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The high percentage of patients carrying germline mutations makes pheochromocytomas/paragangliomas the most heritable of all tumors. However, there are still cases unexplained by mutations in the known genes. We aimed to identify the genetic cause of disease in patients strongly suspected of having hereditary tumors. Whole-exome sequencing was applied to the germlines of a parent–proband trio. Genome-wide methylome analysis, RNA-seq, CRISPR/Cas9 gene editing, and targeted sequencing were also performed. We identified a novel de novo germline mutation in DNMT3A, affecting a highly conserved residue located close to the aromatic cage that binds to trimethylated histone H3. DNMT3A-mutated tumors exhibited significant hypermethylation of homeobox-containing genes, suggesting an activating role of the mutation. CRISPR/Cas9-mediated knock-in in HeLa cells led to global changes in methylation, providing evidence of the DNMT3A-altered function. Targeted sequencing revealed subclonal somatic mutations in six additional paragangliomas. Finally, a second germline DNMT3A mutation, also causing global tumor DNA hypermethylation, was found in a patient with a family history of pheochromocytoma. Our findings suggest that DNMT3A may be a susceptibility gene for paragangliomas and, if confirmed in future studies, would represent the first example of gain-of-function mutations affecting a DNA methyltransferase gene involved in cancer predisposition.

PURPOSE: Anthracyclines are widely used chemotherapeutic drugs that can cause progressive and irreversible cardiac damage and fatal heart failure. Several genetic variants associated with anthracycline-induced cardiotoxicity (AIC) have been identified, but they explain only a small proportion of the interindividual differences in AIC susceptibility. METHODS: In this study, we evaluated the association of low-frequency variants with risk of chronic AIC using the Illumina HumanExome BeadChip array in a discovery cohort of 61 anthracycline-treated breast cancer patients with replication in a second independent cohort of 83 anthracycline-treated pediatric cancer patients, using gene-based tests (SKAT-O). RESULTS: The most significant associated gene in the discovery cohort was ETFB (electron transfer flavoprotein beta subunit) involved in mitochondrial β-oxidation and ATP production (P = 4.16 × 10-4) and this association was replicated in an independent set of anthracycline-treated cancer patients (P = 2.81 × 10-3). Within ETFB, we found that the missense variant rs79338777 (p.Pro52Leu; c.155C > T) made the greatest contribution to the observed gene association and it was associated with increased risk of chronic AIC in the two cohorts separately and when combined (OR 9.00, P = 1.95 × 10-4, 95% CI 2.83-28.6). CONCLUSIONS: We identified and replicated a novel gene, ETFB, strongly associated with chronic AIC independently of age at tumor onset and related to anthracycline-mediated mitochondrial dysfunction. Although experimental verification and further studies in larger patient cohorts are required to confirm our finding, we demonstrated that exome array data analysis represents a valuable strategy to identify novel genes contributing to the susceptibility to chronic AIC.

Aim: To quantify the influence of past archipelago configuration on present-day insular biodiversity patterns, and to compare the role of long-lasting archipelago configurations over the Pleistocene to configurations of short duration such as at the Last Glacial Maximum (LGM) and the present-day.Location: 53 volcanic oceanic islands from 12 archipelagos worldwide—Azores, Canary Islands, Cook Islands, Galápagos, Gulf of Guinea, Hawaii, Madeira, Mascarenes, Pitcairn, Revillagigedo, Samoan Islands and Tristan da Cunha.Time period: The last 800 kyr, representing the nine most recent glacial–interglacial cycles. Major taxa studied: Land snails and angiosperms.Methods: Species richness data for land snails and angiosperms were compiled from existing literature and species checklists. We reconstructed archipelago configurations at the following sea levels: the present-day high interglacial sea level, the intermediate sea levels that are representative of the Pleistocene and the low sea levels of the LGM. We fitted two alternative linear mixed models for each archipelago configuration using the number of single-island endemic, multiple-island endemic and (non-endemic) native species as a response. Model performance was assessed based on the goodness-of-fit of the full model, the variance explained by archipelago configuration and model parsimony.Results: Single-island endemic richness in both taxonomic groups was best explained by intermediate palaeo-configuration (positively by area change, and negatively by palaeo-connectedness), whereas non-endemic native species richness was poorly explained by palaeo-configuration. Single-island endemic richness was better explained by intermediate archipelago configurations than by the archipelago configurations of the LGM or present-day. Main conclusions: Archipelago configurations at intermediate sea levels—which are representative of the Pleistocene—have left a stronger imprint on single-island endemic richness patterns on volcanic oceanic islands than extreme archipelago configurations that persisted for only a few thousand years (such as the LGM). In understanding ecological and evolutionary dynamics of insular biota it is essential to consider longer-lasting environmental conditions, rather than extreme situations alone.

Aim: The majority of documented extinctions world-wide in the last four centuries are of species endemic to islands. However, the phenomenon of delayed extinctions as a result of habitat loss has rarely been assessed on oceanic islands. In this study, we tested whether extinction debt (ED), in general, occurs on islands and for which taxonomical groups this phenomenon is most pronounced by assessing ED for multiple endemic taxa and for each of the main altitudinal ecosystems in a well-studied oceanic archipelago. Location: Canary Islands. Methods: We characterized habitat preferences for all endemic species of several taxonomic groups (vascular plants, ground and darkling beetles, flies and land snails). Using generalized linear mixed models and available data about habitat distributions, we tested for all taxa and habitat types to determine whether past habitat area better explained current richness of habitat specialists than current habitat area. If so, an extinction debt can be assumed. Results: For all five major habitat types and five taxonomic groups studied, present-day richness of habitat specialists fitted better with past than current habitat area, evidencing habitat-and taxon-specific extinction debts. This pattern was consistent for both long-lived vascular plants and short-lived invertebrates. Single island endemics in each taxonomic group showed steeper slopes of the species–area relationship (SAR) compared to archipelago endemics indicating higher sensitivity to habitat loss which might increase sizes of ED. Conclusion: Despite differences in species’ generation times, plants and invertebrates showed delayed extinctions after habitat destruction in the Canary Islands. Our SAR approach suggests that a considerable number of Canary Island endemics will eventually become extinct in the future without further habitat loss. The case of the Canary archipelago is probably not unique. Hence, we interpret our results as a warning for island conservationists that the worst of the extinction crisis on oceanic islands might be yet to come. Conservation actions should focus on habitat restoration to attenuate or reverse current extinction processes. Universidad de Las Palmas de Gran Canaria Universidad de La Laguna

Exceptional longevity (EL) is a rare phenotype that can cluster in families, and co-segregation of genetic variation in these families may point to candidate genes that could contribute to extended lifespan. In this study, for the first time, we have sequenced a total of seven exomes from exceptionally long-lived siblings (probands ≥ 103 years and at least one sibling ≥ 97 years) that come from three separate families. We have focused on rare functional variants (RFVs) which have ≤ 1% minor allele frequency according to databases and that are likely to alter gene product function. Based on this, we have identified one candidate longevity gene carrying RFVs in all three families, APOB. Interestingly, APOB is a component of lipoprotein particles together with APOE, and variants in the genes encoding these two proteins have been previously associated with human longevity. Analysis of nonfamilial EL cases showed a trend, without reaching statistical significance, toward enrichment of APOB RFVs. We have also identified candidate longevity genes shared between two families (5-13) or within individual families (66-156 genes). Some of these genes have been previously linked to longevity in model organisms, such as PPARGC1A, NRG1, RAD52, RAD51, NCOR1, and ADCY5 genes. This work provides an initial catalog of genes that could contribute to exceptional familial longevity.

Land snail shell δ13C value is often used as a paleovegetation proxy assuming that snails ingest all plants in relation to their abundance, and that plants are the only source of carbon. However, carbonate ingestion and variable metabolic rates complicate these relationships. We evaluate if live-collected snails from Lanzarote (Canary Islands) reflect the abundance of C3 and CAM plants. Snails were collected on either CAM or C3 plants for isotope analysis of shell and body, and shell size. Respective shell and body δ13C values of snails collected on CAM plants averaged − 8.5 ± 1.7‰ and − 22.8 ± 1.6‰, whereas specimens from C3 plants averaged − 10.1 ± 0.7‰ and − 24.9 ± 1.1‰. A flux balance model suggests snails experienced comparable metabolic rates. A two-source mass balance equation implies that snails consumed ~ 10% of CAM, which agrees with their abundance in the landscape. Snails collected on CAM plant were smaller than those on C3 plants. Conclusively: 1) snails consume CAM plants when they are available; 2) migration of snails among C3 and CAM plants is a common phenomenon; and 3) C3 plants may be a more energetic food for growth than CAM plants. This study shows that shell δ13C values offer approximate estimates of plants in C3–CAM mixed environments.

Aragonitic and calcitic land snails from carbonate-rich paleosols in northwestern Lanzarote (Canary Islands) were analyzed for 13C/12C and 18O/16O ratios to deduce the Pleistocene–Holocene transition in the westernmost Sahara zone. Modern, mid-late Holocene (~ 2.1–5.5 cal ka BP) and late Pleistocene (~ 23.3–24.0 cal ka BP) aragonitic shells exhibited respective values of − 9.5 ± 1.6‰, − 7.7 ± 1.5‰, and − 2.3 ± 2.8‰ for δ13C; and + 0.3 ± 0.3‰, + 0.1 ± 0.7‰, and + 2.5 ± 0.4‰ for δ18O. Holocene and Pleistocene calcitic shells of the endemic slug Cryptella canariensis showed respective values of − 0.7 ± 2.6‰ and − 8.5 ± 2.5‰ for δ13C; and + 0.8 ± 1.5 and + 3.6 ± 0.4‰ for δ18O. Both aragonitic and calcitic shells showed equivalent temporal isotopic trends. Higher δ13C values during ~ 23.3–24.0 cal ka BP suggest higher abundance of C4 and/or CAM plants, likely associated with drier conditions and/or lower atmospheric CO2 concentration. Maximum shell δ18O values during ~ 23.3–24.0 cal ka BP opposes minimal values of Greenland ice cores and probably reflect the combined effects of (1) higher rain δ18O values linked to higher glacial seawater δ18O values and/or larger snail activity during summer seasons; (2) relative humidity values similar or slightly lower than at present; (3) higher evaporation rates; and (4) cooler temperatures. Bone remains of the extinct Dune Shearwater Puffinus holeae were only recovered from the Holocene bed. Collagen δ13C and δ15N values (− 13.5 ± 0.2‰[PDB] and + 13.7 ± 1.0‰[air], respectively) match with the signature of a low trophic level Macaronesian seabird that fed upon local fish. Bone carbonate δ13C (− 7.4 ± 1.0‰[PDB]) and phosphate δ18O (+ 18.2 ± 0.4‰[SMOW]) values exhibited pristine signals denoting their potential value in future paleoenvironmental studies in the region. The age of P. holeae (~ 2.1–2.7 cal ka BP) supports that the aboriginal population possibly caused its extinction. In contrast, the extinction of the endemic helicid Theba sp. (~ 23.3–24.0 cal ka BP) was likely caused by environmental change.

Pheochromocytomas (PCCs) and paragangliomas (PGLs) are chromaffin-cell tumors that arise from the adrenal medulla and extra-adrenal paraganglia, respectively. The dysfunction of genes involved in the cellular response to hypoxia, such as VHL, EGL nine homolog 1, and the succinate dehydrogenase (SDH) genes, leads to a direct abrogation of hypoxia inducible factor (HIF) degradation, resulting in a pseudo-hypoxic state implicated in PCC/PGL development. Recently, somatic post-zygotic mutations in EPAS1 (HIF2A) have been found in patients with multiple PGLs and congenital erythrocytosis. We assessed 41 PCCs/PGLs for mutations in EPAS1 and herein describe the clinical, molecular and genetic characteristics of the 7 patients found to carry somatic EPAS1 mutations; 4 presented with multiple PGLs (3 of them also had congenital erythrocytosis), whereas 3 were single sporadic PCC/PGL cases. Gene expression analysis of EPAS1-mutated tumors revealed similar mRNA EPAS1 levels to those found in SDH-gene- and VHL-mutated cases and a significant up-regulation of two hypoxia-induced genes (PCSK6 and GNA14). Interestingly, single nucleotide polymorphism array analysis revealed an exclusive gain of chromosome 2p in three EPAS1-mutated tumors. Furthermore, multiplex-PCR screening for small rearrangements detected a specific EPAS1 gain in another EPAS1-mutated tumor and in three non-EPAS1-mutated cases. The finding that EPAS1 is involved in the sporadic presentation of the disease not only increases the percentage of PCCs/PGLs with known driver mutations, but also highlights the relevance of studying other hypoxia-related genes in apparently sporadic tumors. Finally, the detection of a specific copy number alteration affecting chromosome 2p in EPAS1-mutated tumors may guide the genetic diagnosis of patients with this disease.

International audience; Aim: Morphological and taxonomic diversity are intuitive measures of biological diversity. Previous studies have shown discordance between these measures at large spatial and temporal scales, but the implications of this pattern for the underlying processes are not understood. Using oceanic archipelagos as spatial units, we examine potential links between the morphological and taxonomic diversity of their land snail faunas in a biogeographical framework. Location: Eleven major oceanic archipelagos. Methods: For each archipelago, we assembled lists of indigenous land snail species, classified by family and genus, with shell height and width for each species (1723 species in total). We used biogeographic and climatic variables as potential predictors of diversity patterns. We employed regression analyses to evaluate (1) whether morphological diversity scales with taxonomic diversity at the species, genus or family level, and (2) whether morphological and taxonomic diversity correlate similarly with biogeographic/climatic factors. We also assessed which taxonomic level contributes most to morphological variation within archipelagos. Results: Morphological diversity across archipelagos was strongly related to genus but not species richness. Within archipelagos, morphological variation reflected differences among genera and families but not species. Species richness was best explained by archipelago area, but morphological diversity was not significantly related to any of the physical features of archipelagos. Main conclusions: Across archipelagos, species richness and morphological diversity of land snail faunas are decoupled. The relationship between species richness and the available ecological space (captured mainly by area) indicates the prevalence of niche-based processes while, for morphological diversity, the strong conservatism of morphology at the genus level suggests the presence of diversification-based limits. Assuming genera effectively reflect diversification, our findings indicate that morphological space on oceanic archipelagos depends primarily on the number of evolutionary units that have colonized and/or diversified through time. © 2016 John Wiley & Sons Ltd

Aim We collate and analyse data for land snail diversity and endemism, as a means of testing the explanatory power of the general dynamic model of oceanic island biogeography (GDM): a theoretical model linking trends in species immigration, speciation and extinction to a generalized island ontogeny. Location Eight oceanic archipelagos: Azores, Canaries, Hawaii, Galapagos, Madeira, Samoa, Society, Tristan da Cunha. Methods Using data obtained from literature sources we examined the power of the GDM through its derivative ATT2 model (i.e. diversity metric = b1 + b2Area + b3Time + b4Time2), in comparison with all the possible simpler models, e.g. including only area or time. The diversity metrics considered were the number of (1) native species, (2) archipelagic endemic species, and (3) single-island endemic species. Models were evaluated using both log-transformed and untransformed diversity data by means of linear mixed effect models. For Hawaii and the Canaries, responses of different major taxonomic groups were also analysed separately. Results The ATT2 model was always included within the group of best models and, in many cases, was the single-best model and was particularly successful in fitting the log-transformed diversity metrics. In four archipelagos, a hump-shaped relationship with time (island age) is apparent, while the other four archipelagos show a general increase of species richness with island age. In Hawaii and the Canaries outcomes vary between different taxonomic groups. Main conclusions The GDM is an intentionally simplified representation of environmental and diversity dynamics on oceanic islands, which predicts a simple positive relationship between diversity and island area combined with a humped response to time. We find broad support for the applicability of this model, especially when a full range of island developmental stages is present. However, our results also show that the varied mechanisms of island origins and the differing responses of major taxa should be taken into consideration when interpreting diversity metrics in terms of the GDM. This heterogeneity is reflected in the fact that no single model outperforms all the other models for all datasets analysed.

Studies that assess the ecological fidelity—preservation of the original community—of terrestrial shell accumulations are uncommon but essential to infer accurate changes in past ecosystems. When live-dead comparisons are unavailable, the taxonomic agreement between differing taphofacies may be used to evaluate the fidelity of ancient shelly assemblages. This approach was used to approximate the fidelity of Quaternary land snails preserved in carbonate-rich paleosols from the northeastern islets of the Canary Archipelago. Such macroscopic alteration as fragmentation, corrosion, carbonate coating, and color loss affected shells, however, microscopic analyses concluded substantial diagenetic alterations unlikely. The shell abundance negatively correlated with fragmentation, suggesting that a higher proportion of shells may be a consequence of higher shell input rate and lower shell destruction rate rather than lower sedimentation rate, as predicted by taphonomic models. Strongly and weakly altered taphofacies significantly differed in species abundances. Substantial taphonomic bias was improbable, however, because both taphofacies contained taxa with comparable durability. Temporal fluctuations in taphonomy and ecology suggest variable environmental conditions operated through time. The overall decline in shell abundance from the last glacial to interglacial paleosols may be explained by a decline in humidity and reduced island surface area resulting in lowered snail proliferation, and in turn, a decreased net shell input rate. This study emphasizes that the original community is preserved within the studied terrestrial shell accumulations regardless of the degree of taphonomic alteration. Measures of past taxonomic richness and diversity, therefore, may be used as a reliable measure of the original snail community.

The isotopic composition of land snail shells was analyzed to investigate environmental changes in the eastern Canary Islands (28–29°N) over the last ~ 50 ka. Shell δ13C values range from −8.9‰ to 3.8‰. At various times during the glacial interval (~ 15 to ~ 50 ka), moving average shell δ13C values were 3‰ higher than today, suggesting a larger proportion of C4 plants at those periods. Shell δ18O values range from −1.9‰ to 4.5‰, with moving average δ18O values exhibiting a noisy but long-term increase from 0.1‰ at ~ 50 ka to 1.6–1.8‰ during the LGM (~ 15–22 ka). Subsequently, the moving average δ18O values range from 0.0‰ at ~ 12 ka to 0.9‰ at present. Calculations using a published snail flux balance model for δ18O, constrained by regional temperatures and ocean δ18O values, suggest that relative humidity at the times of snail activity fluctuated but exhibited a long-term decline over the last ~ 50 ka, eventually resulting in the current semiarid conditions of the eastern Canary Islands (consistent with the aridification process in the nearby Sahara). Thus, low-latitude oceanic island land snail shells may be isotopic archives of glacial to interglacial and tropical/subtropical environmental change.

The introduction of non-native gastropods on islands has repetitively been related to a decline of the endemic fauna. So far, no quantitative information is available even for the native gastropod fauna from the laurel forests (the so-called Laurisilva) of the Canary Islands. Much of the original laurel forest has been logged in recent centuries. Based on vegetation studies, we hypothesized that densities and the number of introduced species decline with the age of the regrowth forests. We sampled 27 sites from which we collected thirty native and seven introduced species. Two introduced species, Milax nigricans and Oxychilus alliarius, were previously not reported from the Canary Islands. Assemblage composition was mainly structured by disturbance history and attitude. Overall species richness was correlated with slope inclination, prevalence of rocky outcrops, amounts of woody debris and leaf litter depth. Densities were correlated with the depth of the litter layer and the extent of herb layer cover and laurel canopy cover. Introduced species occurred in 22 sites but were neither related to native species richness nor to the time that elapsed since forest regrowth. One introduced slug, Lehmannia valentiana, is already widespread, with densities strongly related to herb cover. Overall species richness seemed to be the outcome of invasibility, thus factors enhancing species richness likely also enhance invasibility. Although at present introduced species contribute to diversity, the potential competition between introduced slugs and the rich native semi-slug fauna, and the effects of introduced predatory snails (Oxychilus spp. and Testacella maugei) warrant further monitoring. (C) 2009 Elsevier Masson SAS. All rights reserved.

Species of the Napaeus subgenera show incongruences between genital anatomy and molecular phylogenetic data. In this study, four new Napaeus species from the Canary Islands are described. Shell drawings of the 56 known Napaeus species were obtained from shell photographs for comparison. Differences between some genital system character-states of the species described here and those of the original subgenera descriptions are evident. Consequently, in the absence of phylogenetic analyses, the new species are not assigned to the Napaeus subgenera. In addition, the possible relationships among Macaronesian enids are preliminarily evaluated. Within the Macaronesian region, enids are exclusively present in the Canaries and the Azores. The absence of enids from Madeira, combined with the differences in genital anatomy between the Canarian and Azorean enids and the relatively large distance between these archipelagos, may indicate different immigration pathways (Africa/Europe, respectively) and possibly different...

Land snails provide a unique opportunity to study terrestrial paleoenvironments because their shells, which are generally highly abundant and well-preserved in the fossil record, contain a temporal record of environmental change in the form of isotope codes. To evaluate the utility of this approach for a low-latitude oceanic setting, 207 modern shells of 18 species of land snail were analyzed for their oxygen and carbon isotope composition along a north and south facing altitudinal gradient (10–2160 m a.s.l.) in Tenerife Island (∼28°N) of the Canary Archipelago. Shells collected at each locality showed a relatively large range in isotope composition which was greater along the south facing transect (drier and hotter), suggesting that the variance in shell isotope values may be related to water-stress. Although pooled isotope values did not generally show strong relationships with environmental variables (i.e., altitude, temperature and precipitation), mean isotope values were strongly associated with some climatic factors when grouped by site. The mean δ18O value of the shell (δ18Oshell) by site displayed a negative correlation with elevation, which is consistent with the positive relationship observed between temperature and the δ18O value of rain (δ18Orain). Calculated δ18O values of the snail body water (δ18Obody) derived from observed temperatures and δ18Oshell values (using the equation of Grossman and Ku [Grossman E. L. and Ku T. L. (1986) Oxygen and carbon isotope fractionation in biogenic aragonite. Chem. Geol. (Isotope Geosci. Sec.) 59, 59–74]) displayed a trend with respect to altitude that was similar to measured and hypothetical δ18O values for local rain water. The calculated δ18Obody values from the shell declined 0.17‰ (VSMOW) per 100 m, which is consistent with the “altitude effect” observed for tropical rains in Western Africa, and it correlated negatively with rainfall amount. Accordingly, lower δ18Oshell values indicate lower temperatures, lower δ18Orain values and possibly, higher rainfall totals. A positive correlation between the mean δ13C values of shells (δ13Cshell) and plants by site suggests that shells potentially record information about the surrounding vegetation. The δ13Cshell values varied between −15.7 and −0.6‰ (VPDB), indicating that snails consumed C3 and C4/CAM plants, where more negative δ13Cshell values probably reflects the preferential consumption of C3 plants which are favored under wetter conditions. Individuals with more positive δ13Cshell values consumed a larger percentage of C4 plants (other potential factors such as carbonate ingestion or atmospheric CO2 contribution were unlikely) that were more common at lower elevations of the hotter and drier south facing transect. The relatively wide range of shell isotope values within a single site requires the analysis of numerous shells for meaningful paleoclimatic studies. Although small differences were observed in isotope composition among snail species collected at a single sampling site, they were not significant, suggesting that isotope signatures extracted from multi-taxa snail data sets may be used to infer environmental conditions over a broad range of habitats.

Quaternary aeolian deposits of the Canary Islands contain well-preserved terrestrial gastropods, providing a suitable setting for assessing the taphonomy and compositional fidelity of their fossil record over ~13 kyr. Nine beds (12, 513 shells) have been analysed in terms of multivariate taphonomic and palaeoecological variables, taxonomic composition, and the stratigraphic and palaeontological context. Shells are affected by carbonate coatings, colour loss and fragmentation. Shell preservation is size-specific: juveniles are less fragmented and show colour preservation more commonly than adults. In palaeosols, the adult shell density correlates negatively with the proportion of fragmented adults, negatively with the proportion of juveniles, and positively with the proportion of adults with coatings. High bioturbation intensity in palaeosols is associated with low shell fragmentation and high proportion of shells with coatings. These relationships imply that high adult density in palaeosols was driven by an increase in shell production rate (related to a decrease in predation rates on adults and a decrease in juvenile mortality) and a decrease in shell destruction rate (related to an increase in durability enhanced by carbonate precipitation). In dunes, the relationships between taphonomic alteration, shell density and bioturbation are insignificant. However, dune assemblages are characterized by a lower frequency of shells with coatings and higher rates of colour loss, indicating lower shell durability in dunes than in palaeosols. Additionally, nonrandom differences in the coating proportion among palaeosols imply substantial temporal variation in the rate of carbonate crust formation, reflecting long-term changes in bioturbation intensity that covaries positively with shell preservation. Dunes and palaeosols do not differ in species abundances despite differences in the degree of shell alteration, suggesting that both weakly and strongly altered assemblages offer data with a high compositional fidelity. Carbonate-rich terrestrial deposits originating in arid conditions can enhance the preservation of gastropods and result in fossil assemblages that are suitable for palaeoecological and palaeoenvironmental studies of terrestrial ecosystems. � Aeolian deposits, Canary Islands, land snail shell assemblages, Quantitative Taphonomy, Quaternary .

Stable isotopes of oxygen and carbon extracted from fossil land snail shells have been used increasingly to interpret past environments. To evaluate the utility of this approach for low-latitude oceanic islands, populations of the modern helicid land snail Theba geminata – a species also abundant in the Quaternary fossil record of the region – were sampled at ten low altitude ( δ D and − 2‰ (V-SMOW) for δ 18 O, ranging from − 11‰ to + 2‰ (V-SMOW) and from − 2.6‰ to − 0.7‰ (V-SMOW), respectively. The local vegetation is heterogeneous, including C 3 , C 4 , and CAM plants. δ 13 C values vary from − 13.0‰ to − 29.0‰ (V-PDB) across plant species. Of the 24 species, five are C 4 , 15 are C 3 , and four are CAM plants. The δ 18 O values for shells represent a narrow range of values (from − 0.3‰ to + 2.5‰ [V-PDB]), which is consistent with the low climate seasonality typifying low-latitude oceanic settings. Hypothetical model of the expected δ 18 O value for shell aragonite precipitated in equilibrium suggests that the most negative δ 18 O shell represent the closest estimate for δ 18 O rain water . The δ 13 C values of shells range from − 9.4‰ to + 1.7‰ (V-PDB). The most positive δ 13 C values are attributed to a diet based on C 4 plants. The comparison of δ 13 C values of soft tissues and shells suggests that snails ingested notable amounts (from ~ 20% up to ~ 40%) of foreign carbonates. Consequently, fossil shells with the most negative δ 13 C values should be selected for radiocarbon dating in future geochronological studies of the region. The δ 13 C values of body tissues vary from − 12.0‰ to − 27.2‰ (V-PDB), indicating that land snails consumed C 3 and C 4 plants indiscriminately. The mean carbon isotopic composition, averaged across multiple fossil specimens, may thus provide a useful tool for reconstructing paleoclimates and paleoenvironments throughout the Quaternary history of the Canary Islands and other comparable low-latitude oceanic settings.

The hypothesis of limiting similarity, which postulates that morphologically and/or ecologically similar species will differ enough in shape, size, or other variables to minimize competition, has been controversial among ecologists and paleoecologists. Many studies have reported the occurrence of limiting similarity in modern environments or in time-averaged fossil deposits; however, empirical high-resolution time series demonstrating limiting similarity over longer time scales are lacking. We have integrated radiocarbon-calibrated amino acid dating techniques, stable isotope estimates, and morphometric data to test the hypothesis of limiting similarity in late Quaternary land snails from the Canary Islands over a period of 42,500 years. We tested for both ecological character displacement (two closely related species will differ in size in order to minimize competition in sympatry and these differences will be minimized in allopatry) and communitywide character displacement (overdispersion of body size among competitors in a guild). Multiple proxies of body size consistently show that two endemic congeneric pulmonate gastropod species (Theba geminata and T. arinagae) maintained a difference in size from ~42,500 B.P. through the last occurrence of T. arinagae 14,900 B.P., with a concomitant trend of a decreasing body size. Theba geminata body size did not converge on that of T. arinagae and variation in T. geminata body size did not increase significantly following the extinction of T. arinagae; therefore, ecological character displacement and release did not occur. Community-wide character displacement was found in only one time bin over the last 42,500 years. These results suggest that limiting similarity is a transient ecological phenomenon rather than a long-term evolutionary process. This study not only demonstrates the problems inherent in biological “snapshot” studies and geological studies of time-averaged deposits to test limiting similarity adequately, but it also presents a more adequate research protocol to test the importance of interspecific competition in the history of life.

Five new species of land snail (family Enidae) are described from La Gomera (Canary Islands) of which the majority, on the basis of anatomy alone, could be incorporated within a new supraspecific taxon. In addition to the morphological study of these new species, a region of the 16S mitochondrial gene is sequenced from three of the new species and a range of species of Napaeus from within its two subgenera (Napaeinus and Napaeus). There is a disparity between the morphological and preliminary molecular phylogenetic data. Possible explanations for this conflict are discussed, as well as the evolutionary relationships among these different taxa, and it is suggested that this group may be an excellent model for further studies of adaptation and diversification. © 2006 The Linnean Society of London, Biological Journal of the Linnean Society, 2006, 89, 169–187.

Aminochronological and aminostratigraphical methods have been used to study the Quaternary aeolian deposits from the islands located east of the Canary Archipelago (Fuerteventura and Lanzarote islands and La Graciosa, Montana Clara and Alegranza islets). The extent of racemisation/epimerisation of four amino acids (isoleucine, aspartic acid, phenylalanine and glutamic acid) was measured in land snail shells of the genus Theba. The age calculation algorithms of these amino acids have been determined to permit the numerical dating of these deposits. Eight Aminozones, each defining dune/palaeosol-formation episodes, have been distinguished and dated at 48.6 ± 6.4, 42.5 ± 6.0, 37.8 ± 4.6, 29.4 ± 4.8, 22.4 ± 4.5, 14.9 ± 3.6, 11.0 ± 4.0 and 5.4 ± 1.1 ka BP, the first five of them defining cycles of 5–7 ka. The alternation of palaeosols and aeolian deposits, which are related to abrupt transitions from humid to arid conditions, are the reflection of globally induced changes in North Africa palaeoenvironmental conditions linked to the effect of African palaeomonsoons on the trade winds and the Saharan Air Layer. Probably these aeolian cycles, with a recurrence period of 5–7 ka, are the expression of multiples of the ∼2.4 ka solar-cycle. Copyright © 2005 John Wiley & Sons, Ltd.

The genus Obelus , so far known from shells only, is re-described on the basis of the anatomy of its genital system. Its range is here restricted to north-western Africa and the Canary Islands. Four species are traditionally listed for the Canary Islands: Obelus despreauxii , O. moderatus , O. mirandae and O. cyclodon . The presence of the last species on the Canary Islands is doubtful, whereas the fossil/subfossil presence of O. pumilio is documented. The species Helix morata also belongs to the genus, as well as a new species, O. discogranulatus sp. nov. The genital systems of all confirmed extant Canarian species are shown. Obelus has a peculiar vaginal stimulator appendix (“appendicula”) which is homologous to the penial appendix of the Orthurethra and to the stimulatory organ of other Stylommatophora, with the exception that the A 3 portion is missing. The genus is diagnosed by characters of the vaginal stimulator appendix, such as a curved, finger-like A 2 portion of the appendicula ending proximally in a blind, well-developed muscular sac, and by the slender tubular A 4 portion arising laterally from the muscular sac duct. We conclude that Obelus belongs to the Cochlicella group because it shares an appendicula with the other genera of the group. However, it differs in anatomical details of this structure. The Cochlicella group should be recognized as a separate family Cochlicellidae Schileyko, 1972, with close relationships to the Helicellidae and the Hygromiidae. A new diagnosis for Cochlicellidae is proposed and its phylogenetic relationships are discussed. This is: Notes on the Malacofauna of the Canary Islands, No. 46.

Background:Breast cancer is one of the most common malignancies in women. Genome-wide association studies have identified FGFR2 as a breast cancer susceptibility gene. Common variation in other fibroblast growth factor (FGF) receptors might also modify risk. We tested this hypothesis by studying genotyped single-nucleotide polymorphisms (SNPs) and imputed SNPs in FGFR1, FGFR3, FGFR4 and FGFRL1 in the Breast Cancer Association Consortium.\ud \ud Methods:Data were combined from 49 studies, including 53 835 cases and 50 156 controls, of which 89 050 (46 450 cases and 42 600 controls) were of European ancestry, 12 893 (6269 cases and 6624 controls) of Asian and 2048 (1116 cases and 932 controls) of African ancestry. Associations with risk of breast cancer, overall and by disease sub-type, were assessed using unconditional logistic regression.\ud \ud Results:Little evidence of association with breast cancer risk was observed for SNPs in the FGF receptor genes. The strongest evidence in European women was for rs743682 in FGFR3; the estimated per-allele odds ratio was 1.05 (95 confidence interval=1.02-1.09, P=0.0020), which is substantially lower than that observed for SNPs in FGFR2.\ud \ud Conclusion:Our results suggest that common variants in the other FGF receptors are not associated with risk of breast cancer to the degree observed for FGFR2. © 2014 Cancer Research UK.

The rugged, volcanic oceanic island of La Palma (Fig. 1), with the oldest subaerial rocks dated at 1.7 Ma, is one of the youngest islands of the Atlantic Canarian Archipelago. La Palma is an elongated island with North-South orientation (about 45 km long and near 28 km wide in the northern half, then tapering towards its southernmost tip), with an area of 708 km2 and an altitude of 2426 m above sea level (a.s.l.). The island is in the second stage (“emergence and subaerial construction”) out of the six phases of the hotspot island’s life cycle (Fernández-Palacios & Whittaker, 2010). The most recent volcanic eruption occurred at the Teneguía volcano in 1971. The island exhibits a considerable range of habitats (from arid lowland shrub zones to humid highland evergreen forests) generated by high mountains that intercept the moist trade winds. This great variety of habitats has enhanced land snail radiation and speciation, so the island accommodates about 30 validly described endemic species of land snails, most of them belonging to the main genera (e. g., Napaeus Albers, 1850, Canariella Hesse, 1918, Insulivitrina Hesse, 1923) living today in the archipelago. The genus Hemicycla Swainson, 1840 is second land gastropods in terms of species richness within the Canary Islands, with about 40 known living species (Neiber et al., 2011). Only two of these Hemicycla species are present in La Palma, H. vermiplicata (Wollaston, 1878) and H. granomalleata (Wollaston, 1878) (Fig. 2 A, E), which were merely studied conchologically back in the 19th century. Moreover, Odhner (1937) mentions the presence in Santa Cruz de La Palma of H. ethelema Mabille, 1882, a species viewed as endemic to the Gran Canaria Island, in basis to three shells placed at his disposal by Count C. Strömfelt, Stockholm, and he compares these shells with those of H. granomalleata, indicating that he finds the best concordance in all essential charecteristics, but having the H. granomalleata shells finer granulation than those of H. ethelema.

The Napaeus variatus (Webb & Berthelot, 1833) species group from the Canary Islands is reviewed from literature information, types, other museum specimens, and newly collected material. Anatomy data is newly provided for six species. Five new species are described: N. elegans and N. esbeltus from Tenerife, N. orientalis and N. beguirae from La Gomera, and N. exilis from Gran Canaria. Eight species lack a diverticulum and are referred to the subgenus Napaeus (Napaeus) Albers, 1850, whereas five species are provided with a diverticulum and arc referred to Napaeus (Napaeinus) Hesse, 1933. Four species cannot be assigned to a subgenus due to a lack of information. Keys of species from the different islands are provided.

Five new species of Napaeus are described, four from Gran Canaria and one from El Hierro (Canary Islands): Napaeus josei n. sp., N. venegueraensis n. sp., N. arinagaensis n. sp., N. validoi n. sp. and N. grohi n. sp. The main differences from the most similar species and data on distribution are presented. At least three of the new species disguise their shells with soil, presumably to avoid predation.

Purpose: Hand-foot syndrome (HFS) is one of the most relevant dose-limiting adverse effects of capecitabine, an oral prodrug of 5-fluorouracil used in the standard treatment of breast and colorectal cancer. We investigated the association between grade 3 HFS and genetic variations in genes involved in capecitabine metabolism. Experimental Design: We genotyped a total of 13 polymorphisms in the carboxylesterase 2 (CES2) gene, the cytidine deaminase (CDD) gene, the thymidine phosphorylase (TP) gene, the thymidylate synthase (TS) gene, and the dihydropyrimidine dehydrogenase (DPD) gene in 130 patients treated with capecitabine. We correlated these polymorphisms with susceptibility to HFS. Results: We found an association of HFS appearance with rs532545 located in the promoter region of CDD (OR = 2.02, 95% CI = 1.02–3.99, P = 0.039). Because we found no association between the rs532545 genotype and CDD mRNA expression in Epstein-Barr virus lymphoblastoid cells, we explored additional genetic variations across the CDD promoter. We found an insertion, rs3215400, in linkage disequilibrium with rs532545 (D′ = 0.92), which was more clearly associated with HFS (OR = 0.51, 95% CI = 0.27–0.95, P = 0.028) in patients and with total CDD gene expression (P = 0.004) in lymphoblastoid cells. In silico analysis suggested that this insertion might create a binding site for the transcriptional regulator E2F. Using a SNaPshot assay in lymphoblastoid cells, we observed a 5.7-fold increased allele-specific mRNA expression from the deleted allele. Conclusions: The deleted allele of rs3215400 shows an increased allele-specific expression and is significantly associated with an increased risk of capecitabine-induced HFS. Clin Cancer Res; 17(7); 2006–13. ©2011 AACR.

The rare variant rs12975333 is a G→T change located at the eighth nucleotide of the mature microRNA-125a (miR-125a). The T allele has been reported to block the processing of pri-miRNA to pre-miRNA precursor and to be extremely rare, being detected only once in a panel of 1200 individuals from diverse ethnic backgrounds assessed by the Centre d'Etude du Polymorphisme Humain.1 A study by Li et al 2 showed the T allele of rs12975333 to be strongly associated with breast cancer risk, with 6 of 72 (8.3%) breast cancer cases from two hospitals in Antwerp, Belgium, being carriers of the T allele and none of 282 controls collected from the general population in the Antwerp area or 587 Caucasian controls collected in the USA.2 The breast cancers were all lymph node negative and received only local treatment (mastectomy or lumpectomy followed by radiation treatment). Genotyping was performed by means of the TaqMan assay, as previously described,1 using whole-genome-amplified DNA obtained from …

Platinum agents cause DNA cross-linking. Nucleotide excision repair genes play a key role in DNA damage repair. This study aims to investigate whether polymorphisms in these genes are associated with tumor response and survival in cisplatin-treated osteosarcoma patients. Eight single nucleotide polymorphisms in ERCC2, XPC, XPA, ERCC1, ERCC4 and ERCC5 genes were analyzed in 91 patients diagnosed with osteosarcoma and treated with cisplatin. A significant association with tumor response, after correction for multiple testing, was found for the Lys751Gln polymorphism in the ERCC2 gene. We found that only 45% of patients with at least one polymorphic G allele responded compared with 80% of patients homozygous for the common T allele (odds ratio=4.9, 95% confidence interval=1.64-14.54, adjusted P-value=0.047). In addition, carrying at least one ERCC2 Lys751GlnG allele was significantly associated with shorter event-free survival (median=184 months, compared with 240 months for TT homozygotes; hazard ratio=5.76, 95% confidence interval=1.30-25.55; P-value=0.021). Although ototoxicity was only recorded in 32 patients, we found weak evidence of an association with the CC genotype of XPC Lys939Gln (P-value= 0.042). This is the first pharmacogenetic study focused on osteosarcoma treatment providing evidence that polymorphic variants in DNA repair genes could be useful predictors of response to cisplatin chemotherapy in osteosarcoma patients.

Hemicycla laurijona sp. nov. and H. fulgida sp. nov. are described from the laurel forests of La Gomera and Tenerife islands, respectively (Canary Islands). Both species belong to the Helicinae group of genera sharing the “presence of a specialized twin papillae system” in the penis, the adaptive advantage of which has not hitherto been discussed. Both species present a proximal penial papilla homologous to the “penial papilla” of other Stylommatophora, and an apomorphic distal penial papilla. The arrangement of these organs is described in a specimen with the distal genital system everted, showing that the distal penial papilla is an accessory papilla whose main function may be to lengthen the male duct in the evaginated penis. The accessory papilla may also have another function; its base forms a protuberant ring in the everted penis, perhaps for anchorage during mating or to impede a too deep penetration. The dart and an undigested part of the spermatophore of H. fulgida are also described, the species status of both H. invernicata (Mousson, 1872) and H. consobrina (A. Ferussac, 1822) is confirmed and some aspects of Hemicycla relationships are discussed.

Canariella jandiaensis sp. nov. and Canariella (Majorata) subgen. nov. are described from the Jandía Peninsula mountains (Fuerteventura Island). The new subgenus, which includes C. jandiaensis and C. eutropis, is characterized mainly by the following synapomorphies: The shell is without hairs and there is a large penial papilla present arising from all the five epiphallar folds. C. jandiaensis differs from C. eutropis in the unkeeled, almost globular shell, which is smaller but taller than that of C. eutropis and has more numerous but smoother radial ribs. Also, C. jandiaensis has a pseudopapilla in the distal penial cavity instead of the thick longitudinal pilaster present in C. eutropis. The range of Majorata is small, declining from 30,000 years ago and the new species should be classified as “Critically Endangered” based on the very small size of its distribution area (smaller than 1 km2) and the very abundant and free-range livestock present. Mainly goats, grazing freely destroy the habitat in the entire Jandía mountains. Protection of their habitat is recommended, mainly by means of strict livestock control.

The family Discidae has undergone extensive speciation in the Macaronesian region (eastern Atlantic Ocean), with 11 endemic species recognised from Madeira and the Canary Islands in recent checklists (Bank, Groh & Ripken 2002; Seddon 2008; Fauna Europaea database project 2011), grouped into the genera Keraea Gude, 1911 and Discus Fitzinger, 1833: K. deflorata (R.T. Lowe, 1855) and D. ( Atlantica ) guerinianus (R.T. Lowe, 1852), from Madeira; and nine species from the Canary Islands: K. garachicoensis (Wollaston, 1878), D. scutula, (Shuttleworth, 1852), D. engonatus (Shuttleworth, 1852), D. textilis (Shuttleworth, 1852), D. retextus, (Shuttleworth, 1852), D. putrescens (R.T. Lowe, 1861), D. ganodus (J. Mabille, 1882), D. gomerensis Rahle, 1994, and D. kompsus (J. Mabille, 1883). In contrast with the anatomical data known for the European and North American genera Discus and Anguispira Morse, 1864 (Uminski 1962; Pilsbry 1948), there has hitherto been no information published on the internal anatomy of the Canary Islands and Madeiran species, which are known only by their shell characters. In this paper we raise Atlantica to the rank of genus in the Discidae and describe shell and anatomical characters for two new species from La Gomera and Tenerife, respectively. They are grouped in a new subgenus of Atlantica , largely restricted to the laurisilva. This laurel-rich forest occurs in humid subtropical and warm-temperate regions with little variability in temperatures and is developed between 600 and 1,200 m above sea level in the Canary Islands (Yanes et al . 2009b: Fig. 2).

Monilearia tubaeformis sp. nov. is described from Fuerteventura (Canary Islands) and placed in the taxon Lyrula Wollaston, 1878, previously considered as monospecific, for its distinctive type of shell ornamentation. Helix multipunctata Mousson, 1872, from the same island, is also placed in Lyrula because it has similar shell ornamentation. The anatomy of the genital system of both species shows that Lyrula should be treated as a subgenus of Monilearia Mousson, 1872. A new diagnosis of Monilearia (Lyrula) is added

Napaeus lajaensis sp. nov. is the oldest Napaeus species found in the Canary Islands, with more than 130 ka. It is described from a Pleistocene aeolian deposit intercalated between two basaltic lava flows located at Mancha de La Laja (Tenerife Island). The new species is characterized mainly by the presence of two very prominent, spiral, semicylindrical ribs on the body whorl shell. The stratigraphic setting and taphonomic features of the land snail association to which N. lajaensis belongs, were also shown.