Phenotypic Polymorphism Research Articles

MU-Opioid Receptor (OPRM1) Gene Polymorphism and its Association with Alcohol Dependence: A Single Centre Study from Southern India

Introduction: Asn40Asp Opioid Receptor (OPRM1) polymorphism of the MU-OPRM1 gene has been widely studied with regard to its association with alcohol dependence however results have been conflicting with evidence of ethnicity mediated effects. Aim: To examine the association between OPRM1 polymorphism and alcohol dependence in patients of South Indian ethnicity. Materials and Methods: This cross-sectional study was conducted at Department of Psychiatry, Sri Ramachandra Institute of Higher Education and Research, Porur, Chennai, Tamil Nadu, India, from November 2018 to May 2019. Cross-sectional assessments and peripheral venous blood genotyping were done in 50 male South Indian participants attending a tertiary care psychiatric setting. Clinical parameters such as severity of dependence and craving were assessed in addition to the subject’s OPRM1 genotype. The data collected was analysed using Statistical Package for the Social Sciences (SPSS) version 20.0. Results: The mean age of the subjects was 39.62±8.50 years. This study showed a statistically significant association between alcohol dependence and the OPRM1 polymorphism Asn40Asp among the study subjects (p-value <0.05). Furthermore, there was a higher than expected prevalence of the polymorphism of 86% among patients. However, there was no significant association between the polymorphism and clinical phenotypes such as severity of dependence or craving. Conclusion: This study indicates a possible role of OPRM1 polymorphism in alcohol dependence in South Indian patients and warrants further research with larger sample sizes. The association if replicated will shed light on aspects of aetiopathogenesis as well as have implications on treatment.

A summary-statistics-based approach to examine the role of serotonin transporter promoter tandem repeat polymorphism in psychiatric phenotypes

In genetic studies of psychiatric disorders in the pre-genome-wide association study (GWAS) era, one of the most commonly studied loci is the serotonin transporter (SLC6A4) promoter polymorphism, a 43-base-pair insertion/deletion polymorphism in the promoter region (5-HTTLPR). The genetic association signals between 5-HTTLPR and psychiatric phenotypes, however, have been inconsistent across many studies. Since the polymorphism cannot be tested via available SNP arrays, we had previously proposed an efficient machine learning algorithm to predict the genotypes of 5-HTTLPR based on the genotypes of eight nearby SNPs, which requires access to individual-level genotype and phenotype data. To utilize the advantage of publicly available GWAS summary statistics obtained from studies with very large sample sizes, we develop a GWAS summary-statistics-based approach for testing the variable number of tandem repeat (VNTR) associations with various phenotypes. We first cross-verify the accuracy of the summary-statistics-based approach for 61 phenotypes in the UK Biobank. Since we observed a strong similarity between the predicted individual-level 5-HTTLPR genotype-based approach and the summary-statistics-based approach, we applied our method to the available neurobehavioral GWAS summary statistics data obtained from large-scale GWAS. We found no genome-wide significant evidence for association between 5-HTTLPR and any of the neurobehavioral traits. We did observe, however, genome-wide significant evidence for association between this locus and human adult height, BMI, and total cholesterol. Our summary-statistics-based approach provides a systematic way to examine the role of VNTRs and related types of genetic polymorphisms in disease risk and trait susceptibility of phenotypes for which large-scale GWAS summary statistics data are available.

Morphogenetic Polyvariance in the Colonial Hydroid Dynamena pumila (L.)

The formation of aberrant modules (internodes) of the shoot was found sporadically in the colonial hydroid Dynamena pumila from the family Sertulariidae, which is distinguished by the symmetrical two-row position of the hydrotheca on the shoot stem. Despite rare significant deviations from the norm in the structure of some modules, the following modules in the shoots are formed normally. All variants of deviation from the norm (called morphovariations) are classified and, in general, are represented by four groups according to the possible reasons for their occurrence. The morphotypes are the most interesting morphological variations and look like similar modules in other genera of hydroids. Considering the position of the aberrant modules on the shoots of one colony, we can confidently infer that they were formed at different times, which undermines the assumption that deviations from the norm in morphogenesis were caused by environmental factors. All morphovariations are characterized by certain occurrences. Consequently, the described phenomenon is not limited to phenotypic plasticity, polymorphism, or sequential changes of phenotypes in the life cycle and, therefore, is singled out as a special phenomenon called morphogenetic polyvariance.

Aymé–Gripp syndrome in a Russian patient with a newly detected mutation in the MAF gene

Aymé–Gripp syndrome is a rare autosomal dominant syndrome caused by mutations in the MAF gene and is characterized by a pronounced phenotypic polymorphism. The core of clinical signs consists of congenital cataracts, sensorineural hearing loss, specific dysmorphic facial features and intellectual disabilities. With varying frequency, patients have: radioulnar synostosis, Arnold–Chiari malformation, aseptic pericarditis, dental anomaly and osteoarthritis. The article presents the clinical and genetic characteristics of the first Russian patient with Aymé–Gripp syndrome caused by a newly identified mutation s.173C>A (p.Thr58Asn NM_005360.4) in a heterozygous state in the MAF gene. The influence of the lo calization and type of amino acid substitutions in the protein product of the gene on the severity and specificity of the clinical manifestations of the syndrome is discussed.

Massive genome inversion drives coexistence of divergent morphs in common quails

The presence of population-specific phenotypes often reflects local adaptation or barriers to gene flow. The co-occurrence of phenotypic polymorphisms that are restricted within the range of a highly mobile species is more difficult to explain. An example of such polymorphisms is in the common quail Coturnix coturnix, a small migratory bird that moves widely during the breeding season in search of new mating opportunities, following ephemeral habitats,1,2 and whose females may lay successive clutches at different locations while migrating.3 In spite of this vagility, previous studies reported a higher frequency of heavier males with darker throat coloration in the southwest of the distribution (I. Jiménez-Blasco etal., 2015, Int. Union Game Biol., conference). We used population genomics and cytogenetics to explore the basis of this polymorphism and discovered a large inversion in the genome of the common quail. This inversion extends 115 Mbp in length and encompasses more than 7,000 genes (about 12% of the genome), producing two very different forms. Birds with the inversion are larger, have darker throat coloration and rounder wings, are inferred to have poorer flight efficiency, and are geographically restricted despite the high mobility of the species. Stable isotope analyses confirmed that birds carrying the inversion have shorter migratory distances or do not migrate. However, we found no evidence of pre- or post-zygotic isolation, indicating the two forms commonly interbreed and that the polymorphism remains locally restricted because of the effect on behavior. This illustrates a genomic mechanism underlying maintenance of geographically structured polymorphisms despite interbreeding with a lineage with high mobility.

Coat Polymorphism in Eurasian Lynx: Adaptation to Environment or Phylogeographic Legacy?

We studied the relationship between the variability and contemporary distribution of pelage phenotypes in one of most widely distributed felid species and an array of environmental and demographic conditions. We collected 672 photographic georeferenced records of the Eurasian lynx throughout Eurasia. We assigned each lynx coat to one of five phenotypes. Then we fitted the coat patterns to different environmental and anthropogenic variables, as well as the effective geographic distances from inferred glacial refugia. A majority of lynx were either of the large spotted (41.5%) or unspotted (uniform, 36.2%) phenotype. The remaining patterns (rosettes, small spots and pseudo-rosettes) were represented in 11.0%, 7.4%, and 3.9% of samples, respectively. Although various environmental variables greatly affected lynx distribution and habitat suitability, it was the effect of least-cost distances from locations of the inferred refugia during the Last Glacial Maximum that explained the distribution of lynx coat patterns the best. Whereas the occurrence of lynx phenotypes with large spots was explained by the proximity to refugia located in the Caucasus/Middle East, the uniform phenotype was associated with refugia in the Far East and Central Asia. Despite the widely accepted hypothesis of adaptive functionality of coat patterns in mammals and exceptionally high phenotypic polymorphism in Eurasian lynx, we did not find well-defined signs of habitat matching in the coat pattern of this species. Instead, we showed how the global patterns of morphological variability in this large mammal and its environmental adaptations may have been shaped by past climatic change.

Amino acid sequence homology between thyroid autoantigens and central nervous system proteins: Implications for the steroid-responsive encephalopathy associated with autoimmune thyroiditis

A few patients with Hashimoto’s thyroiditis or Graves’ disease develop a multiform syndrome of the central nervous system (CNS) termed Hashimoto’s encephalopathy or steroid-responsive encephalopathy associated with autoimmune thyroid disease (HE/SREAT). They have high levels of thyroid autoantibodies (TgAb, TPOAb and/or TSH-R-Ab) in blood and cerebrospinal fluid. Autoantibodies against alpha-enolase, aldehyde reductase-I (AKRIA) and/or dimethylargininase-I (DDAHI), proteins expressed in the CNS among other tissues, were detected in the blood and, when searched, in the cerebrospinal fluid of HE/SREAT patients. Recently, we reported that alpha-enolase, AKRIA and DDAHI share local sequence homology with each of the three autoantigens (TgAb, TPOAb, TSH-R-Ab), often in epitope-containing segments of the thyroid autoantigens. We hypothesized that there might be additional CNS-expressed proteins homologous to thyroid autoantigens, possibly overlapping known epitopes of the thyroid autoantigens. We used bioinformatic methods to address this hypothesis.Six, 27 and 47 of 46,809 CNS-expressed proteins share homology with TSH-R, Tg and TPO, respectively. The homologous regions often contain epitopes, and some match regions of thyroid autoantigens which have homology with alpha-enolase, AKRIA and/or DDAHI. Several of the aforementioned proteins are present in CNS areas that show abnormalities at neuroimaging in HE/SREAT patients. Furthermore, autoantibodies against some of the said six, 27 and 47 proteins were reported to be associated with a number of autoimmune diseases.Not only we validated our hypothesis, but we think that such a variety of potential CNS targets for thyroid Ab against epitopes contained in regions that have local homology with CNS proteins may explain the polymorphic phenotypes of HE/SREAT. Only when elevated amounts of these Ab are synthesized and trespass the blood-brain barrier, HE/SREAT appears. This might explain why HE/SREAT is so relatively rare.

Predatory Bacteria Select for Sustained Prey Diversity.

Predator impacts on prey diversity are often studied among higher organisms over short periods, but microbial predator-prey systems allow examination of prey-diversity dynamics over evolutionary timescales. We previously showed that Escherichia coli commonly evolved minority mucoid phenotypes in response to predation by the bacterial predator Myxococcus xanthus by one time point of a coevolution experiment now named MyxoEE-6. Here we examine mucoid frequencies across several MyxoEE-6 timepoints to discriminate between the hypotheses that mucoids were increasing to fixation, stabilizing around equilibrium frequencies, or heading to loss toward the end of MyxoEE-6. In four focal coevolved prey populations, mucoids rose rapidly early in the experiment and then fluctuated within detectable minority frequency ranges through the end of MyxoEE-6, generating frequency dynamics suggestive of negative frequency-dependent selection. However, a competition experiment between mucoid and non-mucoid clones found a predation-specific advantage of the mucoid clone that was insensitive to frequency over the examined range, leaving the mechanism that maintains minority mucoidy unresolved. The advantage of mucoidy under predation was found to be associated with reduced population size after growth (productivity) in the absence of predators, suggesting a tradeoff between productivity and resistance to predation that we hypothesize may reverse mucoid vs non-mucoid fitness ranks within each MyxoEE-6 cycle. We also found that mucoidy was associated with diverse colony phenotypes and diverse candidate mutations primarily localized in the exopolysaccharide operon yjbEFGH. Collectively, our results show that selection from predatory bacteria can generate apparently stable sympatric phenotypic polymorphisms within coevolving prey populations and also allopatric diversity across populations by selecting for diverse mutations and colony phenotypes associated with mucoidy. More broadly, our results suggest that myxobacterial predation increases long-term diversity within natural microbial communities.

Study of Xmn-I polymorphism in β-thalassemic children in Egypt

Background β-thalassemia (βT) has a wide spectrum of clinical severity that may be attributed to the wide variations in βT gene mutations. β-Globin mutations with the Xmn-I site might be associated with elevated fetal hemoglobin levels, which in turn may affect the severity of βT phenotype. Aim To investigate the frequency of Xmn-I polymorphism (−158 C>T) among Egyptian children with βT, and to examine the relationship between Xmn-I polymorphism and βT phenotypes. Patients and methods This cross-sectional study was conducted on 112 βT patients (55 males and 57 females) with a mean age of 8.34±3.71 years (2–16 years). Laboratory investigations included complete blood count, hemoglobin electrophoresis, β-globin mutation, identification of Xmn-I polymorphism by two methods: PCR–restriction fragment length polymorphism and amplification refractory mutation system. Results All patients (76 with βT major and 36 with βT intermedia) were negative for the Xmn-I SNP whether in homozygous (+/+) or heterozygous (+/−) state. Conclusion This study demonstrated that Xmn-I polymorphism was not detected in the studied patients and this supports the low frequency of this polymorphism in other Egyptian studies.

Association between the chemokine receptor 3 gene polymorphism and clinical asthma phenotypes among Egyptian asthmatic children

Background Asthma is a chronic inflammatory airway disease characterized by episodic reversible airway obstruction. Regarding asthma pathogenesis, two eotaxin polymorphisms were found to be associated with asthma and high serum total immunoglobulin (Ig)E levels, correspondingly. Objective This study was done to explore the association between the underlying gene polymorphisms in chemokine receptor 3 (CCR3) and symptom-based clinical asthma phenotypes among the studied group. Patients and methods This was a case–control study conducted on 60 asthmatic patients with different clinical phenotypes who were compared with 100 healthy controls of matched age and sex. The included asthmatic children aged from 6 to 16 years old and were diagnosed according to the criteria of GINA 2020 by the presence of typical asthma symptoms and with confirmed variable expiratory airflow obstruction. We excluded asthmatic patients with comorbidities. Results A total of 60 asthmatic cases with different clinical phenotypes were compared with 100 healthy controls, and the outcomes showed that total serum IgE had a significant increase in asthmatic cases versus controls. There were no statistically significant differences regarding CCR3 T51C genotype or its allelic polymorphism frequency. There was no clinical significance found correlating eosinophilic percent and serum IgE and CCR3 T51C gene polymorphism in both asthmatic cases and control. There was no statistical significance correlating eosinophilic count, eosinophilic percent, and total serum IgE with different clinical asthma phenotypes. Conclusion Total serum IgE was demonstrated to be significantly increased among asthmatic cases; however, there were no statistically significant differences regarding CCR3 T51C genotype or its allelic polymorphism frequency. Eosinophilic percent and serum IgE and CCR3 T51C gene polymorphism seemed to be comparable among asthmatic cases and controls. Moreover, no significant correlation was detected associating eosinophilic count, eosinophilic percent, and total serum IgE with different clinical asthma phenotypes.

Study of the intrapopulation polymorphism of Trifolium repens L. from Lanivtsi under the anthropogenic load of various intensity

Aim. To study the phenotypic polymorphism of Trifolium repens L. populations growing under various anthropogenic load. Methods. The quantitative calculation of the leaves of the white clover by the presence or absence of the white leaf mark; the identification of the phenotype and genotype of the plant according to the pattern of the white leaf mark; the analysis of the phenotypic diversity and the study of the percentage of rare phenotypes; the calculation of the index of the phenotypes ratio. Results. 4 phenotypes were identified in the pasture area. The most common of them were the plants without the white mark with a frequency of 56.2 %. The plants with a full spot accounted for 27.5 %, with a spot with a gap – 15.4 %, with a central spot – 2.2 %. Heterozygous plants were absent. In the central part of the city, 7 genotypes were identified. Among these genotypes there were the significant decrease of the recessive homozygotes (by 43.6 %) and the increase of the frequency of VV (by 15.2 %) and VHVH (by 21.2 %) genotypes. Heterozygotes accounted for 1.3–3.0 %. The intrapopulation diversity in this territory was the highest (5.1) among the studied areas. In the population growing near Ternopil-Lanivtsi road, we identified 6 genotypes. The plants without spot (vv) and with the full spot (VV) were found with identical frequency of 34–35 %. The plants with a full high spot (VHVH) were about 20.4 %. Other phenotypes amounted to 10 %. Conclusions. In the populations located in ecologically polluted and anthropogenically loaded areas, the sets of alleles expand and the specific phenotypes appear under the influence of the mutation processes and natural selection. In the population without the anthropogenic load the decrease of the polymorphism and the increase of the frequency of individual genotypes (vv, VV) were observed.
 Keywords: Trifolium repens L., leaf phenotype, intrapopulation polymorphism, multiple allelism, bioindication, anthropogenic load.

Chronic hepatitis B in children carried out of the hemochromatosis gene HFE

Purpose: to establish the frequency and clinical significance of mutant variations of the HFE gene polymorphism in chronic hepatitis B (CHB) in children with iron overload syndrome (IOS).Materials and methods: 60 children with chronic hepatitis B with iron overload syndrome (IOS) were examined. When distributing children into groups, we took into account the criteria we developed for assessing the degree of life expectancy in children with CHB: CST>0.5 – mild degree of life expectancy (43,3% of children), CST˃0.5 – mild degree of life expectancy (43,3% of children), CST˂0,5 – moderate severity of life expectancy (31,7% of children) and CST˂0,2 – severe degree of SPL (25,0%). Virological verification of HBV was performed by ELISA and PCR. Using PCR Real Time and molecular genetic analysis, HFE gene C282Y, H63D, S65C mutations were detected from amplified DNA using the PRONTO Hemochromatosis reagent kit (Israel). The transferrin saturation coefficient (CST) was calculated using the formula CST = sTfR / log10.Ft. Results:Results: The study of the hemochromatosis gene HFE showed that the overwhelming majority (84,0%) of children with CHB with IOS were carriers of heterozygous, phenotypically different, mutant types. And only 16,0% of sick children were homozites of the wild (normal) HFE gene. Analysis of the phenotypic polymorphism of the hemochromatosis gene HFE revealed the presence of three point heterozygous mutations: H63D, S65C and combined variations in H63D / S65C, the latter of which is associated with severe forms of CHB and severe IOS.Conclusion. Children with CHB with IOS are characterized by a high incidence of heterozygous mutations in the HFE gene, the phenotypic manifestations of which were S65C, H63D, H63D / S65C. The comparability of the heterozygous combined mutation H63D / S65C with severe forms of CHB and a severe degree of IOS gives grounds to consider this phenotype of the HFE gene as a factor in the progression of the disease.

Prevalence of ABO, Rh and KELL Blood Group Types and Transfusion- Transmissible Infections (TTI) among Blood Donors in Najran City, Saudi Arabia

The knowledge of Red blood cells polymorphism and blood group antigens prevalence at the local and regional levels is necessary for safe blood transfusion services. This study was aimed to estimate the prevalence of significant blood group phenotypes like ABO, Rh, and Kell among the Najran people of Saudi Arabia. The transfusion transmittable infection (TTI) rate and blood abnormalities among various blood types were assessed to ensure safe blood transfusion. ABO and Rh blood prevalence (n=970) and Rh phenotype polymorphism were estimated in over 531 unrelated donors. The blood samples were screened for certain TTIs like AHBC- Anti-hepatitis B core, HTLV-1- human T-lymphotropic virus type I, HCV- hepatitis C virus, HBsAg- Hepatitis B antigen, HIV- Human immunodeficiency virus, SIC- Sickle cell, MP- Malaria parasite, and SYP- Syphilis. The selected samples were also observed for blood abnormalities by performing a complete blood count (CBC). Out of 970 subjects, 966 were males, and only 4 were females. The O>A>B>AB blood groups were identified with 46.89, 29.3, 9.1, and 2.38% prevalence among Rh-positive phenotype. While in the Rh system, 87.6% and 12.3% of Rh positive and Rh negative was observed. Among 953 samples, the prevalence of seropositive donors was approximately 5.66%. The screening showed about 5.036, 0.104, 0.314, 0.209, 2.18, 0.104, and 0.209% positivity for AHBC, HCV, HBsAg, HIV, SIC, MP, and SYP respectively. Results found that the frequency of D, C, E, c, and e were 99.9%, 67.98, 25.8, 77.9, 98.49%, respectively, in over 531 subjects. The e allele was more prevalent in Najran city. After observing the variations in the CBC parameters among the donors, it was perceived that about 28.78, 99.9, 29.41, and 31.6% of blood abnormalities were noticed for O, AB, B, and A blood groups, respectively. For blood banks and transfusion services, which play a significant role in the medical care of the patient, awareness of the distribution of the blood group is essential. Increasing consistency of blood donation programs would improve both donor satisfaction and motivation for potential donations of blood in near future.

Phylogeographic analysis of Saxifraga fortunei complex (Saxifragaceae) reveals multiple origins of morphological and ecological variations in the Japanese Archipelago

Phenotypic polymorphism within a species is a notable phenomenon in evolutionary biology to understand the process of adaptive speciation and other historical events. The Saxifraga fortunei complex is a widespread herb found in East Asia. It includes several ecotypic taxa corresponding to their habitat environments. The distribution of the various ecotypes in a limited area of the Japanese Archipelago makes the species a suitable model to investigate the impact of population demographic history and natural selection on lineage diversification. Here, Sanger-based sequencing was used to estimate the divergence timeframe between populations of the Eurasian continent and Japan. Genome-wide SNPs obtained by ddRAD sequencing were used to investigate the phylogeographic origins of ecotypic taxa. The phylogenetic analyses revealed the divergence of the Japanese population from the continental population in the late Miocene. Two distinct regional clades of North and South Japan were identified; phenotypic diversification was evident only in the southern clade. The South Japan clades displayed a historical distribution expansion from north to south. The phenotypic variations appeared to have generated during the expansion. The ecotypic boundaries were incongruent with the genetic grouping. We propose that morphological and ecological specialization in Japanese populations was repeatedly generated by local natural selection.

Correlational selection in the age of genomics.

Ecologists and evolutionary biologists are well aware that natural and sexual selection do not operate on traits in isolation, but instead act on combinations of traits. This long-recognized and pervasive phenomenon is known as multivariate selection, or-in the particular case where it favours correlations between interacting traits-correlational selection. Despite broad acknowledgement of correlational selection, the relevant theory has often been overlooked in genomic research. Here, we discuss theory and empirical findings from ecological, quantitative genetic and genomic research, linking key insights from different fields. Correlational selection can operate on both discrete trait combinations and quantitative characters, with profound implications for genomic architecture, linkage, pleiotropy, evolvability, modularity, phenotypic integration and phenotypic plasticity. We synthesize current knowledge and discuss promising research approaches that will enable us to understand how correlational selection shapes genomic architecture, thereby linking quantitative genetic approaches with emerging genomic methods. We suggest that research on correlational selection has great potential to integrate multiple fields in evolutionary biology, including developmental and functional biology, ecology, quantitative genetics, phenotypic polymorphisms, hybrid zones and speciation processes.

The prevalence, putative virulence genes and antibiotic resistance profiles of Aeromonas spp. isolated from cultured freshwater fishes in peninsular Malaysia

Aeromonas species are ubiquitous in diverse aquatic habitats. High stocking density and improper farm practices can increase the susceptibility of cultured freshwater fishes to motile Aeromonas septicemia (MAS) outbreak. However, polymorphic phenotypes and genotypes can lead to misidentification of Aeromonas isolates from diseased fish. This study characterized a large collection of Aeromonas spp. that were collected from nine important fish farms in Peninsular Malaysia, and to compare these isolates based on their virulence and antibiotic resistance profiles. A total of 124 isolates were obtained from fish with clinical symptoms of MAS that grew on Aeromonas selective agar, were Gram-negative and were oxidase-positive, indicating these as presumptive Aeromonas spp. Based on a phylogenetic analysis of these isolates using gyrB sequences, along with phenotypic analysis based on a series of biochemical tests, five species of Aeromonas were identified among these isolates. Among these isolates, Aeromonas dhakensis was obtained most frequently (43%), followed by A. veronii (22%), A. hydrophila (20%), A. caviae (8%) and A. jandaei (7%). Moreover, 50% of the isolates were found to harbour at least half of the virulence genes tested such as aer, ahp, alt, hly, lip, fla, ela and/or act, while 2% of the isolates were found to harbour none. The Aeromonas isolates displayed resistance to amikacin (5%), ampicillin (100%), cefotaxime (7%), amoxicillin (65%), gentamicin (2%), chloramphenicol (2%) and tetracycline (15%), but not for levofloxacin (0%). The highest multiple antibiotic resistance (MAR) index of 0.63 was found in 1% of the isolates, while the mean MAR index was determined at 0.25. This study reported the prevalence of Aeromonas in cultured freshwater fishes in Peninsular Malaysia, where A. dhakensis was observed as the predominant species. However, the presence of Aeromonas with multiple virulence genes and antibiotic resistance ability should alarm the freshwater fish industry in this country.

The DRD2/ANKK1 Taq1A polymorphism in CYP2D6 extensive metabolizers is associated with the severity of extrapyramidal side effects of haloperidol treatment in schizophrenia spectrum disorders patients

IntroductionSchizophrenia is one of the most severe mental disorders. Haloperidol and other first-generation antipsychotics are widely used for schizophrenia treatment, but have prominent side effects, primarily extrapyramidal symptoms (EPS). The EPS severity is highly variable and may be underlied by genetic factors.ObjectivesWe performed a prospective study to test the association of DRD2/ANKK1 Taq1A polymorphism (rs18000497) and CYP2D6 phenotype, predicted from genotypes using 8 CYP2D6 alleles (*3, *4, *5, *6,*9, *10,*41, xN) with EPS severity during haloperidol treatment in schizophrenia spectrum disorders patients.Methods57 inpatients with schizophrenia spectrum disorders (42,1% females; mean age - 46,7±11,8 y.o (M±SD) of European ancestry were enrolled in the study. Abnormal Involuntary Movement Scale (AIMS), Barnes Akathisia Rating Scale (BARS), Simpson-Angus Scale (SAS) were used to assess EPS on two timepoints: day 1 and day 21 of haloperidol treatment.ResultsTaqIA T-allele carriers in contrast to wild-type allele homozygous patients had higher scores of BARS (p=0.029) and SAS (p=0.024) on day 21. After stratification by CYP2D6 phenotype, these differences were observed only in extensive metabolizers (p=0.006 and p=0.001 respectively), although the CYP2D6 phenotype itself was not associated with EPS severity. The combined effect of TaqIA T allele with CYP2D6 extensive phenotype on BARS score on day 21 was confirmed by General Linear Model (p=0.013).ConclusionsOur results show that minor TaqIA T-allele is associated with the severity of EPS after 3 weeks of haloperidol treatment only in CYP2D6 extensive metabolizers. That highlights the importance of using both pharmacokinetic and pharmacodynamic genetic markers in pharmacogenetic EPS risk assessment.DisclosureNo significant relationships.

Melatonin Receptor A Gene, Melatonin Receptor C Gene and Ovocalyxin-32 gene polymorphisms associated with some Egg Production in Local Iraqi Chicken

The aim of this research is to detect genetic polymorphisms of some candidate genes associated with eggproduction trait and to find the relationship between some of these genetic sites and the productive traitsof Local Iraqi chickens that will be used for the national poultry breeding programs to increase quality eggproduction in endogenous chicken. Genomic DNA were extracted and then amplified three genes (melatoninreceptor a gene MTNRa, melatonin receptor c gene MTNRc and ovocalyxin-32 gene (OCX-32). (MTNRa)gene amplified by PCR-SSCP method. The distribution of percentages in female Iraqi Local chicken studiedfor (MTNRa) were 73, 20, 5 and 2% for TN, TNA, NN and TT SSCP-genotype respectively. It turnedout that phenotypic polymorphisms of MTNRa gene was significant (p<0.05) with Serum Melatonin andMagnesium concentrations, in addition to First egg weight FEW and Body weight at maturity. (MTNRc)gene amplified by PCR-RFLP method, the distribution of percentages of MTNRc genetic location in femaleIraqi Local chicken Flock studied were 23, 61 and 16 % for MM, Mm, mm RFLP-genotype respectively, itturned out that phenotypic diversity of MTNRc gene was significant (p<0.05) in mean of Serum Melatoninand Magnesium concentration, in addition to First egg weight FEW and Body weight at maturity. (OCX-32)gene amplified by PCR-SSCP method. The distribution of percentages in female Iraqi Local chicken studiedwere 98 and 2% for WS and SS (SSCP-genotype) respectively. It turned out that phenotypic polymorphismsof OCX-32 genetic site were significant (p<0.05) with serum Melatonin and Magnesium concentration andBody weight at maturity. The present research suggests that the genes MTNRa, MTNRc and OCX-32 couldbe used as a possible marker in Marker Assisted Selection (MAS) and genomic selection programs for localIraqi chickens.

The Genomic Architecture and Evolutionary Fates of Supergenes.

Supergenes are genomic regions containing sets of tightly linked loci that control multi-trait phenotypic polymorphisms under balancing selection. Recent advances in genomics have uncovered significant variation in both the genomic architecture as well as the mode of origin of supergenes across diverse organismal systems. Although the role of genomic architecture for the origin of supergenes has been much discussed, differences in the genomic architecture also subsequently affect the evolutionary trajectory of supergenes and the rate of degeneration of supergene haplotypes. In this review, we synthesize recent genomic work and historical models of supergene evolution, highlighting how the genomic architecture of supergenes affects their evolutionary fate. We discuss how recent findings on classic supergenes involved in governing ant colony social form, mimicry in butterflies, and heterostyly in flowering plants relate to theoretical expectations. Furthermore, we use forward simulations to demonstrate that differences in genomic architecture affect the degeneration of supergenes. Finally, we discuss implications of the evolution of supergene haplotypes for the long-term fate of balanced polymorphisms governed by supergenes.

SLCO1B1 Phenotype and CYP3A5 Polymorphism Significantly Affect Atorvastatin Bioavailability.

Atorvastatin, prescribed for the treatment of hypercholesterolemia, demonstrated overwhelming benefits in reducing cardiovascular morbidity and mortality. However, many patients discontinue therapy due to adverse reactions, especially myopathy. The Dutch Pharmacogenetics Working Group (DPWG) recommends an alternative agent to atorvastatin and simvastatin or a dose adjustment depending on other risk factors for statin-induced myopathy in SLCO1B1 rs4149056 CC or TC carriers. In contrast, the Clinical Pharmacogenetics Implementation Consortium (CPIC) published their guideline on simvastatin, but not on atorvastatin. In this work, we aimed to demonstrate the effect of SLCO1B1 phenotype and other variants (e.g., in CYP3A4/5, UGT enzymes or SLC transporters) on atorvastatin pharmacokinetics. For this purpose, a candidate-gene pharmacogenetic study was proposed. The study population comprised 156 healthy volunteers enrolled in atorvastatin bioequivalence clinical trials. The genotyping strategy comprised a total of 60 variants in 15 genes. Women showed higher exposure to atorvastatin compared to men (p = 0.001), however this difference disappeared after dose/weight (DW) correction. The most relevant pharmacogenetic differences were the following: AUC/DW and Cmax /DW based on (a) SLCO1B1 phenotype (p < 0.001 for both) and (b) CYP3A5*3 (p = 0.004 and 0.018, respectively). As secondary findings: SLC22A1 *2/*2 genotype was related to higher Cmax/DW (ANOVA p = 0.030) and SLC22A1 *1/*5 genotype was associated with higher Vd/F (ANOVA p = 0.032) compared to SLC22A1 *1/*1, respectively. Finally, UGT2B7 rs7439366 *1/*1 genotype was associated with higher tmax as compared with the *1/*3 genotype (ANOVA p = 0.024). Based on our results, we suggest that SLCO1B1 is the best predictor for atorvastatin pharmacokinetic variability and that prescription should be adjusted based on it. We suggest that the CPIC should include atorvastatin in their statin-SLCO1B1 guidelines. Interesting and novel results were observed based on CYP3A5 genotype, which should be confirmed with further studies.Atorvastatin, prescribed for the treatment of hypercholesterolemia, demonstrated overwhelming benefits in reducing cardiovascular morbidity and mortality. However, many patients discontinue therapy due to adverse reactions, especially myopathy. The Dutch Pharmacogenetics Working Group (DPWG) recommends an alternative agent to atorvastatin and simvastatin or a dose adjustment depending on other risk factors for statin-induced myopathy in SLCO1B1 rs4149056 CC or TC carriers. In contrast, the Clinical Pharmacogenetics Implementation Consortium (CPIC) published their guideline on simvastatin, but not on atorvastatin. In this work, we aimed to demonstrate the effect of SLCO1B1 phenotype and other variants (e.g., in CYP3A4/5, UGT enzymes or SLC transporters) on atorvastatin pharmacokinetics. For this purpose, a candidate-gene pharmacogenetic study was proposed. The study population comprised 156 healthy volunteers enrolled in atorvastatin bioequivalence clinical trials. The genotyping strategy comprised a total of 60 variants in 15 genes. Women showed higher exposure to atorvastatin compared to men (p = 0.001), however this difference disappeared after dose/weight (DW) correction. The most relevant pharmacogenetic differences were the following: AUC/DW and Cmax /DW based on (a) SLCO1B1 phenotype (p < 0.001 for both) and (b) CYP3A5*3 (p = 0.004 and 0.018, respectively). As secondary findings: SLC22A1 *2/*2 genotype was related to higher Cmax/DW (ANOVA p = 0.030) and SLC22A1 *1/*5 genotype was associated with higher Vd/F (ANOVA p = 0.032) compared to SLC22A1 *1/*1, respectively. Finally, UGT2B7 rs7439366 *1/*1 genotype was associated with higher tmax as compared with the *1/*3 genotype (ANOVA p = 0.024). Based on our results, we suggest that SLCO1B1 is the best predictor for atorvastatin pharmacokinetic variability and that prescription should be adjusted based on it. We suggest that the CPIC should include atorvastatin in their statin-SLCO1B1 guidelines. Interesting and novel results were observed based on CYP3A5 genotype, which should be confirmed with further studies.