Genes have a major role in the control of high-density lipoprotein (HDL) cholesterol (HDL-C) levels. Here we have identified two Tangier disease (TD) families, confirmed 9q31 linkage and refined the disease locus to a limited genomic region containing the gene encoding the ATP-binding cassette transporter (ABC1). Familial HDL deficiency (FHA) is a more frequent cause of low HDL levels. On the basis of independent linkage and meiotic recombinants, we localized the FHA locus to the same genomic region as the TD locus. Mutations in ABC1 were detected in both TD and FHA, indicating that TD and FHA are allelic. This indicates that the protein encoded by ABC1 is a key gatekeeper influencing intracellular cholesterol transport, hence we have named it cholesterol efflux regulatory protein (CERP).

The genome of the crenarchaeon Sulfolobus solfataricus P2 contains 2,992,245 bp on a single chromosome and encodes 2,977 proteins and many RNAs. One-third of the encoded proteins have no detectable homologs in other sequenced genomes. Moreover, 40% appear to be archaeal-specific, and only 12% and 2.3% are shared exclusively with bacteria and eukarya, respectively. The genome shows a high level of plasticity with 200 diverse insertion sequence elements, many putative nonautonomous mobile elements, and evidence of integrase-mediated insertion events. There are also long clusters of regularly spaced tandem repeats. Different transfer systems are used for the uptake of inorganic and organic solutes, and a wealth of intracellular and extracellular proteases, sugar, and sulfur metabolizing enzymes are encoded, as well as enzymes of the central metabolic pathways and motility proteins. The major metabolic electron carrier is not NADH as in bacteria and eukarya but probably ferredoxin. The essential components required for DNA replication, DNA repair and recombination, the cell cycle, transcriptional initiation and translation, but not DNA folding, show a strong eukaryal character with many archaeal-specific features. The results illustrate major differences between crenarchaea and euryarchaea, especially for their DNA replication mechanism and cell cycle processes and their translational apparatus.

The ability of the pathogenic fungus Candida albicans to switch from a yeast to a hyphal morphology in response to external signals is implicated in its pathogenicity. We used glass DNA microarrays to investigate the transcription profiles of 6333 predicted ORFs in cells undergoing this transition and their responses to changes in temperature and culture medium. We have identified several genes whose transcriptional profiles are similar to those of known virulence factors that are modulated by the switch to hyphal growth caused by addition of serum and a 37 degrees C growth temperature. Time course analysis of this transition identified transcripts that are induced before germ tube initiation and shut off later in the developmental process. A strain deleted for the Efg1p and Cph1p transcription factors is defective in hyphae formation, and its response to serum and increased temperature is almost identical to the response of a wild-type strain grown at 37 degrees C in the absence of serum. Thus Efg1p and Cph1p are needed for the activation of the transcriptional program that is induced by the presence of serum.

Symbioses represent a frequent and successful lifestyle on earth and lichens are one of their classic examples. Recently, bacterial communities were identified as stable, specific and structurally integrated partners of the lichen symbiosis, but their role has remained largely elusive in comparison to the well-known functions of the fungal and algal partners. We have explored the metabolic potentials of the microbiome using the lung lichen Lobaria pulmonaria as the model. Metagenomic and proteomic data were comparatively assessed and visualized by Voronoi treemaps. The study was complemented with molecular, microscopic and physiological assays. We have found that more than 800 bacterial species have the ability to contribute multiple aspects to the symbiotic system, including essential functions such as (i) nutrient supply, especially nitrogen, phosphorous and sulfur, (ii) resistance against biotic stress factors (that is, pathogen defense), (iii) resistance against abiotic factors, (iv) support of photosynthesis by provision of vitamin B 12 , (v) fungal and algal growth support by provision of hormones, (vi) detoxification of metabolites, and (vii) degradation of older parts of the lichen thallus. Our findings showed the potential of lichenassociated bacteria to interact with the fungal as well as algal partner to support health, growth and fitness of their hosts. We developed a model of the symbiosis depicting the functional multi-player network of the participants, and argue that the strategy of functional diversification in lichens supports the longevity and persistence of lichens under extreme and changing ecological conditions.

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The phylogenetic relationships of amoebae are poorly resolved. To address this difficult question, we have sequenced 1,280 expressed sequence tags from Mastigamoeba balamuthi and assembled a large data set containing 123 genes for representatives of three phenotypically highly divergent major amoeboid lineages: Pelobionta, Entamoebidae, and Mycetozoa. Phylogenetic reconstruction was performed on Ϸ25,000 aa positions for 30 species by using maximum-likelihood approaches. All well-established eukaryotic groups were recovered with high statistical support, validating our approach. Interestingly, the three amoeboid lineages strongly clustered together in agreement with the Conosa hypothesis [as defined by T. Cavalier-Smith (1998) Biol. Rev. Cambridge Philos. Soc. 73, 203-266]. Two amitochondriate amoebae, the free-living Mastigamoeba and the human parasite Entamoeba, formed a significant sister group to the exclusion of the mycetozoan Dictyostelium. This result suggested that a part of the reductive process in the evolution of Entamoeba (e.g., loss of typical mitochondria) occurred in its free-living ancestors. Applying this inexpensive expressed sequence tag approach to many other lineages will surely improve our understanding of eukaryotic evolution.

Since the discovery of ING1 class II tumor suppressors in 1996, five different ING genes (ING1 to ING5) encoding proteins with highly conserved plant homeodomain (PHD) motifs and several splicing isoforms of the ING1 and ING2 gene have been identified. The ING family functions in DNA repair and apoptosis in response to UV damage through binding to proliferating cell nuclear antigen (PCNA); chromatin remodeling and regulation of gene expression through regulating and/or targeting histone acetyltransferase/deacetylase (HAT/HDAC) activities; binding targets of rare phosphatidylinositol phosphates (PtdInsPs) that function in DNA damage-initiated stress signaling; and regulating brain tumor angiogenesis through transcriptional repression of NF-KB-responsive genes. To elucidate the evolutionary history of ING proteins and summarize what is known about regions highly conserved in the ING family members, we have examined the sequences and phylogenetic relationships of ING proteins across taxonomically diverse organisms. We have identified novel ING family members in rats, frogs, fish, mosquitoes, fruit flies, worms, fungi, and plants. We have also clarified the naming and classification of ING proteins based on our phylogenetic analysis to allow better understanding of the ING protein family. Using sequence similarities, we have identified novel regions and motifs of unknown function that are conserved across family members. An evolutionary history for the ING family of PHD finger proteins is presented that indicates that five ING genes are present in vertebrates. Three of these may be paralogs of ING genes found in arthropods, whereas nematodes, fungi, and green plants contain ING genes that have general features of the vertebrate ING family.

The BRENDA enzyme information system (http://www.brenda-enzymes.org/) has developed into an elaborate system of enzyme and enzyme-ligand information obtained from different sources, combined with flexible query systems and evaluation tools. The information is obtained by manual extraction from primary literature, text and data mining, data integration, and prediction algorithms. Approximately 300 million data include enzyme function and molecular data from more than 30 000 organisms. The manually derived core contains 3 million data from 77 000 enzymes annotated from 135 000 literature references. Each entry is connected to the literature reference and the source organism. They are complemented by information on occurrence, enzyme/disease relationships from text mining, sequences and 3D structures from other databases, and predicted enzyme location and genome annotation. Functional and structural data of more than 190 000 enzyme ligands are stored in BRENDA. New features improving the functionality and analysis tools were implemented. The human anatomy atlas CAVEman is linked to the BRENDA Tissue Ontology terms providing a connection between anatomical and functional enzyme data. Word Maps for enzymes obtained from PubMed abstracts highlight application and scientific relevance of enzymes. The EnzymeDetector genome annotation tool and the reaction database BKM-react including reactions from BRENDA, KEGG and MetaCyc were improved. The website was redesigned providing new query options.