Metabolic trade-offs and the maintenance of the fittest and the flattest

How is diversity maintained? Environmental heterogeneity is considered to be important, yet diversity in seemingly homogeneous environments is nonetheless observed. This, it is assumed, must either be owing to weak selection, mutational input or a fitness advantage to genotypes when rare. Here we demonstrate the possibility of a new general mechanism of stable diversity maintenance, one that stems from metabolic and physiological trade-offs. The model requires that such trade-offs translate into a fitness landscape in which the most fit has unfit near-mutational neighbours, and a lower fitness peak also exists that is more mutationally robust. The 'survival of the fittest' applies at low mutation rates, giving way to 'survival of the flattest' at high mutation rates. However, as a consequence of quasispecies-level negative frequency-dependent selection and differences in mutational robustness we observe a transition zone in which both fittest and flattest coexist. Although diversity maintenance is possible for simple organisms in simple environments, the more trade-offs there are, the wider the maintenance zone becomes. The principle may be applied to lineages within a species or species within a community, potentially explaining why competitive exclusion need not be observed in homogeneous environments. This principle predicts the enigmatic richness of metabolic strategies in clonal bacteria and questions the safety of lethal mutagenesis as an antimicrobial treatment.     

Somatic and germline activating mutations of the ALK kinase receptor in neuroblastoma

Neuroblastoma, a tumour derived from the peripheral sympathetic nervous system, is one of the most frequent solid tumours in childhood. It usually occurs sporadically but familial cases are observed, with a subset of cases occurring in association with congenital malformations of the neural crest being linked to germline mutations of the PHOX2B gene. Here we conducted genome-wide comparative genomic hybridization analysis on a large series of neuroblastomas. Copy number increase at the locus encoding the anaplastic lymphoma kinase (ALK) tyrosine kinase receptor was observed recurrently. One particularly informative case presented a high-level gene amplification that was strictly limited to ALK, indicating that this gene may contribute on its own to neuroblastoma development. Through subsequent direct sequencing of cell lines and primary tumour DNAs we identified somatic mutations of the ALK kinase domain that mainly clustered in two hotspots. Germline mutations were observed in two neuroblastoma families, indicating that ALK is a neuroblastoma predisposition gene. Mutated ALK proteins were overexpressed, hyperphosphorylated and showed constitutive kinase activity. The knockdown of ALK expression in ALK-mutated cells, but also in cell lines overexpressing a wild-type ALK, led to a marked decrease of cell proliferation. Altogether, these data identify ALK as a critical player in neuroblastoma development that may hence represent a very attractive therapeutic target in this disease that is still frequently fatal with current treatments.     

Protein phosphatase 2A protects centromeric sister chromatid cohesion during meiosis I

Segregation of homologous maternal and paternal centromeres to opposite poles during meiosis I depends on post-replicative crossing over between homologous non-sister chromatids, which creates chiasmata and therefore bivalent chromosomes. Destruction of sister chromatid cohesion along chromosome arms due to proteolytic cleavage of cohesin's Rec8 subunit by separase resolves chiasmata and thereby triggers the first meiotic division. This produces univalent chromosomes, the chromatids of which are held together by centromeric cohesin that has been protected from separase by shugoshin (Sgo1/MEI-S332) proteins. Here we show in both fission and budding yeast that Sgo1 recruits to centromeres a specific form of protein phosphatase 2A (PP2A). Its inactivation causes loss of centromeric cohesin at anaphase I and random segregation of sister centromeres at the second meiotic division. Artificial recruitment of PP2A to chromosome arms prevents Rec8 phosphorylation and hinders resolution of chiasmata. Our data are consistent with the notion that efficient cleavage of Rec8 requires phosphorylation of cohesin and that this is blocked by PP2A at meiosis I centromeres.