DNA sequence and analysis of human chromosome 18

Chromosome 18 appears to have the lowest gene density of any human chromosome and is one of only three chromosomes for which trisomic individuals survive to term. There are also a number of genetic disorders stemming from chromosome 18 trisomy and aneuploidy. Here we report the finished sequence and gene annotation of human chromosome 18, which will allow a better understanding of the normal and disease biology of this chromosome. Despite the low density of protein-coding genes on chromosome 18, we find that the proportion of non-protein-coding sequences evolutionarily conserved among mammals is close to the genome-wide average. Extending this analysis to the entire human genome, we find that the density of conserved non-protein-coding sequences is largely uncorrelated with gene density. This has important implications for the nature and roles of non-protein-coding sequence elements.     

Investigations on the toxic action ofAmanita phalloides Fr. on the hepatic cell

Riassunto Nel ratto intossicato con estratto diAmanita phalloide le prime alterazioni strutturali dell'epatocita si realizzano a livello del nucleo e del nucleolo con formazioni di «nucleolar caps». Da queste stesse strutture iniziano i fenomeni di regressione delle alterazioni. Le manifestazioni sia del danno che della sua regressione a livello citoplasmatico risultano essere successive a quelle nucleari. Il comportamento del DNA e di alcuni enzimi del tessuto epatico è risultato nel complesso coerente con le alterazioni morfologiche. In rapporto con la dose usata queste alterazioni risultano reversibili poichè nelle cellule colpite entro 12 h cominciano i fenomeni di ristrutturazione.     

A correlation between mid-ocean-ridge basalt chemistry and distance to continents

To fully understand the structure and dynamics of the Earth's convecting mantle, the origins of temperature variations within the mantle need to be resolved. Different hypotheses have been proposed to account for these temperature variations: for example, heat coming from the decay of radioactive elements or heat flowing out of the Earth's core. In addition, theoretical studies suggest that the thermal properties of continental masses can affect mantle convection, but quantitative data that could allow us to test these models are scarce. To address this latter problem, we have examined the chemistry of mid-ocean-ridge basalt--which reflects the temperature of the source mantle--as a function of the distance of the ridge from the closest continental margin. No correlation is observed for oceanic ridges close to subduction zones or hotspots; subduction zones probably inhibit thermal transfer between the mantle beneath continents and ocean, whereas hotspots influence the major-element chemistry of ridge basalts, which makes their interpretation with respect to mantle temperature more difficult. However, we do observe a significant correlation for mid-oceanic basalts from the Atlantic and Indian oceans. From this, we conclude that the location of continental masses relative to active ridges influences the large-scale thermal structure of the mantle and we estimate that the mantle cools by 0.05 to 0.1 degrees C per kilometre from the continental margins.     

The K-Cl cotransporter KCC3 is mutant in a severe peripheral neuropathy associated with agenesis of the corpus callosum

Peripheral neuropathy associated with agenesis of the corpus callosum (ACCPN) is a severe sensorimotor neuropathy associated with mental retardation, dysmorphic features and complete or partial agenesis of the corpus callosum. ACCPN is transmitted in an autosomal recessive fashion and is found at a high frequency in the province of Quebec, Canada. ACCPN has been previously mapped to chromosome 15q. The gene SLC12A6 (solute carrier family 12, member 6), which encodes the K+-Cl- transporter KCC3 and maps within the ACCPN candidate region, was screened for mutations in individuals with ACCPN. Four distinct protein-truncating mutations were found: two in the French Canadian population and two in non-French Canadian families. The functional consequence of the predominant French Canadian mutation (2436delG, Thr813fsX813) was examined by heterologous expression of wildtype and mutant KCC3 in Xenopus laevis oocytes; the truncated mutant is appropriately glycosylated and expressed at the cellular membrane, where it is non-functional. Mice generated with a targeted deletion of Slc12a6 have a locomotor deficit, peripheral neuropathy and a sensorimotor gating deficit, similar to the human disease. Our findings identify mutations in SLC12A6 as the genetic lesion underlying ACCPN and suggest a critical role for SLC12A6 in the development and maintenance of the nervous system.     

HRPT2, encoding parafibromin,is mutated in hyperparathyroidism-jaw tumor syndrome

We report here the identification of a gene associated with the hyperparathyroidism-jaw tumor (HPT-JT) syndrome. A single locus associated with HPT-JT (HRPT2) was previously mapped to chromosomal region 1q25-q32. We refined this region to a critical interval of 12 cM by genotyping in 26 affected kindreds. Using a positional candidate approach, we identified thirteen different heterozygous, germline, inactivating mutations in a single gene in fourteen families with HPT-JT. The proposed role of HRPT2 as a tumor suppressor was supported by mutation screening in 48 parathyroid adenomas with cystic features, which identified three somatic inactivating mutations, all located in exon 1. None of these mutations were detected in normal controls, and all were predicted to cause deficient or impaired protein function. HRPT2 is a ubiquitously expressed, evolutionarily conserved gene encoding a predicted protein of 531 amino acids, for which we propose the name parafibromin. Our findings suggest that HRPT2 is a tumor-suppressor gene, the inactivation of which is directly involved in predisposition to HPT-JT and in development of some sporadic parathyroid tumors.     

A myogenic differentiation checkpoint activated by genotoxic stress

Cell-cycle checkpoints help to protect the genomes of proliferating cells under genotoxic stress. In multicellular organisms, cell proliferation is often directed toward differentiation during development and throughout adult homeostasis. To prevent the formation of differentiated cells with genetic instability, we hypothesized that genotoxic stress may trigger a differentiation checkpoint. Here we show that exposure to genotoxic agents causes a reversible inhibition of myogenic differentiation. Muscle-specific gene expression is suppressed by DNA-damaging agents if applied prior to differentiation induction but not after the differentiation program is established. The myogenic determination factor, MyoD (encoded by Myod1), is a target of the differentiation checkpoint in myoblasts. The inhibition of MyoD by DNA damage requires a functional c-Abl tyrosine kinase (encoded by Abl1), but occurs in cells deficient for p53 (transformation-related protein 53, encoded by Trp53) or c-Jun (encoded by the oncogene Jun). These results support the idea that genotoxic stress can regulate differentiation, and identify a new biological function for DNA damage-activated signaling network.     

Rapid effects of insulin on cyclic GMP location in an intact protozoan

We studied rapid changes in location of cyclic GMP inTetrahymena pyriformis. Insulin caused cGMP localization in cilia and near the plasma membrane (0.5–1 min). Later (1–5 min) cGMP localization was diffuse in cytoplasm with perinuclear accentuation. Inactive insulin analogs did not elicit these changes.     

A new class of homoserine lactone quorum-sensing signals

Quorum sensing is a term used to describe cell-to-cell communication that allows cell-density-dependent gene expression. Many bacteria use acyl-homoserine lactone (acyl-HSL) synthases to generate fatty acyl-HSL quorum-sensing signals, which function with signal receptors to control expression of specific genes. The fatty acyl group is derived from fatty acid biosynthesis and provides signal specificity, but the variety of signals is limited. Here we show that the photosynthetic bacterium Rhodopseudomonas palustris uses an acyl-HSL synthase to produce p-coumaroyl-HSL by using environmental p-coumaric acid rather than fatty acids from cellular pools. The bacterium has a signal receptor with homology to fatty acyl-HSL receptors that responds to p-coumaroyl-HSL to regulate global gene expression. We also found that p-coumaroyl-HSL is made by other bacteria including Bradyrhizobium sp. and Silicibacter pomeroyi. This discovery extends the range of possibilities for acyl-HSL quorum sensing and raises fundamental questions about quorum sensing within the context of environmental signalling.