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.     

Mutations in PCSK9 cause autosomal dominant hypercholesterolemia

Autosomal dominant hypercholesterolemia (ADH; OMIM144400), a risk factor for coronary heart disease, is characterized by an increase in low-density lipoprotein cholesterol levels that is associated with mutations in the genes LDLR (encoding low-density lipoprotein receptor) or APOB (encoding apolipoprotein B). We mapped a third locus associated with ADH, HCHOLA3 at 1p32, and now report two mutations in the gene PCSK9 (encoding proprotein convertase subtilisin/kexin type 9) that cause ADH. PCSK9 encodes NARC-1 (neural apoptosis regulated convertase), a newly identified human subtilase that is highly expressed in the liver and contributes to cholesterol homeostasis.     

Radiation embryology

Prenatal development, characterized by intensive cell proliferation, cell differentiation and cell migration, shows a high radiosensitivity. Therefore, radiation exposure of embryos and fetuses is of great concern for radiological protection and human health. Irradiation during gestation can cause death, growth disorders, malformations, functional impairment and malignant diseases in childhood. These effects are strongly dependent on the developmental stage at exposure and on the radiation dose. The first trimester of pregnancy is regarded as the period with the highest risk for malformation and cancer induction. The developing nervous system shows a special susceptibility to ionizing radiation over a long period and is therefore of great significance for risk estimation. Knowledge about radiation effects on prenatal development has been derived from animal experimentation and from the exposure of human embryos. There is evidence that doses between 1 and 10 cGy may lead to developmental anomalies and that the radiation response can be modified by additional factors.     

Cyclic nucleotides vs. adenosine analogs as inhibitors of adenylate cyclase activity: Nonidentity of sites of action

Zusammenfassung Substitution einerN ⁶-Aminogruppe eines zyklischen Nukleotids führt zu einer erh?hten Hemmwirkung des Nukleotids gegenüber Adenyl-Cyclase von Meerschweinchenlungen, w?hrend dieN ⁶-Amino-Substition von Adenosin-Analogen eine herabgesetzte Inhibitionswirksamkeit gegenüber demselben Enzym zur Folge hat. Die experimentellen Daten führen zu dem Schluss, dass der Inhibitionsmechanismus gegenüber Cyclase für beide Verbindungstypen verschieden ist.      

华南武夷山早古生代构造事件的^40Ar／^39Ar同位素年龄研究

华南武夷山地区广泛发育一套强烈韧性剪切变形的中、高级变质岩系,其新生矿物白云母非常普遍.对武夷山南麓政和县蝴碟街大理岩和北麓弋阳县慈竹片麻状花岗岩中的动力变质矿物白云母进行40Ar/39Ar法同位素测年,分别获得391±3Ma和421±8Ma的坪年龄值,以及385±5Ma和422±6Ma的等时线年龄值,时代相当于志留纪末到泥盆纪初.结合地质证据,认为武夷山地区存在过一期早古生代沉积作用和早古生代末期的构造热事件.至少有一期的强烈韧性剪切变形和糜棱岩化作用是该构造事件所导致     

Basigin is a receptor essential for erythrocyte invasion by Plasmodium falciparum

Erythrocyte invasion by Plasmodium falciparum is central to the pathogenesis of malaria. Invasion requires a series of extracellular recognition events between erythrocyte receptors and ligands on the merozoite, the invasive form of the parasite. None of the few known receptor-ligand interactions involved are required in all parasite strains, indicating that the parasite is able to access multiple redundant invasion pathways. Here, we show that we have identified a receptor-ligand pair that is essential for erythrocyte invasion in all tested P. falciparum strains. By systematically screening a library of erythrocyte proteins, we have found that the Ok blood group antigen, basigin, is a receptor for PfRh5, a parasite ligand that is essential for blood stage growth. Erythrocyte invasion was potently inhibited by soluble basigin or by basigin knockdown, and invasion could be completely blocked using low concentrations of anti-basigin antibodies; importantly, these effects were observed across all laboratory-adapted and field strains tested. Furthermore, Ok(a-) erythrocytes, which express a basigin variant that has a weaker binding affinity for PfRh5, had reduced invasion efficiencies. Our discovery of a cross-strain dependency on a single extracellular receptor-ligand pair for erythrocyte invasion by P. falciparum provides a focus for new anti-malarial therapies.     

53BP1 facilitates long-range DNA end-joining during V(D)J recombination

Variable, diversity and joining (V(D)J) recombination and class-switch recombination use overlapping but distinct non-homologous end joining pathways to repair DNA double-strand-break intermediates. 53BP1 is a DNA-damage-response protein that is rapidly recruited to sites of chromosomal double-strand breaks, where it seems to function in a subset of ataxia telangiectasia mutated (ATM) kinase-, H2A histone family member X (H2AX, also known as H2AFX)- and mediator of DNA damage checkpoint 1 (MDC1)-dependent events. A 53BP1-dependent end-joining pathway has been described that is dispensable for V(D)J recombination but essential for class-switch recombination. Here we report a previously unrecognized defect in the joining phase of V(D)J recombination in 53BP1-deficient lymphocytes that is distinct from that found in classical non-homologous-end-joining-, H2ax-, Mdc1- and Atm-deficient mice. Absence of 53BP1 leads to impairment of distal V-DJ joining with extensive degradation of unrepaired coding ends and episomal signal joint reintegration at V(D)J junctions. This results in apoptosis, loss of T-cell receptor alpha locus integrity and lymphopenia. Further impairment of the apoptotic checkpoint causes propagation of lymphocytes that have antigen receptor breaks. These data suggest a more general role for 53BP1 in maintaining genomic stability during long-range joining of DNA breaks.