence intervals (CI). The frequency of mutant allele G for rs1867503 and rs9951150 polymorphisms was found 48% and 44%, respectively. In our analysis, both TF and TCF4 polymorphisms showed an increased risk for the development of ASD. AG heterozygote, GG mutant homozygote, AG+GG combined genotype, and G mutant allele of TF rs1867503 showed a significantly elevated risk of ASD development (OR=3.18, p=0.0003; OR=2.62, p=0.0128; OR=2.98, p=0.0002; and OR=1.94, p=0.001, respectively). Likewise, AG heterozygote, GG mutant homozygote, AG+GG combined genotype, and G minor allele of TCF4 rs9951150 also showed a significantly elevated risk of ASD development (OR=2.92, p=0.0007; OR=2.36, p=0.0273; OR=2.72, p=0.0005; and OR=1.92; p=0.0014, respectively). Our results indicate that TF rs1867503 and TCF4 rs9951150 polymorphisms are strongly associated with the development of ASD in Bangladeshi children.

Polymorphisms of CYP1A1 Genes and Its Correlation with Clinical Variant of Pterygium

Background and Objective: CYP1A1 gene, which has role in carcinogenic metabolisms, is also detected in pterygium tissue. The aim of the study is to determine the polymorphisms of CYP1A1 m2 (rs1048943) and m4 (rs1799814) gene and its correlation with clinical variant of the pterygium. Methods: DNA isolation was performed from blood sample of 80 pterygium patients consisting of 40 inflammatory and 40 non-inflammatory pterygium. Genotyping of rs1048943 SNP AG (m2) in the CYP1A1 gene was performed using Alel Specific Polymerase Chain reaction (AS-PCR) and rs1048943) SNP Genotyping was performed using PCR. Polymorphism results are characterized as wild type (AA), mutant homozygote (GG), and mutant heterozygote (AG). Results: CYP1A1 m2 and m4 gene polymorphism consist of wild type (AA), mutant homozygote (GG), and mutant heterozygote (AG). Both CYP1A1 m2 and m4 genes polymorphism of both groups of inflammatory and non-inflammatory pterygium was mostly consist of wild type polymorphism, followed by the mutant heterozygote polymorphism. The wild type polymorphism was found to be higher in inflammatory pterygium, meanwhile the mutant heterozygote was found to be higher in non-inflammatory pterygium. Conclusion: There were differences in CYP1A1 m2 and m4 gene polymorphism in both pterygium group, but none has been shown to be statistically associated with the clinical variant of the pterygium.

Evolutionary rescue in randomly mating, selfing, and clonal populations

Severe environmental change can drive a population extinct unless the population adapts in time to the new conditions (“evolutionary rescue”). How does bi-parental sexual reproduction influence the chances of population persistence compared to clonal reproduction or selfing? In this paper, we set up a one-locus two-allele model for adaptation in diploid species, where rescue is contingent on the establishment of the mutant homozygote. Reproduction can occur by random mating, selfing, or clonally. Random mating generates and destroys the rescue mutant; selfing is efficient at generating it but at the same time depletes the heterozygote, which can lead to a low mutant frequency in the standing genetic variation and also affects the establishment probability of the mutation. Due to these antagonistic effects, we find a non-trivial dependence of population survival on the rate of sex/selfing, which is strongly affected by the dominance coefficient of the mutation before and after the environmental change. Importantly, since mating with the wildtype breaks the mutant homozygote up, a slow decay of the wildtype population size can impede rescue in randomly mating populations.

High Frequency of a Single Nucleotide Substitution (c.-6-180T>G) of the CanineMDR1/ABCB1Gene Associated with Phenobarbital-Resistant Idiopathic Epilepsy in Border Collie Dogs

A single nucleotide substitution (c.-6-180T>G) associated with resistance to phenobarbital therapy has been found in the canineMDR1/ABCB1gene in Border Collies with idiopathic epilepsy. In the present study, a PCR-restriction fragment length polymorphism assay was developed for genotyping this mutation, and a genotyping survey was carried out in a population of 472 Border Collies in Japan to determine the current allele frequency. The survey demonstrated the frequencies of the T/T wild type, T/G heterozygote, and G/G mutant homozygote to be 60.0%, 30.3%, and 9.8%, respectively, indicating that the frequency of the mutant G allele is extremely high (24.9%) in Border Collies. The results suggest that this high mutation frequency of the mutation is likely to cause a high prevalence of phenobarbital-resistant epilepsy in Border Collies.

Magnitude of length-dependent changes in contractile properties varies with titin isoform in rat ventricles

The effects of differential expression of titin isoforms on sarcomere length (SL)-dependent changes in passive force, maximum Ca2+-activated force, apparent cooperativity in activation of force ( nH), Ca2+ sensitivity of force (pCa50), and rate of force redevelopment ( ktr) were investigated in rat cardiac muscle. Skinned right ventricular trabeculae were isolated from wild-type (WT) and mutant homozygote (Ho) hearts expressing predominantly a smaller N2B isoform (2,970 kDa) and a giant N2BA-G isoform (3,830 kDa), respectively. Stretching WT and Ho trabeculae from SL 2.0 to 2.35 μm increased passive force, maximum Ca2+-activated force, and pCa50, and it decreased nH and ktr. Compared with WT trabeculae, the magnitude of SL-dependent changes in passive force, maximum Ca2+-activated force, pCa50, and nH was significantly smaller in Ho trabeculae. These results suggests that, at least in rat ventricle, the magnitude of SL-dependent changes in passive force, maximum Ca2+-activated force, pCa50, nH, and ktr is defined by the titin isoform.

The Population Genetics of Synthetic Lethals

Synthetic lethals are variants at different loci that have little or no effect on viability singly but cause lethality in combination. The importance of synthetic lethals and, more generally, of synthetic deleterious loci (SDL) has been controversial. Here, we derive the expected frequencies for SDL under a mutation-selection balance for the complete haploid model and selected cases of the diploid model. We have also obtained simple approximations that demonstrate good fit to exact solutions based on numerical iterations. In the haploid case, equilibrium frequencies of carrier haplotypes (individuals with only a single mutation) are comparable to analogous single-locus results, after allowing for the effects of linkage. Frequencies in the diploid case, however, are much higher and more comparable to the square root of the single-locus results. In particular, when selection operates only on the double-mutant homozygote and linkage is not too tight, the expected frequency of the carriers is approximately the quartic root of the ratio between the mutation rate and the selection coefficient of the synthetics. For a reasonably wide set of models, the frequencies of carriers can be on the order of a few percent. The equilibrium frequencies of these deleterious alleles can be relatively high because, with SDL, both dominance and epistasis act to shield carriers from exposure to selection. We also discuss the possible role of SDL in maintaining genetic variation and in hybrid breakdown.

Destruction of immaturin activity in early mature mutants of Paramecium caudatum

Cells of Paramecium in the sexually immature period of the clonal life cycle contain a protein called immaturin, which represses mating activity when injected into sexually mature cells. The amount of immaturin at various stages of the immaturity period was examined by injecting cytoplasm from immature cells of one wild-type and two early mature mutant clones into mature cells of wild-type. The proportion of immature cells brought about by the injection increased until about 10–15 fissions after conjugation of the donor cells in all three clones. But the percentage of immature cells induced by the injection decreased rapidly from the 25th to the 30th fission of both early mature donors, while the percentage was still high with a wild-type donor of the same fission age. When cytoplasm of the Emt A (early mature mutant) homozygote taken immediately before maturation (about 27 fissions) was injected into the wild-type immature cells of 45 fissions after conjugation, 13% of the recipient cells expressed mating reactivity. But when cytoplasm of Emt A cells 20 and 50 fissions after conjugation was injected into the same cells, no reactive cell appeared. The results suggest that cytoplasm of the early mature mutant immediately before maturation contains some material that accelerates maturation when injected into wild-type cells in the late stage of immaturity. On the other hand, the immature cytoplasm of wild-type cells about 25 fissions after conjugation showed no effect when injected into early mature cells immediately before maturation. The function of the early mature gene product was suggested to be the destruction of immaturin activity.

Absorption and distribution of sodium [2-14C]barbital in tissues of normal and dystrophic mice

The absorption and distribution of [2-14C]barbital after oral administration was studied in various tissues, including skeletal muscle, of normal and dystrophic mice. There appeared to be a more rapid gastric emptying in the mutant homozygote as reflected in lower levels of the drug recuperated from the gastrointestinal tract. This resulted in initially higher plasma and tissue concentrations of barbital in the dystrophic mice. Two hours after oral administration, this kinetic profile was reversed so that less barbital remained in the tissues of the dystrophic mouse. The tissue:plasma concentration ratios were consistently, but not significantly, higher in all tissues of the dystrophic animals. Analysis of the half-life of the drug in both groups suggests that there is an increase in the distribution volume of barbital in the dystrophic mice. The phenomenon of more rapid absorption of the barbiturate seems to be more consistent as the symptoms of the disease progress. The altered absorption and disposition of barbital in various tissues of the dystrophic mouse support the concept that a generalized multisystemic disorder may be crucial to the pathogenesis of murine muscular dystrophy, in contradistinction to a purely myogenic origin.