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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

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