The Polycomb group protein EZH2 directly controls DNA methylation

The establishment and maintenance of epigenetic gene silencing is fundamental to cell determination and function. The essential epigenetic systems involved in heritable repression of gene activity are the Polycomb group (PcG) proteins and the DNA methylation systems. Here we show that the corresponding silencing pathways are mechanistically linked. We find that the PcG protein EZH2 (Enhancer of Zeste homolog 2) interacts-within the context of the Polycomb repressive complexes 2 and 3 (PRC2/3)-with DNA methyltransferases (DNMTs) and associates with DNMT activity in vivo. Chromatin immunoprecipitations indicate that binding of DNMTs to several EZH2-repressed genes depends on the presence of EZH2. Furthermore, we show by bisulphite genomic sequencing that EZH2 is required for DNA methylation of EZH2-target promoters. Our results suggest that EZH2 serves as a recruitment platform for DNA methyltransferases, thus highlighting a previously unrecognized direct connection between two key epigenetic repression systems.     

Late middle Eocene epoch of Libya yields earliest known radiation of African anthropoids

Reconstructing the early evolutionary history of anthropoid primates is hindered by a lack of consensus on both the timing and biogeography of anthropoid origins. Some prefer an ancient (Cretaceous) origin for anthropoids in Africa or some other Gondwanan landmass, whereas others advocate a more recent (early Cenozoic) origin for anthropoids in Asia, with subsequent dispersal of one or more early anthropoid taxa to Africa. The oldest undoubted African anthropoid primates described so far are three species of the parapithecid Biretia from the late middle Eocene Bir El Ater locality of Algeria and the late Eocene BQ-2 site in the Fayum region of northern Egypt. Here we report the discovery of the oldest known diverse assemblage of African anthropoids from the late middle Eocene Dur At-Talah escarpment in central Libya. The primate assemblage from Dur At-Talah includes diminutive species pertaining to three higher-level anthropoid clades (Afrotarsiidae, Parapithecidae and Oligopithecidae) as well as a small species of the early strepsirhine primate Karanisia. The high taxonomic diversity of anthropoids at Dur At-Talah indicates either a much longer interval of anthropoid evolution in Africa than is currently documented in the fossil record or the nearly synchronous colonization of Africa by multiple anthropoid clades at some time during the middle Eocene epoch.     

Mutations in MRAP, encoding a new interacting partner of the ACTH receptor, cause familial glucocorticoid deficiency type 2

Familial glucocorticoid deficiency (FGD), or hereditary unresponsiveness to adrenocorticotropin (ACTH; OMIM 202200), is an autosomal recessive disorder resulting from resistance to the action of ACTH on the adrenal cortex, which stimulates glucocorticoid production. Affected individuals are deficient in cortisol and, if untreated, are likely to succumb to hypoglycemia or overwhelming infection in infancy or childhood. Mutations of the ACTH receptor (melanocortin 2 receptor, MC2R) account for approximately 25% of cases of FGD. FGD without mutations of MC2R is called FGD type 2. Using SNP array genotyping, we mapped a locus involved in FGD type 2 to chromosome 21q22.1. We identified mutations in a gene encoding a 19-kDa single-transmembrane domain protein, now known as melanocortin 2 receptor accessory protein (MRAP). We show that MRAP interacts with MC2R and may have a role in the trafficking of MC2R from the endoplasmic reticulum to the cell surface.     

Host-plant adaptation drives the parallel evolution of reproductive isolation

Parallel evolution of similar traits in independent populations that inhabit ecologically similar environments strongly implicates natural selection as the cause of evolution. Parallel speciation is a special form of parallel evolution where traits that determine reproductive isolation evolve repeatedly, in closely related populations, as by-products of adaptation to ecological conditions. The outcome of such parallel evolution is that ecologically divergent pairs of populations exhibit greater levels of reproductive isolation than ecologically similar pairs of populations of a similar or younger age. The parallel evolution of reproductive isolation provides strong evidence for natural selection in the process of speciation, but only one conclusive example from nature is known. Populations of the walking-stick insect Timema cristinae that use different host-plant species have diverged in body size and shape, host preference, behaviour and the relative frequency of two highly cryptic colour-pattern morphs. Here we report that divergent selection for host adaptation, and not genetic drift, has promoted the parallel evolution of sexual isolation in this species. Our findings represent a clear demonstration that host-plant adaptation can play a crucial and repeatable role in the early stages of speciation.     

Brain norepinephrine levels and turnover rates in castrated mice isolated for 13 months

Zusammenfassung Funktionsdynamik von Gehirn-Norepinephrin (NE) in kastrierten und scheinkastrierten männlichen, geschlechtsreifen (C57Br/6J)-Mäusen wurde nach 13 Monaten Isolierung untersucht. Kastrierung bewirkt starken Abfall des ursprünglichen Niveaus und der Stoffwechselgeschwinddigkeit von NE.

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Supported in part by a USPHS Predoctoral Fellowship toB. K. Bernard and NIMH Grant No. MH 15352 toR. M. Paolino.     

Malaria risk: estimating clinical episodes of malaria

Estimates of the disease burden caused by malaria are crucial for informing malaria control programmes. Snow and colleagues claim that their estimate of 515 million cases of malaria caused by Plasmodium falciparum globally is up to 50% higher than that reported by the World Health Organization (WHO), and 200% higher for areas outside Africa. However, this comparison refers to the WHO's estimates from 1990 and 1998, and not to the range of 300 million to 500 million that the WHO has used since 2000 (ref. 2). Both groups agree that the burden of malaria disease outside Africa, especially in South Asia, is greater than was estimated in the 1990s.     

Genome evolution in yeasts

Identifying the mechanisms of eukaryotic genome evolution by comparative genomics is often complicated by the multiplicity of events that have taken place throughout the history of individual lineages, leaving only distorted and superimposed traces in the genome of each living organism. The hemiascomycete yeasts, with their compact genomes, similar lifestyle and distinct sexual and physiological properties, provide a unique opportunity to explore such mechanisms. We present here the complete, assembled genome sequences of four yeast species, selected to represent a broad evolutionary range within a single eukaryotic phylum, that after analysis proved to be molecularly as diverse as the entire phylum of chordates. A total of approximately 24,200 novel genes were identified, the translation products of which were classified together with Saccharomyces cerevisiae proteins into about 4,700 families, forming the basis for interspecific comparisons. Analysis of chromosome maps and genome redundancies reveal that the different yeast lineages have evolved through a marked interplay between several distinct molecular mechanisms, including tandem gene repeat formation, segmental duplication, a massive genome duplication and extensive gene loss.     

Lifespan and mitochondrial control of neurodegeneration

We examine the allometric (comparative scaling) relationships between rates of neurodegeneration resulting from equivalent mutations in a diverse group of genes from five mammalian species with different maximum lifespan potentials. In both retina and brain, rates of neurodegeneration vary by as much as two orders of magnitude and are strongly correlated with maximum lifespan potential and rates of formation of mitochondrial reactive oxygen and nitrogen species (RONS). Cell death in these disorders is directly or indirectly regulated by the intrinsic mitochondrial cell death pathway. Mitochondria are the main source of RONS production and integrate cellular stress signals to coordinate the intrinsic pathway. We propose that these two functions are intimately related and that steady-state RONS-mediated signaling or damage to the mitochondrial stress-integration machinery is the principal factor setting the probability of cell death in response to a diverse range of cellular stressors. This provides a new and unifying framework for investigating neurodegenerative disorders.