Genetic determinism

The 11q terminal deletion disorder (11q-) is a rare chromosomal disorder caused by a deletion in distal 11q. Fifty-six percent of patients have clinically significant congenital heart defects. A cardiac ''critical region'' has been identified in distal 11q that contains over 40 annotated genes. In this study, we identify the distal breakpoint of a patient with a paracentric inversion in distal 11q who had hypoplastic left heart and congenital thrombocytopenia. The distal breakpoint mapped to JAM-3, a gene previously identified as a candidate gene for causing HLHS in 11q-. To determine the role of JAM-3 in cardiac development, we performed a comprehensive cardiac phenotypic assessment in which the mouse homolog for JAM-3, JAM-C, has been deleted. These mice have normal cardiac structure and function, indicating that haplo-insufficiency of JAM-3 is unlikely to cause the congenital heart defects that occur in 11q-patients. Notably, we identified a previously undescribed phenotype, jitteriness, in most of the sick or dying adult JAM-C knockout mice. These data provide further insights into the identification of the putative disease-causing cardiac gene(s) in distal 11q, as well as the functions of JAM-C in normal organ development.

Duane syndrome is a congenital eye movement disorder characterized most typically by absence of abduction, restricted adduction, and retraction of the globe on attempted adduction. Duane syndrome can be coinherited with radial ray anomalies as an autosomal dominant trait, referred to as "Okihiro syndrome" or "Duane radial ray syndrome" (DRRS). We ascertained three pedigrees with DRRS and mapped their disease gene to a 21.6-cM region of chromosome 20 flanked by markers D20S888 and D20S102. A new member of the SAL family of proposed C 2 H 2 zinc finger transcription factors, SALL4, falls within the region. Mutation analysis of SALL4 in the three pedigrees revealed one nonsense and two frameshift heterozygous mutations. SALL4 represents the first identified Duane syndrome gene and the second malformation syndrome resulting from mutations in SAL genes and likely plays a critical role in abducens motoneuron development. Several forms of congenital ophthalmoplegia are hypothesized to result from errors in the development of the ocular cranial nuclei . The most common of these, Duane syndrome (MIM 126800 and MIM 604356), is characterized by restricted or absent abduction and variably restricted adduction with retraction of the globe on attempted adduction, and results from absence of the abducens (nVI) motoneurons and nerve, with sparing of the internuclear neurons . Two Duane syndrome loci (DURS1 and DURS2) have been mapped, but neither gene has been identified . Duane syndrome can be coinherited with radial anomalies in an autosomal dominant fashion (fig. ). In affected individuals, radial dysplasia ranges from hypoplasia of the thenar eminence to absence of the radial bone or forearm. Variable expression of sensorineural hearing loss and cardiac, renal, vertebral, and lower extremity malformations can occur. De-

Individuals with a diagnosis of adult separation anxiety (ASAD) have extreme anxiety about separations, actual or imagined, from major attachment figures. ASAD might represent a psychological/behavioral model for research probably involving a dysregulation of those neurobiological mechanisms of attachment, in particular central oxytocin (OT), described in numerous animal studies. As experimental strategy, we chose the nucleotidic sequencing of the human OT gene of patients with ASAD to evaluate whether OT mutations were related to potential alteration of its production. With this aim, mutation scanning of proximal promoter and untranslated and coding regions of the OT gene was carried out in 36 patients with ASAD, 14 patients without ASAD, and 26 controls. No mutations were found in promoter and coding regions of the OT gene in our population. One rare 3′UTR single nucleotide variant (rs17339677) and one intron 2 molecular variant (rs34097556), which showed a high frequency, were evidenced. There was no significant difference in the genotype distribution of this intron 2 polymorphism between patients and healthy individuals. Further research is needed to investigate the association between ASAD and OT peptide and receptor polymorphisms.

The extent to which the genetic risk for alcohol dependence (AD) and conduct disorder (CD) and their common genetic risk overlap with genetic factors contributing to variation in dimensions of personality was examined in a study of 6,453 individuals from 3,383 adult male and female same-sex and unlike-sex twin pairs from the Australian Twin Registry. The associations between the personality dimensions of positive emotionality, negative emotionality, and AD and CD risk were modest, whereas the associations between behavioral undercontrol and AD and CD risk were substantially higher. Genetic influences contributing to variation in behavioral undercontrol accounted for about 40% of the genetic variation in AD and CD risk and about 90% of the common genetic risk for AD and CD. These results suggest that genetic factors contributing to variation in dimensions of personality, particularly behavioral undercontrol, account for a substantial proportion of the genetic diathesis for AD and most of the common genetic diathesis for AD and CD among both men and women.

Objective: Using a sample of sibling pairs discordant for psychosis, the authors attempted to replicate the findings of previous studies suggesting that the functional genetic polymorphism Val158Met in the catechol O-methyltransferase (COMT) gene influences prefrontal cognitive function and increases the risk for schizophrenia. Method: Eighty-nine sibling pairs discordant for psychosis were genotyped for this polymorphism and were assessed with the Wisconsin Card Sorting Test, a measure of prefrontal function. Additionally, the preferential transmission of alleles for this polymorphism was analyzed in a sample of 89 nuclear families in order to examine the genetic association. Results: In the healthy siblings, a linear relationship was seen in which performance on the Wisconsin Card Sorting Test was associated in an allele dosage fashion with COMT genotype (i.e., fewer perseverative errors with higher number of methionine alleles). However, this association was not observed in patients. Furthermore, no evidence of genetic association with psychosis was detected. Conclusions: These results seem to confirm the role of COMT genotype in the modulation of executive functions related to frontal lobe function in healthy individuals but not in schizophrenia patients.

Behavioral genetic investigations have consistently demonstrated large genetic influences for the core symptom dimensions of attention-deficit/hyperactivity disorder (ADHD), namely inattention (INATT) and hyperactivity (HYP). Yet little is known regarding potential similarities and differences in the type of genetic influence (i.e., additive vs. nonadditive) on INATT and HYP. As these symptom dimensions form the basis of the current Diagnostic and Statistical Manual of Mental Disorders subtype classification system, evidence of differential genetic influences would have important implications for research investigating causal mechanisms for ADHD. The current meta-analysis aimed to investigate the nature of etiological influences for INATT and HYP by comparing the type and magnitude of genetic and environmental influences each. A comprehensive literature search yielded 79 twin and adoption studies of INATT and/or HYP. Of these, 13 samples of INATT and 9 samples of HYP were retained for analysis. Results indicated that both dimensions were highly heritable (genetic factors accounted for 71% and 73% of the variance in INATT and HYP, respectively). However, the 2 dimensions were distinct as to the type of genetic influence. Dominant genetic effects were significantly larger for INATT than for HYP, whereas additive genetic effects were larger for HYP than for INATT. Estimates of unique environmental effects were small to moderate and shared environmental effects were negligible for both symptom dimensions. The pattern of results generally persisted across several moderating factors, including gender, age, informant, and measurement method. These findings highlight the need for future studies to disambiguate INATT and HYP when investigating the causal mechanisms, and particularly genetic influences, behind ADHD.

Behavioral genetic investigations have consistently demonstrated large genetic influences for the core symptom dimensions of attention-deficit/hyperactivity disorder (ADHD), namely inattention (INATT) and hyperactivity (HYP). Yet little is known regarding potential similarities and differences in the type of genetic influence (i.e., additive vs. nonadditive) on INATT and HYP. As these symptom dimensions form the basis of the current Diagnostic and Statistical Manual of Mental Disorders subtype classification system, evidence of differential genetic influences would have important implications for research investigating causal mechanisms for ADHD. The current meta-analysis aimed to investigate the nature of etiological influences for INATT and HYP by comparing the type and magnitude of genetic and environmental influences each. A comprehensive literature search yielded 79 twin and adoption studies of INATT and/or HYP. Of these, 13 samples of INATT and 9 samples of HYP were retained for analysis. Results indicated that both dimensions were highly heritable (genetic factors accounted for 71% and 73% of the variance in INATT and HYP, respectively). However, the 2 dimensions were distinct as to the type of genetic influence. Dominant genetic effects were significantly larger for INATT than for HYP, whereas additive genetic effects were larger for HYP than for INATT. Estimates of unique environmental effects were small to moderate and shared environmental effects were negligible for both symptom dimensions. The pattern of results generally persisted across several moderating factors, including gender, age, informant, and measurement method. These findings highlight the need for future studies to disambiguate INATT and HYP when investigating the causal mechanisms, and particularly genetic influences, behind ADHD.

Attention-Deficit/Hyperactivity Disorder (ADHD) is a prime candidate for exploration of geneby-environment interaction (i.e., G × E), particularly in relation to dopamine system genes, due to strong evidence that dopamine systems are dysregulated in the disorder. Using a G × E design, we examined whether the DRD4 promoter 120-bp tandem repeat polymorphism, previously associated with ADHD, moderated the effects of inconsistent parenting and marital conflict on ADHD or Oppositional-Defiant Disorder (ODD). Participants were 548 children with ADHD and non-ADHD comparison children and their parents. Homozygosity for the DRD4 promoter 120-bp tandem repeat insertion allele increased vulnerability for ADHD and ODD only in the presence of inconsistent parenting and appeared to increase susceptibility to the influence of increased child self-blame for marital conflict on ADHD inattention. DRD4 genotypes may interact with these proximal family environmental risk factors by increasing the individual's responsivity to environmental contingencies.

Personality traits may be viable candidates for mediators of the relationship between genetic risk and ADHD. Participants were 578 children (331 boys; 320 children with ADHD) between the ages of six and 18. Parents and teachers completed a comprehensive, multistage diagnostic procedure to assess ADHD and comorbid disorders. Mother completed the California Q-Sort to assess child Big Five personality traits. Children provided buccal samples of DNA which were assayed for selected markers on DRD4, DAT1, and ADRA2A. An additive genetic risk composite was associated with ADHD symptoms and maladaptive personality traits; maladaptive personality traits were associated with ADHD symptoms. Low conscientiousness and high neuroticism partially mediated the relationship between genetic risk and ADHD symptoms. Mediation effects for conscientiousness were specific to inattentive symptoms; effects for neuroticism generalized to all disruptive behaviors. High neuroticism and low conscientiousness may be useful as early markers for children at risk for ADHD.

X-linked retinitis pigmentosa (XLRP) is a clinically and genetically heterogeneous degenerative disease of the retina. At least five loci have been mapped for XLRP; of these, RP2 and RP3 account for 10%-20% and 70%-90% of genetically identifiable disease, respectively. However, mutations in the respective genes, RP2 and RPGR, were detected in only 10% and 20% of families with XLRP. Mutations in an alternatively spliced RPGR exon, ORF15, have recently been shown to account for 60% of XLRP in a European cohort of 47 families. We have performed, in a North American cohort of 234 families with RP, a comprehensive screen of the RP2 and RPGR (including ORF15) genes and their 5 upstream regions. Of these families, 91 (39%) show definitive X-linked inheritance, an additional 88 (38%) reveal a pattern consistent with X-linked disease, and the remaining 55 (23%) are simplex male patients with RP who had an early onset and/or severe disease. In agreement with the previous studies, we show that mutations in the RP2 gene and in the original 19 RPGR exons are detected in !10% and ∼20% of XLRP probands, respectively. Our studies have revealed RPGR-ORF15 mutations in an additional 30% of 91 welldocumented families with X-linked recessive inheritance and in 22% of the total 234 probands analyzed. We suggest that mutations in an as-yet-uncharacterized RPGR exon(s), intronic changes, or another gene in the region might be responsible for the disease in the remainder of this North American cohort. We also discuss the implications of our studies for genetic diagnosis, genotype-phenotype correlations, and gene-based therapy.

Objective-To investigate the significance of functional polymorphisms of inflammatory response genes by analysis of a large population of patients, both with and without severe sepsis, and representative of the diverse populations (geographic diversity, physician diversity, clinical treatment diversity) that would be encountered in critical care clinical practice.

Objective-To investigate the significance of functional polymorphisms of inflammatory response genes by analysis of a large population of patients, both with and without severe sepsis, and representative of the diverse populations (geographic diversity, physician diversity, clinical treatment diversity) that would be encountered in critical care clinical practice.

Matrix metalloproteinases (MMPs) are a family of zinc-dependent proteinases that are capable of cleaving all extra cellular matrix (ECM) substrates. Degradation of matrix is a key event in progression, invasion and metastasis of potentially malignant and malignant lesions of the head and neck. It might have an important polymorphic association at the promoter regions of several MMPs such as MMP-1 (-1607 1G/2G), MMP-2 (-1306 C/T), MMP-3 (-1171 5A/6A), MMP-9 (-1562 C/T) and TIMP-2 (-418 G/C or C/C). Tissue inhibitors of metalloproteinases (TIMPs) are naturally occurring inhibitors of MMPs, which inhibit the activity of MMPs and control the breakdown of ECM. Currently, many MMP inhibitors (MMPIs) are under development for treating different malignancies. Useful markers associated with molecular aggressiveness might have a role in prognostication of malignancies and to better recognize patient groups that need more antagonistic treatment options. Furthermore, the introduction of novel prognostic markers may also promote exclusively new treatment possibilities, and there is an obvious need to identify markers that could be used as selection criteria for novel therapies. The objective of this review is to discuss the molecular functions and polymorphic association of MMPs and TIMPs and the possible therapeutic aspects of these proteinases in potentially malignant and malignant head and neck lesions. So far, no promising drug target therapy has been developed for MMPs in the lesions of this region. In conclusion, further research is required for the development of their potential diagnostic and therapeutic possibilities.

Molecular variants of the angiotensinogen gene, a key component of the renin-angiotensin system, are considered genetic risk factors for primary hypertension. A relation between the angiotensinogen gene locus and hypertension has been found in whites, Japanese, and African Caribbeans but not in Chinese. The lack of a consistent association between M235T polymorphism at exon 2 and hypertension has suggested that another site in linkage disequilibrium with M235T is the causal mutation. We studied the relations among plasma angiotensinogen concentrations, blood pressure, related clinical variables, and mutations of the 5Ј upstream core promoter region of the human angiotensinogen gene in 274 subjects recruited from our outpatient clinic. We confirmed that plasma angiotensinogen concentration was significantly correlated with AϪ20C mutation and percent body fat and found that systolic and diastolic blood pressures were significantly correlated with GϪ6A and Tϩ68C mutations. These results suggest that mutations near the transcription start site may be associated with increased blood pressure. (Hypertension.

The human microsomal 11β-hydroxysteroid dehydrogenase type 2 (11βHSD2) metabolizes active cortisol into cortisone and protects the mineralocorticoid receptor from glucocorticoid occupancy. In a congenital deficiency of 11β-HSD2, the protective mechanism fails and cortisol gains inappropriate access to mineralocorticoid receptor, resulting in low-renin hypertension and hypokalemia. In the present study, we describe the clinical and molecular genetic characterization of a patient with a new mutation in the HSD11B2 gene. This is a 4-yr-old male with arterial hypertension. The plasma renin activity and serum aldosterone were undetectable in the presence of a high cortisol to cortisone ratio. PCR amplification and sequence analysis of HSD11B2 gene showed the homozygous mutation in exon 4 Asp223Asn (GAC→AAC) and a single nucleotide substitution C→T in intron 3. Using site-directed mutagenesis, we generated a mutant 11βHSD2 cDNA containing the Asp223Asn mutation. Wild-type and mutant cDNA ...

Decrease in leaf growth rate under water deficit can be seen as an adaptive process. The analysis of its genetic variability is therefore important in the context of drought tolerance. Several mechanisms are widely believed to drive the reduction in leaf growth rate under water deficit, namely leaf carbon balance, incomplete turgor maintenance, and decrease in cell wall plasticity or in cell division rate, with contributions from hormones such as abscisic acid or ethylene. Each of these mechanisms is still controversial, and involves several families of genes. It is argued that gene regulatory networks are not feasible for modelling such complex systems. Leaf growth can be modelled via response curves to environmental conditions, which are considered as ‘meta-mechanisms’ at a higher degree of organisation. Response curves of leaf elongation rate to meristem temperature, atmospheric vapour pressure deficit, and soil water status were established in recombinant inbred lines (RILs) of ...

In common with several other autoimmune diseases, autoimmune Addison's disease (AAD) is thought to be caused by a combination of deleterious susceptibility polymorphisms in several genes, together with undefined environmental factors and stochastic events. To date, the strongest genomic association with AAD has been with alleles at the HLA locus, DR3-DQ2 and DR4. The contribution of other genetic variants has been inconsistent. We have studied the association of 16 single-nucleotide polymorphisms (SNPs) within the CD28-CTLA-4-ICOS genomic locus, in a cohort comprising 691 AAD patients of Norwegian and UK origin with matched controls. We have also performed a meta-analysis including 1002 patients from European countries. The G-allele of SNP rs231775 in CTLA-4 is associated with AAD in Norwegian patients (odds ratio (OR) = 1.35 (confidence interval (CI) 1.10-1.66), P = 0.004), but not in UK patients. The same allele is associated with AAD in the total European population (OR = 1.37 (CI 1.13-1.66), P = 0.002). A three-marker haplotype, comprising PROMOTER_1661, rs231726 and rs1896286 was found to be associated with AAD in the Norwegian cohort only (OR 2.43 (CI 1.68-3.51), P = 0.00013). This study points to the CTLA-4 gene as a susceptibility locus for the development of AAD, and refines its mapping within the wider genomic locus.

More than 90% of the cases of congenital adrenal hyperplasia are caused by mutations of the CYP21 gene. Approximately 75% of the defective CYP21 genes are generated through intergenic recombination, termed apparent gene conversion, from the neighboring CYP21P pseudogene. Among them, mutation of the aberrant splicing donor site of IVS2 –12A/C>G at nucleotide (nt) 655 is believed to be a result derived from this mechanism and is the most prevalent case among all ethnic groups. However, mutation of 707–714delGAGACTAC rarely exists alone, although this locus is a distance of 53 nt away from IVS2 –12A/C>G. From the molecular characterization of the mutation of IVS2 –12A/C>G combined with 707–714delGAGACTAC in patients with congenital adrenal hyperplasia, we found that it appeared to be in a 3.2-rather than a 3.7-kb fragment generated by Taq I digestion in a PCR product of the CYP21 gene. Interestingly, the 5′ end region of such a CYP21 haplotype had CYP21P-specific sequences. Ou...

Background-Serotonin transporter promoter (5-HTTLPR) genotype appears to increase risk for depression in the context of stressful life events. However, the effects of this genotype on measures of stress sensitivity are poorly understood. Therefore, this study examined whether 5-HTTLPR genotype was associated with negative information processing biases in early childhood. Method-Thirty-nine unselected seven-year-old children completed a negative mood induction procedure and a self-referent encoding task designed to measure positive and negative schematic processing. Children were also genotyped for the 5-HTTLPR gene. Results-Children who were homozygous for the short allele of the 5-HTTLPR gene showed greater negative schematic processing following a negative mood prime than those with other genotypes. 5-HTTLPR genotype was not significantly associated with positive schematic processing.

The immunodysregulation, polyendocrinopathy, enteropathy syndrome (IPEX), is a rare disorder of immune regulation resulting in multiple autoimmune disorders, which demonstrates X-linked recessive inheritance. The disease gene, FOXP3, was identified in 2001, and several mutations within this gene have since been described in patients with IPEX. We used linkage analysis, mutational screening of the FOXP3 gene, human leukocyte antigen typing, and analysis of X-chromosome inactivation to investigate 2 kindreds (21 subjects in total) with 4 male infants (3 now deceased) and 1 girl affected by IPEX. In 1 family a novel FOXP3 mutation was identified in the proband, with a single base deletion at codon 76 of exon 2, leading to a frameshift, which predicted a truncated protein product (108 residues vs. 431 in wild type). In the second family, the FOXP3 locus was excluded by recombination, and mutational analysis of the gene was negative. The affected girl from this family was shown to have h...

Summaryobjective Strong evidence indicates that at least one key tumour suppressor gene important for the development of malignant parathyroid tumours is located on chromosome 13, but the critical target gene remains unknown. Importantly, the region of acquired DNA loss includes two established tumour suppressor genes, the retinoblastoma gene, RB (RB1) and BRCA2. Resolution of whether RB or BRCA2 is the critical 13q tumour suppressor gene in parathyroid cancer requires analysis of these genes’ sequences for intragenic inactivating mutations. Therefore, RB and BRCA2 were analysed in a group of parathyroid carcinomas in which mutations of these genes should be most readily detectable.patients and design Six parathyroid carcinomas from four patients which showed loss of heterozygosity (LOH) at the RB locus and/or 13q loss by comparative genomic hybridazation (CGH) were selected from a CGH/LOH‐screened panel of 16 carcinoma specimens from 10 patients. These tumours were examined for mut...

Glutathione S-transferases (GSTs) are enzymes involved in the detoxification of several environmental mutagens, carcinogens, and anticancer drugs. GST polymorphisms resulting in decreased enzymatic activity have been associated with several types of solid tumors. We determined the prognostic significance of the deletion of 2 GST subfamilies genes, M1 and T1, in patients with acute myeloid leukemia (AML). Using polymerase chain reactions, we analyzed theGSTM1 and GSTT1 genotype in 106 patients with AML (median age, 60.5 years; range, 19-76 years). The relevance ofGSTM1 and GSTT1 homozygous deletions was studied with respect to patient characteristics, response to therapy, and survival. Homozygous deletions resulting in null genotypes at theGSTM1 and GSTT1 loci were detected in 45 (42%) and 30 (28%) patients, respectively. The double-null genotype was present in 19 patients (18%). GST deletions predicted poor response to chemotherapy (P = .04) and shorter survival (P = .04). The prese...

We investigated cardiac energetics in subjects with mutations in three different familial hypertrophic cardiomyopathy (HCM) disease genes, some of whom were nonpenetrant carriers without hypertrophy, using phosphorus-31 magnetic resonance spectroscopy. BACKGROUND Familial hypertrophic cardiomyopathy is caused by mutations in sarcomeric protein genes. The mechanism by which these mutant proteins cause disease is uncertain. A defect of myocyte contractility had been proposed, but in vitro studies of force generation have subsequently shown opposing results in different classes of mutation. An alternative hypothesis of "energy compromise" resulting from inefficient utilization of adenosine triphosphate (ATP) has been suggested, but in vivo data in humans with genotyped HCM are lacking. The cardiac phosphocreatine (PCr) to ATP ratio was determined at rest in 31 patients harboring mutations in the genes for either beta-myosin heavy chain, cardiac troponin T, or myosin-binding protein C, and in 24 controls. Transthoracic echocardiography was used to measure left ventricular (LV) dimensions and maximal wall thickness. The PCr/ATP was reduced in the HCM subjects by 30% relative to controls (1.70 Ϯ 0.43 vs. 2.44 Ϯ 0.30; p Ͻ 0.001), and the reduction was of a similar magnitude in all three disease-gene groups. The PCr/ATP was equally reduced in subjects with (n ϭ 24) and without (n ϭ 7) LV hypertrophy. CONCLUSIONS Our data provide evidence of a bioenergetic deficit in genotype-confirmed HCM, which is present to a similar degree in three disease-gene groups. The presence of energetic abnormalities, even in those without hypertrophy, supports a proposed link between altered cardiac energetics and development of the disease phenotype. (

Objective: Protein interacting with C-kinase-1 (PICK1) plays a role in the targeting and clustering of dopamine transporter, which is the primary target site for the abused drug methamphetamine. Based on the interaction of PICK1 with dopamine transporter, it is of particular interest to investigate the association between the PICK1 gene and methamphetamine abusers. The authors studied the association between PICK1 gene polymorphisms and methamphetamine abusers in a Japanese group. Two hundred and eight methamphetamine abusers and 218 healthy comparison subjects were enrolled in the study. Furthermore, the authors also examined the effects of single nucleotide polymorphisms (SNPs) in the promoter and 5′-untranslated region on transcription levels of PICK1.

In a previous work, we showed that non-nodulating agrobacteria strains were able to colonize root nodules of common bean. Both rhizobia and agrobacteria coexisted in the infected nodules. No impact on symbiosis was found in laboratory conditions when using sterile gravel as a support for growth. In this study, soil samples originating from different geographic and agronomic regions in Tunisia were inoculated with a mixture of agrobacteria strains isolated previously from root nodules of common bean. A significant effect on nodulation and vegetal growth of common bean was observed. Characterization of nodulating rhizobia and comparison with non-inoculated controls showed a biased genetic structure. It seemed that Rhizobium gallicum was highly inhibited, whereas nodulation by Sinorhizobium medicae was favored. Co-inoculation of non-sterile soils with R. gallicum and agrobacteria confirmed these findings. In vitro antibiosis assays indicated that agrobacteria exercised a significant antagonism against R. gallicum.

The study was carried out at Biochemistry, Agricultural Chemistry and Environmental Science laboratory of Sher-e-Bangla Agricultural University, Dhaka, Bangladesh from March, 2020 to September, 2021 to estimate oil content and fatty acids composition of some Brassica rapa L. genotypes. The experiment was laid out in a completely randomized design with three replications and consisted of four genotypes viz., BARI Sarisha-14, Brown Special, Yellow Special, Tori-7 and their F1s. Result revealed that the oil content ranged from 34.25-45.05% among the studied genotypes. The parent, Yellow Special contained the highest amount of oil (45.05%) and Brown Special contained the lowest amount (39.48%), while among the F1s, (Brown Special×Yellow Special) contained the highest amount (39.04%) and (BARI Sar-14×Brown Special) contained the lowest amount (34.25%). The major saturated and unsaturated fatty acids content ranged from 3.92-5.42% and 92.39-93.50% respectively. The parent, Brown Special a...

Background: The purpose of this study is to examine the prevalence of affective temperaments between clinically unaffected relatives of bipolar patients and secondarily to investigate the impact of these "subaffective" forms on their quality of life (QoL). Methods: The study was performed in seven sites across Argentina. We administered the scales TEMPS-A and Quality of Life Index to a sample of 114 non-ill first degree relatives of bipolar disorder patients ("cases") and 115 comparison subjects without family history of affective illness ("controls"). We used The Mood Disorder Questionnaire to rule out clinical bipolarity. Results: Mean scores on all TEMPS-A subscales were significantly higher in cases, except for hyperthymia. The prevalence of affective temperaments, according to Argentinean cut-off points, was also higher, with statistical significance for cyclothymic and anxious temperaments. Regarding QoL, we found no significant differences between both groups, except for interpersonal functioning, which was better in controls. A detailed subanalysis showed significant effects of QoL domains for all temperaments, except for the hyperthymic. Limitations: We used self-report measures. A larger sample size would have provided us greater statistical power for certain analyses.

Background: Schizophrenia is a complex genetic disorder with no clear pattern of inheritance. Epigenetic modification of genes may thus play a role in its transmission. Methods: In our study, 439 families with at least two ill siblings with schizophrenia (208 with unilineal transmission) were examined for evidence of a parent-of-origin effect (e.g., evidence of parental imprinting on the familial transmission of schizophrenia). Results: No significant difference in the prevalence of maternal compared with paternal transmission was found. In addition, affected male subjects did not differ from affected female subjects in the proportion of their offspring diagnosed with schizophrenia. Conclusions: Although the transmission of schizophrenia may be influenced by epigenetic events, our study fails to find evidence that one epigenetic mechanism, a parent-oforigin imprinting effect, determines whether an individual expresses the illness.

To create novel tomato (Solanum lycopersicum) germplasm, a wild tomato relative, S. pimpinellifolium (a red-fruited LA1585 accession), was used as the male parent to cross with the yellow-fruited tomato mutant, e9292 (S. lycopersicum). Forty-four morphological characteristics were examined in the present study; 22 S. pimpinellifolium (LA1585) traits and six S. lycopersicum (e9292) traits were dominant in the hybrids (first generation, F1); 10 were intermediate types, and the remaining six resulted in a nonmorphological difference. Ten representative lines were chosen from 1338 line of the second generation of the hybrid (e9292 × LA1585). The ascorbic acid content was higher in three F2 hybrids than in LA1585, which had higher parental levels, as well as the lycopene content in two of the hybrid lines. The fructose and glucose contents were higher in five F2 hybrids compared to e9292, and the sugar/acid value was higher in three hybrid lines. The broad-sense heritability values range...

Background: The purpose of this study is to examine the prevalence of affective temperaments between clinically unaffected relatives of bipolar patients and secondarily to investigate the impact of these "subaffective" forms on their quality of life (QoL). Methods: The study was performed in seven sites across Argentina. We administered the scales TEMPS-A and Quality of Life Index to a sample of 114 non-ill first degree relatives of bipolar disorder patients ("cases") and 115 comparison subjects without family history of affective illness ("controls"). We used The Mood Disorder Questionnaire to rule out clinical bipolarity. Results: Mean scores on all TEMPS-A subscales were significantly higher in cases, except for hyperthymia. The prevalence of affective temperaments, according to Argentinean cut-off points, was also higher, with statistical significance for cyclothymic and anxious temperaments. Regarding QoL, we found no significant differences between both groups, except for interpersonal functioning, which was better in controls. A detailed subanalysis showed significant effects of QoL domains for all temperaments, except for the hyperthymic. Limitations: We used self-report measures. A larger sample size would have provided us greater statistical power for certain analyses.

Background: Disrupted in Schizophrenia 1 (DISC1) is currently one of the most interesting candidate genes for major mental illness, having been demonstrated to associate with schizophrenia, bipolar disorder, major depression, autism, and Asperger's syndrome. We have previously reported a DISC1 haplotype, HEP3, and an NDE1 spanning tag haplotype to associate to schizophrenia in Finnish schizophrenia families. Because both DISC1 and NDE1 display association in our study sample, we hypothesized that other genes interacting with DISC1 might also have a role in the etiology of schizophrenia. Methods: We selected 11 additional genes encoding components of the "DISC1 pathway" and studied these in our study sample of 476 families including 1857 genotyped individuals. We performed single nucleotide polymorphism (SNP) and haplotype association analyses in two independent sets of families. For markers and haplotypes found to be consistently associated in both sets, the overall significance was tested with the combined set of families. We identified three SNPs to be associated with schizophrenia in PDE4D (rs1120303, p = .021), PDE4B (rs7412571, p = .018), and NDEL1 (rs17806986, p = .0038). Greater significance was observed with allelic haplotypes of PDE4D (p = .00084), PDE4B (p = .0022 and p = .029), and NDEL1 (p = .0027) that increased or decreased schizophrenia susceptibility. Our findings with other converging lines of evidence support the underlying importance of DISC1-related molecular pathways in the etiology of schizophrenia and other major mental illnesses.

We examined three microsatellites in the arginine vasopressin 1a receptor gene (AVPR1a), two in the promoter region (RS1 and RS3) and an intronic microsatellite (AVR), for association with autism as well as scores on the Vineland Adaptive Behavior Scale (VABS), the Autism Diagnostic Interview-Revised (ADI-R) and the Autism Diagnostic Observation Scale-Generic (ADOS-G), measures that are widely used to diagnose autism spectrum disorders. We tested for association between the AVPR1a microsatellites and autism in 116 families (128 probands diagnosed with the ADI-R and ADOS-G using a family-based association test (UNPHASED)). Testing each individual microsatellite showed significant transmission disequilibrium in these families with the AVR intronic microsatellite (UNPHASED: LRS = 11.46, global P-value = 0.009, df = 3). Haplotype analysis of three microsatellites also showed significant association (LRS = 144.94, df = 103, global P = 0.004). Additionally, significant association is observed between these three microsatellite haplotypes and the VABS scores (P = 0.009), with the ADI-R (P = 0.009) and the ADOS-G (P = 0.0000765) diagnoses of autistic disorder versus pervasive developmental disorder-not otherwise specified (PDD-NOS) that were available for 47 of these probands. This is the third consecutive report of an association between the AVPR1a gene and autism spectrum disorders and in the current study a third microsatellite is shown to be associated with autism spectrum disorders as well as haplotypes consisting of all three markers. Importantly, the association appears to be mainly mediated by the role of the AVPR1a gene in shaping socialization skills, similar to its role in lower vertebrates.

The mutations in the FMR1 gene have been described as a family of disorders called fragile Xassociated disorders (FXD) including fragile X syndrome (FXS), fragile X-associated tremor/ ataxia syndrome (FXTAS), primary ovarian insufficiency and other problems associated with the premutation, such as hypothyroidism, hypertension, neuropathy, anxiety, depression, attention deficit hyperactivity disorders and autism spectrum disorders. The premutation is relatively common in the general population affecting 1 of 130-250 female individuals and 1 of 250-800 male individuals. Therefore, to provide appropriate treatment and genetic counseling for all of the carriers and affected individuals in a family, a detailed family history that reviews many of the disorders that are related to both the premutation and the full mutation should be carried out as exemplified in these cases. To facilitate the integration of this knowledge into clinical practice, this is the first case report that demonstrates only premutation involvement across 3 generations.

We investigated the relationships between functional genetic variants of 5-HT 2C receptor and multi drug resistant protein (MDR1), coding for P-glycoprotein, and second generation antipsychotic (SDA)-induced weight gain among 108 female schizophrenic patients treated with olanzapine or risperidone for up to 4 months. No significant differences in -759C/T allelic and genotype variants of 5HT 2C were found between patients who gained more than 7% of their initial weight compared to those who gained less. Haplotype based analysis of two MDR1 loci -exon 21 G2677T and exon 26 C3435T revealed borderline less representation of the G2677/C3435 haplotype in ≥7% group. In the subgroup of patients treated with risperidone, we found borderline overrepresentations of 2677T and significant overrepresentations of 3435T variant and borderline overrepresentation of 2677T/3435T haplotype the ≥7% group, whereas G2677/C3435 haplotype was found to be less represented in the ≥7% group. Our data indicate a non significant role of 759C/T 5HT 2C in SDAs-induced weight gain, and stronger influence of MDR1 G2677T and C3435T polymorphisms on risperidone-induced weight gain in female schizophrenic patients. 3435T and 2677T MDR1 variants, both associated with lower P-gp function might predispose to higher risperidone accessibility to the brain allowing its stronger effects, including weight gain.

We investigated the relationships between functional genetic variants of 5-HT 2C receptor and multi drug resistant protein (MDR1), coding for P-glycoprotein, and second generation antipsychotic (SDA)-induced weight gain among 108 female schizophrenic patients treated with olanzapine or risperidone for up to 4 months. No significant differences in -759C/T allelic and genotype variants of 5HT 2C were found between patients who gained more than 7% of their initial weight compared to those who gained less. Haplotype based analysis of two MDR1 loci -exon 21 G2677T and exon 26 C3435T revealed borderline less representation of the G2677/C3435 haplotype in ≥7% group. In the subgroup of patients treated with risperidone, we found borderline overrepresentations of 2677T and significant overrepresentations of 3435T variant and borderline overrepresentation of 2677T/3435T haplotype the ≥7% group, whereas G2677/C3435 haplotype was found to be less represented in the ≥7% group. Our data indicate a non significant role of 759C/T 5HT 2C in SDAs-induced weight gain, and stronger influence of MDR1 G2677T and C3435T polymorphisms on risperidone-induced weight gain in female schizophrenic patients. 3435T and 2677T MDR1 variants, both associated with lower P-gp function might predispose to higher risperidone accessibility to the brain allowing its stronger effects, including weight gain.

Age-related maculopathy (ARM), or age-related macular degeneration, is one of the most common causes of visual impairment in the elderly population of developed nations. In a combined analysis of two previous genomewide scans that included 391 families, containing up to 452 affected sib pairs, we found linkage evidence in four regions: 1q31, 9p13, 10q26, and 17q25. We now have added a third set of families and have performed an integrated analysis incorporating 530 families and up to 736 affected sib pairs. Under three diagnostic models, we have conducted linkage analyses using parametric (heterogeneity LOD [HLOD] scores under an autosomal dominant model) and nonparametric (S all statistic) methods. There is ongoing evidence of susceptibility loci within the 1q31, 10q26, and 17q25 regions. If we treat the third set of families as a replication set, then two regions (10q26 and 17q25) are replicated, with LOD scores 11.0. If we pool all our data together, then four regions (1q31, 2q14.3, 10q26, and 17q25) show HLOD or S all scores у2.0. Within the 1q31 region, we observed an HLOD of 2.72 (genomewide ) under our least stringent diagnostic model, whereas the 17q25 region contained a maximal P p .061 HLOD of 3.53 (genomewide ) under our intermediate diagnostic model. We have evaluated our results P p .007 with respect to the findings from several new independent genomewide linkage studies and also have completed ordered subset analyses (OSAs) with apolipoprotein E alleles, smoking history, and age at onset as stratifying covariates. The OSAs generate the interesting hypothesis that the effect of smoking on the risk of ARM is accentuated by a gene in the 10q26 region-a region implicated by four other studies.

This chapter contains six parts. Part I summarizes the Genes on Trial program and introduces the issues raised by it. Part II explains why behavioral genetics research tends to focus on discrete and insular populations that overlap with socially constructed racial or ethnic groups. Part III locates behavioral genetics research on a spectrum spanning from single-gene disorders to complex behavioral traits, positing that the behavioral end of the spectrum carries the most potential for stigma. Part IV explores how the blame-shifting mechanisms of genetic reductionism and genetic determinism affect the individual, family, community, and society when genetics research focuses on criminal or antisocial behavior. Part V analyzes how racial and ethnic stigma arise from behavioral genetics research and perpetuate inequality. Part VI concludes by considering the ethical dilemmas that geneticists face when choosing who and what to study.

T helper (h) lymphocytes in pathogenic immune response at mucosal effector site play a key role in IgA nephropathy (IgAN). We evaluated the impact of some Th1/Th2/Th3/T R -type, and of monocyte/ macrophage cytokines on IgAN susceptibility with a family-based association study including 53 patients, 45 complete trios, 4 incomplete trios and 36 discordant siblings. Cytokine gene polymorphisms with a potential regulatory role on their production were investigated using the family-based association test (FBAT): IFNc intron-1 CA repeat at position 1349 -1373; IL-13 À1055C/T; TGFb þ 915G/C; IL-10 5 0 -proximal and distal microsatellites; TNFa À308G/A, À238G/A. The FBAT multi-allelic analysis showed an association between IFNc polymorphism and susceptibility to IgAN (P ¼ 0.03). The bi-allelic analysis evidenced that the 13-CA repeat allele was preferentially transmitted to the affected individuals (P ¼ 0.006; Bonferroni P-value ¼ 0.04). The direct sequencing of IFNc amplicons showed a strict association between the 13-CA repeat allele and the A variant of the þ 874T/A single nucleotide polymorphism (SNP rs2430561) directly adjacent to the 5 0 end of the microsatellite. The in vitro production of IFNc evaluated in peripheral blood mononuclear cells from 10 genotyped patients demonstrated a correlation between the þ 874A allele and a lower production of IFNc (P ¼ 0.028 Mann -Whitney test). This SNP affects IFNc production lying within a binding site for the transcription factor NF-jB. No significant difference was observed in the 15 years renal survival between IgAN patients carrying different IFNc gene polymorphisms. This first family-based association study demonstrates that the þ 874A allele, strictly associated with IFNc 13-CA repeat allele, confers susceptibility to IgAN, without influencing renal survival.

Human chromosome 10q21-22 harbors USH1F in a region of conserved synteny to mouse chromosome 10. This region of mouse chromosome 10 contains Pcdh15, encoding a protocadherin gene that is mutated in ames waltzer and causes deafness and vestibular dysfunction. Here we report two mutations of protocadherin 15 (PCDH15) found in two families segregating Usher syndrome type 1F. A Northern blot probed with the PCDH15 cytoplasmic domain showed expression in the retina, consistent with its pathogenetic role in the retinitis pigmentosa associated with USH1F.

White-footed mice (Perornyscus leucopus) chronically exposed to polychlorinated biphenyls (PCBs) in the diet at a level of l0 ppm (jxg/g) through the second generation were evaluated in regard to reproductive success, growth (body weight) and development of reproductive organs. PCBs-treated second generation mice exhibited poor reproductive success in comparison with second generation controls and the parental generation. Although young from second generation control and PCBs-treated litters did not differ in weight at birth, PCBs-treated young were significantly smaller at 4, 8, and 12 weeks of age. Similarly, reproductive organs of females (uteri, ovaries) and accessory glands of males were smaller in PCBs-treated mice at 8 and 12 weeks of age. Testes weights were unaffected by PCBs exposure. These results provide insight into the cumulative effects of chronic PCBs exposure.

Background: Thyroid peroxidase (TPO) gene mutations are one of the most common causes of thyroid disorders. Objective: To investigate the effect of genetic polymorphisms in the TPO promoter region on gene expression in early-diagnosed hyperthyroid patients. Methods: Genomic DNA was extracted from 100 blood samples (75 hyperthyroid patients and 25 healthy controls), then the TPO promoter region was amplified and sequenced for genotyping rs2071399, rs2071400, and rs2071403 SNPs. Total RNA was also isolated, and cDNA synthesis was performed to determine quantitatively the expression of TPO by using qPCR. The level of TPO antibodies in serum was determined by using an enzyme-linked immunosorbent assay (ELISA). Results: The prevalence of hyperthyroidism in women was significantly higher than in men, as were serum levels of TPO-Abs. There was a significant increase in serum TPO-Abs in hyperthyroid patients (235.29 IU/ml) compared with healthy controls. Genotypes of three SNPs (rs2071399 G/A, rs2071400 C/T, and rs2071403 A/G) in the TPO promoter region were TPO rs2071399 AG and GG, and rs2071400 CT and TT genotypes were more frequent in hyperthyroid patients. There are no significant differences between rs2071403 polymorphic and non-polymorphic genotypes among hyperthyroid patients and healthy controls. The rs2071399 G/A and rs2071400 C/T gene promoter polymorphism significantly down-regulated constitutive TPO gene expression in hyperthyroid patients, but rs2071403 A/G has no major effect on gene expression. Conclusion: There was an association between the mutation in the promoter region of TPO and the incidence of hyperthyroidism.

Introduction and Aim: Hyperthyroidism is a disorder characterized by excessively high amounts of triiodothyronine and thyroxine in the bloodstream. TPO is a thyroid-specific antigen. TPO gene mutations affect thyroid hormone synthesis, causing full or partial iodide organification abnormalities. In this study, we aimed to look at the single nucleotide polymorphisms (SNPs) in the TPO gene and find possible relation of these SNPs to the development or prognosis of hyperthyroidism. Materials and Methods: Blood samples were collected from hyperthyroid patients (n=75) and healthy individuals (n=25). The concentration of triiodothyronine (T3), Tetra-iodothyronine (T4), and thyroid stimulating hormone (TSH) were estimated in all samples. The autoantibodies TPOAbs and TR-Ab levels were measured using the ELISA assay. The extracted genomic DNA from blood of participants was investigated for polymorphism in the SNPs rs1126799, rs1126797, and rs732609 within the TPO gene. Statistical methods were used to evaluate the association between the TPO SNPs studied to hyperthyroidism susceptibility. Results: No significant correlation was observed between the SNPs studied and prognosis of hyperthyroidism. However, it was found that hyperthyroid patients carrying the TPO rs1126799 T allele (CT + CC genotypes) had significantly higher serum levels of TPOAb compared to those with the TT genotype (P<0.01). Similarly, hyperthyroid patients with the TPO rs1126797 C allele (CT + TT genotypes) and TPO rs732609 A allele (CA + AA genotypes) exhibited significantly elevated levels of TPOAbs compared to individuals with the CC genotype and AA genotype, respectively (P<0.01). Conclusion: There was no correlation between the TPO rs1126799, rs1126797, and rs732609 polymorphisms with the occurrence of hyperthyroidism in the Iraqi population. However, TPO rs2071400 and rs2048722 polymorphisms were found to be correlated to serum levels of TPOAb.

Skates are cartilaginous fish whose body plan features enlarged wing-like pectoral fins, enabling them to thrive in benthic environments 1,2 . However, the molecular underpinnings of this unique trait remain unclear. Here we investigate the origin of this phenotypic innovation by developing the little skate Leucoraja erinacea as a genomically enabled model. Analysis of a high-quality chromosome-scale genome sequence for the little skate shows that it preserves many ancestral jawed vertebrate features compared with other sequenced genomes, including numerous ancient microchromosomes. Combining genome comparisons with extensive regulatory datasets in developing fins-including gene expression, chromatin occupancy and three-dimensional conformation-we find skate-specific genomic rearrangements that alter the three-dimensional regulatory landscape of genes that are involved in the planar cell polarity pathway. Functional inhibition of planar cell polarity signalling resulted in a reduction in anterior fin size, confirming that this pathway is a major contributor to batoid fin morphology. We also identified a fin-specific enhancer that interacts with several hoxa genes, consistent with the redeployment of hox gene expression in anterior pectoral fins, and confirmed its potential to activate transcription in the anterior fin using zebrafish reporter assays. Our findings underscore the central role of genome reorganization and regulatory variation in the evolution of phenotypes, shedding light on the molecular origin of an enigmatic trait. The origin and diversification of vertebrates was accompanied by the appearance of key developmental innovations 2,3 . Among them, paired appendages show an exquisite diversity of forms and adaptations not only in tetrapods, but also in chondrichthyans (cartilaginous fish) in which fin structures are considerably diverse 2 . The wing-like appendages of batoid fishes (skates and rays) (Fig. ) are fascinating examples, in which the pectoral fins extend anteriorly and fuse with the head. This unique structure creates power for forward propulsion and led to the emergence of swimming mechanisms that enabled skates to colonize the sea floor 1 . Transcriptomic analysis of skate developing fins revealed a major reorganization of signalling gradients relative to other vertebrates 1 . The redeployment of developmental transcription factors, such as 3′ hox genes, initiates an anterior signalling centre analogous to the posterior apical ectodermal ridge (AER). These changes