Variation In Genetic Background Research Articles

The optimize project: beyond first-line therapy in metastatic renal cell carcinoma

The treatment of patients with metastatic renal cell carcinoma (mRCC) has changed dramatically over the past 5 years, and a new paradigm has evolved. Angiogenesis in general, and the vascular endothelial growth factor and mammalian target of rapamycin pathways in particular, are validated targets in renal cell carcinoma. This Supplement Issue examines several interesting topics consequent to the failure of first-line treatment in patients with mRCC, including (1) the reasons why patients fail on first-line treatment with targeted agents; (2) preclinical and clinical rationales for selecting a secondor subsequent-line therapy for these patients; (3) recommendations for managing the main adverse events of targeted therapies, both in normal and special populations; (4) the role of pharmacogenomics in mRCC to date and whether it is possible to predict an individual patient's outcome and level of toxicity experienced; and lastly (5) how quality of life and supportive care for these patients may be improved. Currently, tumor progression is most commonly assessed on the basis of the Response Evaluation Criteria in Solid Tumors (RECIST v 1.0 or v 1.1). Targeted agents tend to stabilize disease, however, rather than significantly decreasing tumor mass. In the first article, the need for additional methods to assess disease response is discussed. It is also important to evaluate existing prognostic and predictive factors after failure of first-line treatment in order to increase the chances of delivering the most effective and personalized therapy possible. Despite significant improvements in the first-line treatment of mRCC, therapies rarely produce complete responses, and all patients eventually develop resistance and progress. In addition, some tumors display intrinsic resistance, which further limits therapeutic options. One approach to overcoming tumor resistance is the use of sequential therapy. Unfortunately, knowledge about the mechanisms of action of new therapies, and the intrinsic and extrinsic mechanism of resistance, has not evolved as rapidly as their development and many questions remain unanswered. In the second article, authors review the available evidence from clinical studies on sequential therapy for mRCC, including those that are still in progress. In addition, information on the mechanisms of resistance or tolerance to first-line therapy, recommendations on the main practice guidelines for second-line treatment, potential therapies for third or successive treatment lines, and the reasons why patients who progress may benefit from a change of mechanism of action are also discussed. In the third article, authors review the toxicity profiles of targeted therapies, and develop important recommendations for treating adverse events to avoid acute, life-threatening situations, dose reductions, interruptions, or early treatment discontinuation. This is essential because the early recognition and management of severe adverse events is one of the most important factors for maintaining the optimum efficacy of sequential therapy. Pharmacogenomics is the topic of the fourth article, in which the authors evaluate how variation in genetic background affects an individual's response to a specific drug and/or its metabolism. Using knowledge about the genes that produce the enzymes to metabolize a specific drug, a physician may decide to raise or lower the dose, or even change to a different drug. Although few studies have identified biomarkers that predict the response to targeted drugs in the treatment of mRCC, some important associations have been found and are described in this article. Pharmacogenomics holds the potential in the near future to hone D. Castellano (*) Medical Oncology Department, University Hospital 12 de Octubre, Madrid, Spain e-mail: cdanicas@hotmail.com

Signaling defects in iPSC-derived fragile X premutation neurons

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a leading monogenic neurodegenerative disorder affecting premutation carriers of the fragile X (FMR1) gene. To investigate the underlying cellular neuropathology, we produced induced pluripotent stem cell-derived neurons from isogenic subclones of primary fibroblasts of a female premutation carrier, with each subclone bearing exclusively either the normal or the expanded (premutation) form of the FMR1 gene as the active allele. We show that neurons harboring the stably-active, expanded allele (EX-Xa) have reduced postsynaptic density protein 95 protein expression, reduced synaptic puncta density and reduced neurite length. Importantly, such neurons are also functionally abnormal, with calcium transients of higher amplitude and increased frequency than for neurons harboring the normal-active allele. Moreover, a sustained calcium elevation was found in the EX-Xa neurons after glutamate application. By excluding the individual genetic background variation, we have demonstrated neuronal phenotypes directly linked to the FMR1 premutation. Our approach represents a unique isogenic, X-chromosomal epigenetic model to aid the development of targeted therapeutics for FXTAS, and more broadly as a model for the study of common neurodevelopmental (e.g. autism) and neurodegenerative (e.g. Parkinsonism, dementias) disorders.

Sex and the circuitry: progress toward a systems‐level understanding of vertebrate sex determination

In vertebrates, the gonad arises as a bipotential primordium that can differentiate as a testis or ovary. Cells are initially primed to adopt either fate by balanced antagonistic signaling pathways and transcription networks. Sexual fate is determined by activating the testis or ovarian pathway and repressing the alternative pathway. A complex, dynamic transcription network underlies this process, as approximately half the genome is being transcribed during this period, and many genes are expressed in a sexually dimorphic manner. This network is highly plastic; however, multiple lines of evidence suggest that many elements of the pathway converge on the stabilization or disruption of Sox9 expression. The single gene mutational approach has led to the identification of ∼30 additional genes involved in vertebrate sex determination. However, >50% of human disorders of sexual development (DSDs) are not explained by any of these genes, suggesting many critical elements of the system await discovery. Emerging technologies and genetic resources enable the investigation of the sex determination network on a global scale in the context of a variable genetic background or environmental influences. Using these new tools we can investigate how cells establish a bipotential state that is poised to adopt either sexual fate, and how they integrate multiple signaling and transcriptional inputs to drive a cell fate decision. Elucidating the genetic architecture underlying sex determination in model systems can lead to the identification of conserved modules correlated with phenotypic outcomes, and critical pressure points in the network that predict genes involved in DSDs in humans.

Hypertension and exercise

Levels of physical activity in modern urbanized society are clearly insufficient to maintain good health, and to prevent cardiovascular and other disease. Aerobic exercise is almost completely free of secondary effects, and is a useful adjunctive therapy in treating hypertension. There are several possible mechanisms to account for the beneficial effects of exercise in reducing blood pressure, the resulting physiological effects usually being classified as acute, post-exercise or chronic. Variations in genetic background, hypertension etiology, pharmacodynamics and pharmacokinetics may explain the different blood pressure responses to exercise among hypertensive patients. The present review discusses the different pathophysiological aspects of the response to exercise in hypertensives, including its modulators and diagnostic and prognostic usefulness, as well as the latest guidelines on prescribing and monitoring exercise regimes and drug therapy in the clinical follow-up of active hypertensive patients.

Hipertensão arterial e exercício físico

Levels of physical activity in modern urbanized society are clearly insufficient to maintain good health, and to prevent cardiovascular and other disease. Aerobic exercise is almost completely free of secondary effects, and is a useful adjunctive therapy in treating hypertension. There are several possible mechanisms to account for the beneficial effects of exercise in reducing blood pressure, the resulting physiological effects usually being classified as acute, post-exercise or chronic. Variations in genetic background, hypertension etiology, pharmacodynamics and pharmacokinetics may explain the different blood pressure responses to exercise among hypertensive patients. The present review discusses the different pathophysiological aspects of the response to exercise in hypertensives, including its modulators and diagnostic and prognostic usefulness, as well as the latest guidelines on prescribing and monitoring exercise regimes and drug therapy in the clinical follow-up of active hypertensive patients.

Genetic Variations Strongly Influence Phenotypic Outcome in the Mouse Retina

Variation in genetic background can significantly influence the phenotypic outcome of both disease and non-disease associated traits. Additionally, differences in temporal and strain specific gene expression can also contribute to phenotypes in the mammalian retina. This is the first report of microarray based cross-strain analysis of gene expression in the retina investigating genetic background effects. Microarray analyses were performed on retinas from the following mouse strains: C57BL6/J, AKR/J, CAST/EiJ, and NOD.NON-H2 -nb1 at embryonic day 18.5 (E18.5) and postnatal day 30.5 (P30.5). Over 3000 differentially expressed genes were identified between strains and developmental stages. Differential gene expression was confirmed by qRT-PCR, Western blot, and immunohistochemistry. Three major gene networks were identified that function to regulate retinal or photoreceptor development, visual perception, cellular transport, and signal transduction. Many of the genes in these networks are implicated in retinal diseases such as bradyopsia, night-blindness, and cone-rod dystrophy. Our analysis revealed strain specific variations in cone photoreceptor cell patterning and retinal function. This study highlights the substantial impact of genetic background on both development and function of the retina and the level of gene expression differences tolerated for normal retinal function. These strain specific genetic variations may also be present in other tissues. In addition, this study will provide valuable insight for the development of more accurate models for human retinal diseases.

Neurotoxicity of cobalt

Cobalt exerts well-known and documented toxic effects on the thyroid, heart and the haematopoietic system, in addition to the occupational lung disease, allergic manifestations and a probably carcinogenic action. Cobalt neurotoxicity is reported in isolated cases, and it has never been systematically treated. Bilateral optic atrophy and retinopathy, bilateral nerve deafness and sensory-motor polyneuropathy have been described long ago as a result of chronic occupational exposure to cobal powder or during long-term treatment of anaemia with cobalt chloride. Recently, some patients with high levels of cobalt released from metal prosthesis have been referred as presenting with tinnitus, deafness, vertigo, visual changes, optic atrophy, tremor and peripheral neuropathy. The aim of this work is to group these cases and to identify a possible mechanism of cobalt neurotoxicity, focusing on hypothetic individual susceptibility such as altered metal-binding proteins, altered transport processes in target cells or polymorphic variation of genetic background.

Generation of Isogenic Pluripotent Stem Cells Differing Exclusively at Two Early Onset Parkinson Point Mutations

Patient-specific induced pluripotent stem cells (iPSCs) derived from somatic cells provide a unique tool for the study of human disease, as well as a promising source for cell replacement therapies. One crucial limitation has been the inability to perform experiments under genetically defined conditions. This is particularly relevant for late age onset disorders in which in vitro phenotypes are predicted to be subtle and susceptible to significant effects of genetic background variations. By combining zinc finger nuclease (ZFN)-mediated genome editing and iPSC technology, we provide a generally applicable solution to this problem, generating sets of isogenic disease and control human pluripotent stem cells that differ exclusively at either of two susceptibility variants for Parkinson's disease by modifying the underlying point mutations in the α-synuclein gene. The robust capability to genetically correct disease-causing point mutations in patient-derived hiPSCs represents significant progress for basic biomedical research and an advance toward hiPSC-based cell replacement therapies.

The airway microbiome in cystic fibrosis and implications for treatment

Lung disease in cystic fibrosis (CF) results from chronic airway infection and inflammation leading to progressive bronchiectasis and respiratory failure. Bacterial pathogens, including Pseudomonas aeruginosa, Staphylococcus aureus, and Burkholderia cepacia, are known contributors. Recent studies using culture-independent molecular techniques and anaerobic cultures have broadened our view of CF airway bacterial communities. Sanger sequencing, high-throughput pyrosequencing, and phylogenetic microarray analysis have been used to comprehensively examine the airway microbiome in CF. Findings confirm that CF airway bacterial communities are highly complex structures with anaerobes frequently present. Importantly, there is evidence that loss of community diversity and richness is associated with older age and decreased lung function in CF. Bacterial communities are also likely influenced by antibiotic use, chronic P. aeruginosa infection, host genetic background (ΔF508 CFTR mutation) and geographic variations. Quantitative anaerobic cultures also detect high quantities of anaerobes from CF airway samples, including during pulmonary exacerbations. The effect of antimicrobial therapy on the airway microbiome needs further investigation. In addition, probiotic approaches have been recently studied; whether probiotics act by altering microbial communities or by modulating host inflammatory response is unknown. Complex bacterial communities, including traditional CF-associated pathogens and anaerobic bacteria, are common in CF airways. Novel therapeutic approaches aimed at modulating airway bacterial communities may lead to improved treatment of CF lung disease.

Genome-Wide Association Study of Survival in Non–Small Cell Lung Cancer Patients Receiving Platinum-Based Chemotherapy

Interindividual variation in genetic background may influence the response to chemotherapy and overall survival for patients with advanced-stage non-small cell lung cancer (NSCLC). To identify genetic variants associated with poor overall survival in these patients, we conducted a genome-wide scan of 307,260 single-nucleotide polymorphisms (SNPs) in 327 advanced-stage NSCLC patients who received platinum-based chemotherapy with or without radiation at the University of Texas MD Anderson Cancer Center (the discovery population). A fast-track replication was performed for 315 patients from the Mayo Clinic followed by a second validation at the University of Pittsburgh in 420 patients enrolled in the Spanish Lung Cancer Group PLATAX clinical trial. A pooled analysis combining the Mayo Clinic and PLATAX populations or all three populations was also used to validate the results. We assessed the association of each SNP with overall survival by multivariable Cox proportional hazard regression analysis. All statistical tests were two-sided. SNP rs1878022 in the chemokine-like receptor 1 (CMKLR1) was statistically significantly associated with poor overall survival in the MD Anderson discovery population (hazard ratio [HR] of death = 1.59, 95% confidence interval [CI] = 1.32 to 1.92, P = 1.42 × 10(-6)), in the PLATAX clinical trial (HR of death = 1.23, 95% CI = 1.00 to 1.51, P = .05), in the pooled Mayo Clinic and PLATAX validation (HR of death = 1.22, 95% CI = 1.06 to 1.40, P = .005), and in pooled analysis of all three populations (HR of death = 1.33, 95% CI = 1.19 to 1.48, P = 5.13 × 10(-7)). Carrying a variant genotype of rs10937823 was associated with decreased overall survival (HR of death = 1.82, 95% CI = 1.42 to 2.33, P = 1.73 × 10(-6)) in the pooled MD Anderson and Mayo Clinic populations but not in the PLATAX trial patient population (HR of death = 0.96, 95% CI = 0.69 to 1.35). These results have the potential to contribute to the future development of personalized chemotherapy treatments for individual NSCLC patients.

The role of constraints and limitation in driving individual variation in immune response

Summary 1. Life history theory predicts that immunity should be plastic and reflect environmental contexts. However, individual variation in immune investment may arise not just because of individual adjustment, but because of developmental, physiological, genetic or immunological constraints which lead to non‐adaptive responses by limiting or eliminating flexibility in immune investment. Constraints can arise because organisms are single integrated units with interconnected and interacting components, in which physiological and genetic control mechanisms may limit or constrain immunity. We review some of the key underlying genetic and physiological factors that may constrain the occurrence and intensity of immune responses. 2. A major part of individual variability may rest on variation in genetic background. Genetic‐based constraints can limit or influence immune responses, particularly through pleiotropy and epistatic interactions. In addition, genetic variation, an important driver of variation in antigen recognition and immune system polarization, can be constrained through linkage disequilibrium and genetic drift. Epigenetic changes can also constrain or limit immune responses in future generations based on individual experience. 3. The immune system itself can influence individual flexibility in immune investment. Throughout development individuals face tradeoffs within the immune system that favour the expression of one trait at the expense of another. Ontogenetic differences can cause juveniles and adults to produce entirely different immune responses to the same pathogen. T‐helper 1 (Th1)/T‐helper 1 (Th2) polarization during infection also imposes constraints upon an individual’s immune responsiveness, with the consequence that hosts cannot simultaneously mount strong responses using both Th1 and Th2 cells. In addition, evidence suggests that flexibility in immune responses becomes constrained with age through accumulation of memory cells at the expense of naïve cells, decreased function of cells involved in adaptive and innate immunity, and programming of HPA‐immune interactions. 4. In summary, selection on a particular immune trait can have effects on other immune components or phenotypic characters, as revealed by artificial selection studies. In particular selection for increased investment in compartments of the immune system leads to decreased investment in other competing life history functions and/or marked changes in other immune components. The role of past experience, even the past experience of parents, may limit and constrain immune responses through influencing the ontogeny of immunity, as well as through epigenetic influences.

Geographical variation of photoperiodic wing form determination and genetic background of reproductive diapause in arrhenotokous populations of Thrips nigropilosus Uzel (Thysanoptera: Thripidae) in Japan

To determine the level of inter-population variation in wing form and the induction of reproductive diapause as affected by photoperiod, females of five populations of arrhenotokous Thrips nigropilosus Uzel were reared under four different photoperiodic conditions at 18°C. The experimental populations originated from Nakijin-son, Motobu-cho, and Uruma-shi in Okinawa Island, Amami-shi in Amami-Oshima Island, and Wakayama-shi on Honshu Island. In all five populations, only macropterae were observed when the photoperiod was 13 h light/11 h dark. Brachypterae were observed as the light period was reduced to 11.5 or 12 h in the Wakayama population, and to 10 or 11.5 h in the Nakijin, Motobu, and Uruma populations. Brachypterous females were observed in the Amami population only when the light period was 10 h. With the same photoperiod, only brachypterae were observed in the Wakayama and Uruma populations. Short-day conditions also induced reproductive diapause in the Wakayama population but not in the Amami and Okinawa Island populations. Under 10 h light/14 h dark, almost all hybrids obtained from crossing Wakayama with Amami populations entered reproductive diapause. Some populations in Okinawa Island may have been originated in northern localities.

Mate Quality and Novelty Influence Post‐Copulatory Female Choice in Decorated Crickets, Gryllodes sigillatus

AbstractFemales of many taxa prefer to mate with novel males rather than previous mates, but also favor males that have traits indicative of higher genetic quality or compatibility. However, it may not be possible for females to simultaneously choose males that are both novel and of high quality, and the female response to this dilemma has not previously been examined. In this paper, we ask whether female decorated crickets, Gryllodes sigillatus, exert their choice for novel males via post‐copulatory choice (sperm ampulla removal) and whether male genetic background (variation in male quality) affects this decision. We found that after matings with inbred males, females removed the ampullae of familiar mates sooner than those of novel males, whereas after matings with outbred males, there was no difference in the ampulla‐retention times of familiar mates and novel partners. This suggests that when male do not vary in quality, females prefer novel partners. However, when males vary in quality, female preferences for male traits are more important than preferences for novel partners.

Characterization of aryl hydrocarbon receptor interacting protein (AIP) mutations in familial isolated pituitary adenoma families.

Familial isolated pituitary adenoma (FIPA) is an autosomal dominant condition with variable genetic background and incomplete penetrance. Germline mutations of the aryl hydrocarbon receptor interacting protein (AIP) gene have been reported in 15–40% of FIPA patients. Limited data are available on the functional consequences of the mutations or regarding the regulation of the AIP gene. We describe a large cohort of FIPA families and characterize missense and silent mutations using minigene constructs, luciferase and β-galactosidase assays, as well as in silico predictions. Patients with AIP mutations had a lower mean age at diagnosis (23.6±11.2 years) than AIP mutation-negative patients (40.4±14.5 years). A promoter mutation showed reduced in vitro activity corresponding to lower mRNA expression in patient samples. Stimulation of the protein kinase A-pathway positively regulates the AIP promoter. Silent mutations led to abnormal splicing resulting in truncated protein or reduced AIP expression. A two-hybrid assay of protein–protein interaction of all missense variants showed variable disruption of AIP-phosphodiesterase-4A5 binding. In summary, exonic, promoter, splice-site, and large deletion mutations in AIP are implicated in 31% of families in our FIPA cohort. Functional characterization of AIP changes is important to identify the functional impact of gene sequence variants. Hum Mutat 31:1–11, 2010. © 2010 Wiley-Liss, Inc.

495 Genetic Factors Predict Weight Loss After Roux-en-Y Gastric Bypass

Introduction: Although Roux-en-Y gastric bypass (RYBG) leads to substantial weight loss, the magnitude of this effect is highly variable. The determinants of weight loss following RYGB are poorly understood. Clinical factors have been able to account for only a fraction of the observed variation, and several studies have implicated additional biological determinants. In this study, we sought to determine the role of genetic contributions to weight loss after RYGB. Methods: We collected liver samples from 1018 patients undergoing RYGB. DNA from these samples was genotyped for 660,000 single nucleotide polymorphisms (SNPs). Percent excess weight loss (%EWL) for the nadir weight after surgery was calculated against a reference BMI of 25 kg/m2. We identified 40 genetically related individuals within this cohort, based on percentage of their genome shared. Using electronic medical records, we identified 20 additional individuals who were cohabitating and genetically unrelated. We used mixed effects models to determine whether degree of relatedness (1°, 2°, or 3°, or cohabitating) is associated with%EWL. In addition, we performed a genome-wide association study (GWAS) of the 789 non-related Caucasians within the total cohort. Results: The average difference in %EWL was 13.7%, 25.1% and 36.8% for 1°, 2°, and 3° relatives, and 25.4% for cohabitating individuals, respectively. There was a significant association of %EWL between 1° relatives (p=0.04, Intraclass Correlation Coefficient [ICC]=57.3%), which was not seen between 2° relatives (p=0.54, ICC=38.2%), 3° relatives (p=0.36, ICC=0%), or cohabitating individuals (p=0.53, ICC=0). The GWAS identified a single region on chromosome 6 that was significantly associated with %EWL (p=2.1x10-7; false discovery rate=9.2% for the highest ranked SNP in this region). Conclusions: These data suggest that there are genetic determinants of weight loss after RYGB. Despite the small number of related individuals, the significant correlation between outcomes of 1° relatives indicates that there is a significant genetic impact beyond any shared environmental influences. In addition, even in this modest-sized cohort, we identified a chromosomal region significantly associated with %EWL. These observations underscore the biological nature of the response to RYGB and suggest that variation in the genetic background of individuals influences weight loss after this operation. Identification of the genes involved in this response could provide information about the method of action of RYGB and facilitate strategies for selecting patients most likely to benefit from this effective yet invasive procedure.

Biodiversity of mannose-specific adhesion in Lactobacillus plantarum revisited: strain-specific domain composition of the mannose-adhesin

Recently, we have identified the mannose-specific adhesin encoding gene (msa) of Lactobacillus plantarum. In the current study, structure and function of this potentially probiotic effector gene were further investigated, exploring genetic diversity of msa in L. plantarum in relation to mannose adhesion capacity. The results demonstrate that there is considerable variation in quantitative in vitro mannose adhesion capacity, which is paralleled by msa gene sequence variation. The msa genes of different L. plantarum strains encode proteins with variable domain composition. Construction of L. plantarum 299v mutant strains revealed that the msa gene product is the key-protein for mannose adhesion, also in a strain with high mannose adhering capacity. However, no straightforward correlation between adhesion capacity and domain composition of Msa in L. plantarum could be identified. Nevertheless, differences in Msa sequences in combination with variable genetic background of specific bacterial strains appears to determine mannose adhesion capacity and potentially affects probiotic properties. These findings exemplify the strain-specificity of probiotic characteristics and illustrate the need for careful and molecular selection of new candidate probiotics.

Spontaneous mutations decrease sensitivity of gene expression to random environmental variation in Caenorhabditis elegans.

BackgroundBiological phenotypes are described as “canalized” if they are robust to minor variation of environment and/or genetic background. The existence of a robust phenotype logically implies that some underlying mechanism must be variable, in the sense of “able to vary”, in order to compensate for variation in the environment and/or genetic effects. Several lines of evidence lead to the conclusion that deleterious mutations predictably render morphological, developmental, and life-history traits more sensitive to small random environmental perturbations - that is, mutations de-canalize the phenotype.Methodology/Principal FindingsUsing conventional dye-swap microarray methodology, we compared transcript abundance in a sample of >7,000 genes between four mutation accumulation (MA) lines of the nematode Caenorhabditis elegans and the common (unmutated) ancestor. There was significantly less environmental variance in the MA lines than in the ancestor, both among replicates of the same gene and among genes.Conclusions/SignificanceDeleterious mutations consistently decrease the within-line component of variance in transcript abundance, which is straightforwardly interpreted as reducing the sensitivity of gene expression to small random variation in the environment. This finding is consistent with the idea that underlying variability in gene expression might be mechanistically responsible for phenotypic robustness.

Trehalose promotes the survival ofSaccharomyces cerevisiaeduring lethal ethanol stress, but does not influence growth under sublethal ethanol stress

Trehalose is known to protect cells from various environmental assaults; however, its role in the ethanol tolerance of Saccharomyces cerevisiae remains controversial. Many previous studies report correlations between trehalose levels and ethanol tolerance across a variety of strains, yet variations in genetic background make it difficult to separate the impact of trehalose from other stress response factors. In the current study, investigations were conducted on the ethanol tolerance of S. cerevisiae BY4742 and BY4742 deletion strains, tsl1Delta and nth1Delta, across a range of ethanol concentrations. It was found that trehalose does play a role in ethanol tolerance at lethal ethanol concentrations, but not at sublethal ethanol concentrations; differences of 20-40% in the intracellular trehalose concentration did not provide any growth advantage for cells incubated in the presence of sublethal ethanol concentrations. It was speculated that the ethanol concentration-dependent nature of the trehalose effect supports a mechanism for trehalose in protecting cellular proteins from the damaging effects of ethanol.

A diallel study of yield components and fruit quality in chilli pepper (Capsicum baccatum)

The aim of this work was to estimate the general and specific combining ability of peppers by measuring fruit quality and yield traits. This experiment was carried out on the garden field from Universidade Federal de Vicosa (UFV), Minas Gerais State—Brazil. Eight lines of Capsicum baccatum belonging to the UFV Horticultural Germplasm Bank were chosen based on their broad genetic and phenotypical background variation and then they were crossed in a complete diallel way. The F1 seeds of the 56 hybrids and eight parents were planted in the field in a randomized complete block design. The data were submitted to ANOVA and the means were grouped by Scott–Knott test (P ≤ 0.01). Significant variation for fruit quality and yield components was observed among parents and F1 generation. Analysis of variance for the combining ability showed that GCA effects exhibited significant difference and SCA effects of the crosses were significant, except for the height of first bifurcation. For almost all characters both additive and non-additive effects influenced the performance of hybrids.

Effects of elevated Pax6 expression and genetic background on mouse eye development.

To analyze the effects of Pax6 overexpression and its interaction with genetic background on eye development. Histologic features of eyes from hemizygous PAX77(+/-) transgenic (high Pax6 gene dose) and wild-type mice were compared on different genetic backgrounds. Experimental PAX77(+/-)<-->wild-type and control wild-type<-->wild-type chimeras were analyzed to investigate the causes of abnormal eye development in PAX77(+/-) mice. PAX77(+/-) mice showed an overlapping but distinct spectrum of eye abnormalities to Pax6(+/-) heterozygotes (low Pax6 dose). Some previously reported PAX77(+/-) eye abnormalities did not occur on all three genetic backgrounds examined. Several types of eye abnormalities occurred in the experimental PAX77(+/-)<-->wild-type chimeras, and they occurred more frequently in chimeras with higher contributions of PAX77(+/-) cells. Groups of RPE cells intruded into the optic nerve sheath, indicating that the boundary between the retina and optic nerve may be displaced. Both PAX77(+/-) and wild-type cells were involved in this ingression and in retinal folds, suggesting that neither effect was cell-autonomous. Cell-autonomous effects included failure of PAX77(+/-) and wild-type cells to mix normally and overrepresentation of PAX77(+/-) in the lens epithelium and RPE. The extent of PAX77(+/-) eye abnormalities depended on PAX77(+/-) genotype, genetic background, and stochastic variation. Chimera analysis identified two types of cell-autonomous effects of the PAX77(+/-) genotype. Abnormal cell mixing between PAX77(+/-) and wild-type cells suggests altered expression of cell surface adhesion molecules. Some phenotypic differences between PAX77(+/-)<-->wild-type and Pax6(+/-)<-->wild-type chimeras may reflect differences in the levels of PAX77(+/-) and Pax6(+/-) contributions to chimeric lenses.