The genome of the model beetle and pest Tribolium castaneum

Tribolium castaneum is a member of the most species-rich eukaryotic order, a powerful model organism for the study of generalized insect development, and an important pest of stored agricultural products. We describe its genome sequence here. This omnivorous beetle has evolved the ability to interact with a diverse chemical environment, as shown by large expansions in odorant and gustatory receptors, as well as P450 and other detoxification enzymes. Development in Tribolium is more representative of other insects than is Drosophila, a fact reflected in gene content and function. For example, Tribolium has retained more ancestral genes involved in cell-cell communication than Drosophila, some being expressed in the growth zone crucial for axial elongation in short-germ development. Systemic RNA interference in T. castaneum functions differently from that in Caenorhabditis elegans, but nevertheless offers similar power for the elucidation of gene function and identification of targets for selective insect control.     

Neanderthals in central Asia and Siberia

Morphological traits typical of Neanderthals began to appear in European hominids at least 400,000 years ago and about 150,000 years ago in western Asia. After their initial appearance, such traits increased in frequency and the extent to which they are expressed until they disappeared shortly after 30,000 years ago. However, because most fossil hominid remains are fragmentary, it can be difficult or impossible to determine unambiguously whether a fossil is of Neanderthal origin. This limits the ability to determine when and where Neanderthals lived. To determine how far to the east Neanderthals ranged, we determined mitochondrial DNA (mtDNA) sequences from hominid remains found in Uzbekistan and in the Altai region of southern Siberia. Here we show that the DNA sequences from these fossils fall within the European Neanderthal mtDNA variation. Thus, the geographic range of Neanderthals is likely to have extended at least 2,000 km further to the east than commonly assumed.     

Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease

We sought to identify new susceptibility loci for Alzheimer's disease through a staged association study (GERAD+) and by testing suggestive loci reported by the Alzheimer's Disease Genetic Consortium (ADGC) in a companion paper. We undertook a combined analysis of four genome-wide association datasets (stage 1) and identified ten newly associated variants with P ≤ 1 × 10(-5). We tested these variants for association in an independent sample (stage 2). Three SNPs at two loci replicated and showed evidence for association in a further sample (stage 3). Meta-analyses of all data provided compelling evidence that ABCA7 (rs3764650, meta P = 4.5 × 10(-17); including ADGC data, meta P = 5.0 × 10(-21)) and the MS4A gene cluster (rs610932, meta P = 1.8 × 10(-14); including ADGC data, meta P = 1.2 × 10(-16)) are new Alzheimer's disease susceptibility loci. We also found independent evidence for association for three loci reported by the ADGC, which, when combined, showed genome-wide significance: CD2AP (GERAD+, P = 8.0 × 10(-4); including ADGC data, meta P = 8.6 × 10(-9)), CD33 (GERAD+, P = 2.2 × 10(-4); including ADGC data, meta P = 1.6 × 10(-9)) and EPHA1 (GERAD+, P = 3.4 × 10(-4); including ADGC data, meta P = 6.0 × 10(-10)).     

Positional cloning of Sorcs1, a type 2 diabetes quantitative trait locus

We previously mapped the type 2 diabetes mellitus-2 locus (T2dm2), which affects fasting insulin levels, to distal chromosome 19 in a leptin-deficient obese F2 intercross derived from C57BL/6 (B6) and BTBR T+ tf/J (BTBR) mice. Introgression of a 7-Mb segment of the B6 chromosome 19 into the BTBR background (strain 1339A) replicated the reduced insulin linked to T2dm2. The 1339A mice have markedly impaired insulin secretion in vivo and disrupted islet morphology. We used subcongenic strains derived from 1339A to localize the T2dm2 quantitative trait locus (QTL) to a 242-kb segment comprising the promoter, first exon and most of the first intron of the Sorcs1 gene. This was the only gene in the 1339A strain for which we detected amino acid substitutions and expression level differences between mice carrying B6 and BTBR alleles of this insert, thereby identifying variation within the Sorcs1 gene as underlying the phenotype associated with the T2dm2 locus. SorCS1 binds platelet-derived growth factor, a growth factor crucial for pericyte recruitment to the microvasculature, and may thus have a role in expanding or maintaining the islet vasculature. Our identification of the Sorcs1 gene provides insight into the pathway underlying the pathophysiology of obesity-induced type 2 diabetes mellitus.     

C-terminal truncations in human 3'-5' DNA exonuclease TREX1 cause autosomal dominant retinal vasculopathy with cerebral leukodystrophy

Autosomal dominant retinal vasculopathy with cerebral leukodystrophy is a microvascular endotheliopathy with middle-age onset. In nine families, we identified heterozygous C-terminal frameshift mutations in TREX1, which encodes a 3'-5' exonuclease. These truncated proteins retain exonuclease activity but lose normal perinuclear localization. These data have implications for the maintenance of vascular integrity in the degenerative cerebral microangiopathies leading to stroke and dementias.     

Seed dispersal, seed entrapment, and seedling recruitment in a temporally variable desert playa

Natural establishment of seedlings in desert playas with temporally variable precipitation hinges on many factors, including seed production, seed dispersal, seed entrapment, seed germination, and seedling survival. We investigated natural seed dispersal patterns and the effects of surface texture, wind barriers, resource availability (water and nutrients), and protection from herbivory on seedling establishment in a desert playa. We hypothesized that the seed rain would be consistent throughout the year and that seedling establishment would improve in resource-amended plots with barriers to wind dispersal. Contrary to our hypotheses, seed flux peaked seasonally during the winter, and fertilization had no consistent effect on seedling establishment. Seed availability for dispersal correlated with precipitation in the previous water year, whereas seedling recruitment was greatest when current-year precipitation during the spring germination and summer seedling growth periods was high. Gravel and barrier surface treatments contained more surviving seedlings than other surface treatments. Comparison with plots located outside of herbivore exclosures, however, showed that greater seedling presence in gravel plots may be due somewhat to protection from herbivory provided by the gravel, rather than simply to the greater seed-trapping quality of the gravel. With abundant seed availability, application of surface treatments, like coarse gravel, combined with increased seasonal water availability could lead to improved shrub establishment from seed in desert playas.     

High nitrogen availability does not improve salinity tolerance in Sarcobatus vermiculatus

Natural and anthropogenic changes in basin lake levels in the western U.S. expose saline, alkaline substrates that are commonly colonized by shrubs in the Chenopodiaceae. On a chronosequence of recently exposed substrates at Mono Lake, California, Sarcobatus vermiculatus has greatest biomass accrual, seed production, seedling establishment, and leaf N at younger sites where soils are extremely saline and alkaline. These field observations and an understanding of the role of N-containing compatible solutes in salinity tolerance of halophytes led to our prediction that Na and N interactions stimulate Sarcobatus performance. To test this, we grew Sarcobatus juveniles for 2 years in the greenhouse at 4 levels of NaCl (5, 100, 300, and 450 mM) and 3 levels of N (0.04, 0.4, and 8 mM) in a randomized, complete-block design. Contrary to our expectations, high N availability did not induce salt-stimulated growth nor did it increase salinity tolerance in Sarcobatus . Increased N nutrition also had no significant effect on leaf cation ratios or selectivity. Plants grown at high salinity had significantly lower leaf K:Na, Ca:Na, and Mg:Na ratios than plants grown at lower salinity. However, plant selectivity for the macronutrient cations remained high, even at 450 mM NaCl. Without such high selectivity, the cation nutrition of Sarcobatus would decline to even lower levels, resulting in severe nutrient deficiencies. This study suggests that the ability of Sarcobatus to attain high leaf N, rather than an interaction between Na and N, enhances its performance at saline sites. In addition, the ability of Sarcobatus to maintain high macronutrient cation selectivity despite high salinity allows its distribution to extend to extremely saline and alkaline substrates in this arid system.     

Genome-wide mapping with biallelic markers in Arabidopsis thaliana.

Single-nucleotide polymorphisms, as well as small insertions and deletions (here referred to collectively as simple nucleotide polymorphisms, or SNPs), comprise the largest set of sequence variants in most organisms. Positional cloning based on SNPs may accelerate the identification of human disease traits and a range of biologically informative mutations. The recent application of high-density oligonucleotide arrays to allele identification has made it feasible to genotype thousands of biallelic SNPs in a single experiment. It has yet to be established, however, whether SNP detection using oligonucleotide arrays can be used to accelerate the mapping of traits in diploid genomes. The cruciferous weed Arabidopsis thaliana is an attractive model system for the construction and use of biallelic SNP maps. Although important biological processes ranging from fertilization and cell fate determination to disease resistance have been modelled in A. thaliana, identifying mutations in this organism has been impeded by the lack of a high-density genetic map consisting of easily genotyped DNA markers. We report here the construction of a biallelic genetic map in A. thaliana with a resolution of 3.5 cM and its use in mapping Eds16, a gene involved in the defence response to the fungal pathogen Erysiphe orontii. Mapping of this trait involved the high-throughput generation of meiotic maps of F2 individuals using high-density oligonucleotide probe array-based genotyping. We developed a software package called InterMap and used it to automatically delimit Eds16 to a 7-cM interval on chromosome 1. These results are the first demonstration of biallelic mapping in diploid genomes and establish means for generalizing SNP-based maps to virtually any genetic organism.     

Platelets as a model for neurones?

The multiple biochemical and pharmacological similarities existing between blood platelets and 5-hydroxytryptamine (5-HT)-containing neurones of the CNS point to the platelets as a reliable model for the biochemical characterization of 5-HT releasers and uptake blockers which interfere with the storage and the active carrier mechanism of 5-HT in the neurones, respectively. In addition, the affinity displayed by dopamine and by dopaminergic neurotoxin MPP+ for the platelet 5-HT transport and storage indicates also some similarities between platelets and the dopaminergic system of the CNS. Since human platelets contain almost exclusively monoamine oxidase type B (MAO-B), they can be used as a source for the purification and characterization of this human enzyme. Human platelets thus offer an excellent peripheral model to indirectly assess the degree and duration of MAO-B inhibition occurring in the CNS. To date, knowledge of the many biochemical mechanisms underlying platelet physiology is still fragmentary. In fact, the functional role of binding sites located on the platelet cytoplasmic membrane, i.e. their coupling to a specific transmembrane signalling mechanism, is still in need of a precise biochemical and physiological characterization.     

Benzodiazepine receptors resolved

Summary To date, attempts to map the distribution and density of benzodiazepine receptors in the CNS have been dominated by radiohistochemical techniques with conventional receptor binding. Their limited resolution, however, prompted us to try an immunohistochemical approach. Purified GABA/benzodiazepine receptors, prepared from bovine cerebral cortex, have been used to raise monoclonal antibodies for this purpose. Immunoreactive sites in rat brain, spinal cord and retina as well as in bovine and post-mortem human brain were found to be concentrated on neuronal cell bodies and processes in those regions known to be innervated by GABAergic neurons. Electron microscopic analysis revealed a selective staining of axosomatic and axodendritic pre- and postsynaptic contacts.