The genetic architecture of Drosophila sensory bristle number

We have mapped quantitative trait loci (QTL) for Drosophila mechanosensory bristle number in six recombinant isogenic line (RIL) mapping populations, each of which was derived from an isogenic chromosome extracted from a line selected for high or low, sternopleural or abdominal bristle number and an isogenic wild-type chromosome. All RILs were evaluated as male and female F(1) progeny of crosses to both the selected and the wild-type parental chromosomes at three developmental temperatures (18 degrees, 25 degrees, and 28 degrees ). QTL for bristle number were mapped separately for each chromosome, trait, and environment by linkage to roo transposable element marker loci, using composite interval mapping. A total of 53 QTL were detected, of which 33 affected sternopleural bristle number, 31 affected abdominal bristle number, and 11 affected both traits. The effects of most QTL were conditional on sex (27%), temperature (14%), or both sex and temperature (30%). Epistatic interactions between QTL were also common. While many QTL mapped to the same location as candidate bristle development loci, several QTL regions did not encompass obvious candidate genes. These features are germane to evolutionary models for the maintenance of genetic variation for quantitative traits, but complicate efforts to understand the molecular genetic basis of variation for complex traits.     

Dissociable and nondissociable forms of platelet-activating factor acetylhydrolase in human plasma LDL: implications for LDL oxidative susceptibility

Platelet-activating factor acetylhydrolase (PAF-AH) is transported by lipoproteins in plasma and is thought to possess both anti-inflammatory and anti-oxidative activity. It has been reported that PAF-AH is recovered primarily in small, dense LDL and HDL following ultracentrifugal separation of lipoproteins. In the present studies, we aimed to further define the distribution of PAF-AH among lipoprotein fractions and subfractions, and to determine whether these distributions are affected by the lipoprotein isolation strategy (FPLC versus sequential ultracentrifugation) and LDL particle distribution profile. When lipoproteins were isolated by FPLC, the bulk (～85%) of plasma PAF-AH activity was recovered within LDL-containing fractions, whereas with ultracentrifugation, there was a redistribution to HDL (which contained ～18% of the activity) and the d>1.21 g/ml fraction (which contained ～32%). Notably, re-ultracentrifugation of isolated LDL did not result in any further movement of PAF-AH to higher densities, suggesting the presence of dissociable and nondissociable forms of the enzyme on LDL. Differences were noted in the distribution of PAF-AH activity among LDL subfractions from subjects exhibiting the pattern A (primarily large, buoyant LDL) versus pattern B (primarily small, dense LDL) phenotype. In the latter group, there was a relative depletion of PAF-AH activity in subfractions in the intermediate to dense range (d=1.039–1.047 g/ml) with a corresponding increase in enzyme activity recovered within the d>1.21 g/ml ultracentrifugal fraction. Thus, there appears to be a greater proportion of the dissociable form of PAF-AH in pattern B subjects. In both populations, most of the nondissociable activity was recovered in a minor small, dense LDL subfraction. Based on conjugated dienes as a measure of lipid peroxidation, variations in PAF-AH activity appeared to contribute to variations in oxidative behavior among ultracentrifugally isolated LDL subfractions. The physiologic relevance of PAF-AH dissociability and the minor PAF-AH-enriched oxidation-resistant LDL subpopulation remains to be determined.     

1H, 13C, and 15N backbone resonance assignments of the L124D mutant of StAR-related lipid transfer domain protein 4 (StARD4)

Protein-mediated cholesterol trafficking is central to maintaining cholesterol homeostasis in cells. START (Steroidogenic acute regulatory protein-related lipid transfer) domains constitute a sterol and lipid binding motif and the START domain protein StARD4 typifies a small family of mammalian sterol transport proteins. StARD4 consists of a single START domain and has been reported to act as a general cholesterol transporter in cells. However, the structural basis of cholesterol uptake and transport is not well understood and no cholesterol-bound START domain structures have been reported. We have undertaken the study of cholesterol binding and transport by StARD4 using solution state NMR spectroscopy. To this end, we report nearly complete ¹H, ¹⁵N, and ¹³C backbone resonance assignments of an inactive but well behaved mutant (L124D) of StARD4.     

The Plant-Associated Microbe Gene Ontology (PAMGO) Consortium: community development of new Gene Ontology terms describing biological processes involved in microbe-host interactions

All microbes that form beneficial, neutral, or pathogenic associations with hosts face similar challenges. They must physically adhere to and/or gain entry to host tissues; they must avoid, suppress, or tolerate host defenses; they must acquire nutrients from the host and successfully multiply. Microbes that associate with hosts come from many kingdoms of life and include bacteria, fungi, oomycetes, and nematodes. The increasing numbers of full genome sequences from these diverse microbes provide the opportunity to discover common mechanisms by which the microbes forge and maintain intimate associations with host organisms. However, cross-genome analyses have been hindered by lack of a universal vocabulary for describing biological processes involved in the interplay between microbes and their hosts. The Plant-Associated Microbe Gene Ontology (PAMGO) Consortium has been working for three years as an official interest group of the Gene Ontology (GO) Consortium to develop well-defined GO terms that describe many of the biological processes common to diverse plant- and animal-associated microbes. Creating these terms, over 700 at this time, has required a synthesis of diverse points of view from many research communities. The use of these terms in genome annotation will allow cross-genome searches for genes with common function (without demand for sequence similarity) and also improve the interpretation of data from high-throughput microarray and proteomic analyses. This article, and the more focused mini-reviews that make up this supplement to BMC Microbiology, describe the development and use of these terms.     

Common processes in pathogenesis by fungal and oomycete plant pathogens,described with Gene Ontology terms

Plant diseases caused by fungi and oomycetes result in significant economic losses every year. Although phylogenetically distant, the infection processes by these organisms share many common features. These include dispersal of an infectious particle, host adhesion, recognition, penetration, invasive growth, and lesion development. Previously, many of these common processes did not have corresponding Gene Ontology (GO) terms. For example, no GO terms existed to describe processes related to the appressorium, an important structure for infection by many fungi and oomycetes. In this mini-review, we identify common features of the pathogenic processes of fungi and oomycetes and create a pathogenesis model using 256 newly developed and 38 extant GO terms, with an emphasis on the appressorium and signal transduction. This set of standardized GO terms provides a solid base to further compare and contrast the molecular underpinnings of fungal and oomycete pathogenesis.     

Loss of patched and disruption of granule cell development in a pre-neoplastic stage of medulloblastoma

Medulloblastoma is the most common malignant brain tumor in children. It is thought to result from the transformation of granule cell precursors (GCPs) in the developing cerebellum, but little is known about the early stages of the disease. Here, we identify a pre-neoplastic stage of medulloblastoma in patched heterozygous mice, a model of the human disease. We show that pre-neoplastic cells are present in the majority of patched mutants, although only 16% of these mice develop tumors. Pre-neoplastic cells, like tumor cells, exhibit activation of the Sonic hedgehog pathway and constitutive proliferation. Importantly, they also lack expression of the wild-type patched allele, suggesting that loss of patched is an early event in tumorigenesis. Although pre-neoplastic cells resemble GCPs and tumor cells in many respects, they have a distinct molecular signature. Genes that mark the pre-neoplastic stage include regulators of migration, apoptosis and differentiation, processes crucial for normal development but previously unrecognized for their role in medulloblastoma. The identification and molecular characterization of pre-neoplastic cells provides insight into the early steps in medulloblastoma formation, and may yield important markers for early detection and therapy of this disease.     

Aging in the post-genomic era: simple or complex?

A report on the Third Genetic Effects on Aging Meeting, The Jackson Laboratory, Bar Harbor, Maine, August 4-8, 2000.