A customized pigmentation SNP array identifies a novel SNP associated with melanoma predisposition in the SLC45A2 gene

As the incidence of Malignant Melanoma (MM) reflects an interaction between skin colour and UV exposure, variations in genes implicated in pigmentation and tanning response to UV may be associated with susceptibility to MM. In this study, 363 SNPs in 65 gene regions belonging to the pigmentation pathway have been successfully genotyped using a SNP array. Five hundred and ninety MM cases and 507 controls were analyzed in a discovery phase I. Ten candidate SNPs based on a p-value threshold of 0.01 were identified. Two of them, rs35414 (SLC45A2) and rs2069398 (SILV/CKD2), were statistically significant after conservative Bonferroni correction. The best six SNPs were further tested in an independent Spanish series (624 MM cases and 789 controls). A novel SNP located on the SLC45A2 gene (rs35414) was found to be significantly associated with melanoma in both phase I and phase II (P<0.0001). None of the other five SNPs were replicated in this second phase of the study. However, three SNPs in TYR, SILV/CDK2 and ADAMTS20 genes (rs17793678, rs2069398 and rs1510521 respectively) had an overall p-value<0.05 when considering the whole DNA collection (1214 MM cases and 1296 controls). Both the SLC45A2 and the SILV/CDK2 variants behave as protective alleles, while the TYR and ADAMTS20 variants seem to function as risk alleles. Cumulative effects were detected when these four variants were considered together. Furthermore, individuals carrying two or more mutations in MC1R, a well-known low penetrance melanoma-predisposing gene, had a decreased MM risk if concurrently bearing the SLC45A2 protective variant. To our knowledge, this is the largest study on Spanish sporadic MM cases to date.     

Dissecting Genetic Structure in Farmer Selections of Theobroma Cacao in the Peruvian Amazon: Implications for on Farm Conservation and Rehabilitation

Knowledge of genetic diversity in farmers?? selections is essential for planning on-farm conservation and rehabilitation. Using 15 microsatellite loci, we analyzed parentage and population structure in 220 farmer selections of cacao from the Huallaga valley in Peruvian Amazon. A high level of allele richness and heterozygosity were detected in these selections. Coordination analysis showed that these farmer selections are mainly comprised of hybrids derived from Trinitario and Upper Amazon Forastero germplasm. Bayesian clustering analysis assigned 54 selections as Trinitario and 166 as Upper Amazon Forastero hybrids. Parentage analysis identified 15 international clones as probable parents for 96 farmer selections, which corresponded to a fraction of the known hybrid families disseminated in this region in the late 1980s. Combined analysis of demographic and molecular data revealed a significant spatial autocorrelation (r?=?0.235; P?=?0.006) at short geographical distances (<5.0 km). This patch-like distribution of spatial heterogeneity suggests a significant ??neighborhood effects?? in seeds distribution or variety adoption, where closely related hybrid progenies were adopted in the neighboring farms or villages. The outcomes of this study indicate that in spite of the introgressions of exotic germplasm in the past, Upper Amazon Forastero is still the dominant component in the Huallaga valley of Peru. The high level of on-farm diversity can offer needed variability for participatory selection of superior clones in this low input, small-scale production system, where adaptability to specific environment is more preferred than in a high input, large scale production system.     

Copy number variation in patients with disorders of sex development due to 46,XY gonadal dysgenesis

Disorders of sex development (DSD), ranging in severity from mild genital abnormalities to complete sex reversal, represent a major concern for patients and their families. DSD are often due to disruption of the genetic programs that regulate gonad development. Although some genes have been identified in these developmental pathways, the causative mutations have not been identified in more than 50% 46,XY DSD cases. We used the Affymetrix Genome-Wide Human SNP Array 6.0 to analyse copy number variation in 23 individuals with unexplained 46,XY DSD due to gonadal dysgenesis (GD). Here we describe three discrete changes in copy number that are the likely cause of the GD. Firstly, we identified a large duplication on the X chromosome that included DAX1 (NR0B1). Secondly, we identified a rearrangement that appears to affect a novel gonad-specific regulatory region in a known testis gene, SOX9. Surprisingly this patient lacked any signs of campomelic dysplasia, suggesting that the deletion affected expression of SOX9 only in the gonad. Functional analysis of potential SRY binding sites within this deleted region identified five putative enhancers, suggesting that sequences additional to the known SRY-binding TES enhancer influence human testis-specific SOX9 expression. Thirdly, we identified a small deletion immediately downstream of GATA4, supporting a role for GATA4 in gonad development in humans. These CNV analyses give new insights into the pathways involved in human gonad development and dysfunction, and suggest that rearrangements of non-coding sequences disturbing gene regulation may account for significant proportion of DSD cases.     

Leaf-litter processing in headwater streams of northern Iberian Peninsula: moderate levels of eutrophication do not explain breakdown rates

Agricultural and urban runoffs result in increased nitrogen and phosphorus inputs in rivers and are the cause of eutrophication. Headwater streams are less frequently affected by these impairments because of the low-to-moderate human activities there. Eutrophication can affect the structure and function of benthic communities in headwater streams, stimulating the activity of heterotrophic microorganisms and macroinvertebrates on a pivotal process such as leaf-litter decomposition. In this study, we monitored the breakdown of alder leaves in six headwater streams that constitute a moderate nutrient enrichment gradient. Breakdown experiments were conducted in autumn–winter and leaf carbon, nitrogen and phosphorus, and associated aquatic hyphomycetes and macroinvertebrates were determined. The increase in nutrient availability in the stream water enhanced leaf-litter quality and led to an increase in the hyphomycete assemblage evenness and a reduction of shredder densities. However, contrary to our expectations, dissolved nutrient availability did not explain the breakdown rates. Thus, the absence of a clear effect of nutrient enrichment of stream water on the leaf breakdown rate highlights the difficulties of predicting the response of this ecosystem process to slight levels of eutrophication in headwater streams.     

Phosphatase and Tensin Homolog Deleted on Chromosome 10 (PTEN) Signaling Regulates Mitochondrial Biogenesis and Respiration via Estrogen-related Receptor α (ERRα)

Mitochondrial abnormalities are associated with cancer development, yet how oncogenic signals affect mitochondrial functions has not been fully understood. In this study, we investigate the relationship between mitochondrial alterations and PI3K/protein kinase B (AKT) signaling activation using hepatocytes and liver tissues as our experimental models. We show here that liver-specific deletion of Pten, which leads to activation of PI3K/AKT, is associated with elevated oxidative stress, increased mitochondrial mass, and augmented respiration accompanied by enhanced glycolysis. Consistent with these observations, estrogen-related receptor α (ERRα), an orphan nuclear receptor known for its role in mitochondrial biogenesis, is up-regulated in the absence of phosphatase and tensin homolog deleted on chromosome 10 (PTEN). Our pharmacological and genetic studies show that PI3K/AKT activity regulates the expression of ERRα and mitochondrial biogenesis/respiration. Furthermore, cAMP-response element-binding protein, as a downstream target of AKT, plays a role in the regulation of ERRα, independent of PKA signaling. ERRα regulates reactive oxygen species production, and ERRα knockdown attenuates proliferation and colony-forming potential in Pten-null hepatocytes. Finally, analysis of clinical datasets from liver tissues showed a negative correlation between expressions of ERRα and PTEN in patients with liver cancer. Therefore, this study has established a previously unrecognized link between a growth signal and mitochondrial metabolism.     

Electrophysiological evidence for the presence of cystic fibrosis transmembrane conductance regulator (CFTR) in mouse sperm

Mammalian sperm must undergo a maturational process, named capacitation, in the female reproductive tract to fertilize the egg. Sperm capacitation is regulated by a cAMP/protein kinase A (PKA) pathway and involves increases in intracellular Ca²⁺, pH, Cl^?, protein tyrosine phosphorylation, and in mouse and some other mammals a membrane potential hyperpolarization. The cystic fibrosis transmembrane conductance regulator (CFTR), a Cl^? channel modulated by cAMP/PKA and ATP, was detected in mammalian sperm and proposed to modulate capacitation. Our whole‐cell patch‐clamp recordings from testicular mouse sperm now reveal a Cl^? selective component to membrane current that is ATP‐dependent, stimulated by cAMP, cGMP, and genistein (a CFTR agonist, at low concentrations), and inhibited by DPC and CFTR_inh‐172, two well‐known CFTR antagonists. Furthermore, the Cl^? current component activated by cAMP and inhibited by CFTR_inh‐172 is absent in recordings on testicular sperm from mice possessing the CFTR ΔF508 loss‐of‐function mutation, indicating that CFTR is responsible for this component. A Cl^? selective like current component displaying CFTR characteristics was also found in wild type epididymal sperm bearing the cytoplasmatic droplet. Capacitated sperm treated with CFTR_inh‐172 undergo a shape change, suggesting that CFTR is involved in cell volume regulation. These findings indicate that functional CFTR channels are present in mouse sperm and their biophysical properties are consistent with their proposed participation in capacitation. J. Cell. Physiol. 228: 590–601, 2013. © 2012 Wiley Periodicals, Inc.     

Testing Bergmann’s rule and the Rosenzweig hypothesis with craniometric studies of the South American sea lion

We tested the validity of Bergmann’s rule and Rosenzweig’s hypothesis through an analysis of the geographical variation of the skull size of Otaria flavescens along the entire distribution range of the species (except Brazil). We quantified the sizes of 606 adult South American sea lion skulls measured in seven localities of Peru, Chile, Uruguay, Argentina, and the Falkland/Malvinas Islands. Geographical and environmental variables included latitude, longitude, and monthly minimum, maximum, and mean air and ocean temperatures. We also included information on fish landings as a proxy for productivity. Males showed a positive relationship between condylobasal length (CBL) and latitude, and between CBL and the six temperature variables. By contrast, females showed a negative relationship between CBL and the same variables. Finally, female skull size showed a significant and positive correlation with fish landings, while males did not show any relationship with this variable. The body size of males conformed to Bergmann’s rule, with larger individuals found in southern localities of South America. Females followed the converse of Bergmann’s rule at the intraspecific level, but showed a positive relationship with the proxy for productivity, thus supporting Rosenzweig’s hypothesis. Differences in the factors that drive body size in females and males may be explained by their different life-history strategies. Our analyses demonstrate that latitude and temperature are not the only factors that explain spatial variation in body size: others such as food availability are also important for explaining the ecogeographical patterns found in O. flavescens.     

Latest occurrences of the Mesozoic family Elcanidae (Insecta: Orthoptera), in Cretaceous amber from Myanmar and Spain

Mesozoic orthopterans of the family Elcanidae are reported (as nymphs) in amber, from the latest Albian-Cenomanian of northern Myanmar and the Albian of northern Spain. Four distinct new species in two new genera occur, Burmelcana longirostris n. gen, n. sp. in amber from Myanmar and Hispanelcana arilloi n. gen, n. sp., H. alavensis n. sp. and H. lopezvallei n. sp. from Spanish amber. Detailed preservation reveals the fine structure of the tibial spurs and spines that are so distinctive to Elcanidae, as well as details of the abdominal styli, cerci, tarsomeres, and mouthparts. Elcanidae and their stem group, Permelcanidae, are known from the Early Permian to the Early Cretaceous (Aptian), so the amber fossils represent the latest known occurrence of this clade.