Robust score statistics for QTL linkage analysis

The traditional variance components approach for quantitative trait locus (QTL) linkage analysis is sensitive to violations of normality and fails for selected sampling schemes. Recently, a number of new methods have been developed for QTL mapping in humans. Most of the new methods are based on score statistics or regression-based statistics and are expected to be relatively robust to non-normality of the trait distribution and also to selected sampling, at least in terms of type I error. Whereas the theoretical development of these statistics is more or less complete, some practical issues concerning their implementation still need to be addressed. Here we study some of these issues such as the choice of denominator variance estimates, weighting of pedigrees, effect of parameter misspecification, effect of non-normality of the trait distribution, and effect of incorporating dominance. We present a comprehensive discussion of the theoretical properties of various denominator variance estimates and of the weighting issue and then perform simulation studies for nuclear families to compare the methods in terms of power and robustness. Based on our analytical and simulation results, we provide general guidelines regarding the choice of appropriate QTL mapping statistics in practical situations.     

Structural-Thermodynamic Relationships of Interactions in the N-Terminal ATP-Binding Domain of Hsp90

Despite its importance as a target in anti-cancer therapeutics and the numerous rational-based inhibitor design efforts aimed at it, there are only limited data available on structural-thermodynamic relationships of interactions of the N-terminal ATP-binding domain of Hsp90 (N-Hsp90). Here, we redress this by presenting an investigation of binding of nucleotides and ansamycin compounds to this domain. Interactions of nucleotides with N-Hsp90 are relatively weak (> 10 μM) and are strongly enthalpy driven over the temperature range 10-25 °C. Geldanamycin (GA) and its analogues 17-AAG [17-(allylamino)-17-demethoxy-GA] and 17-DMAG (17-N,N-dimethylaminoethylamino-17-demethoxy-GA) bind more strongly and have a dominant favourable enthalpic contribution over the temperature range investigated. We investigated the temperature dependence of the enthalpic contribution to binding. We found that while the ansamycin compounds have the commonly observed negative value, the nucleotides show a negligible or even a positive ΔC_p of binding. These data represent the first observation of a single binding site for which interactions with different ligands result in both negative and positive ΔC_p values. By addressing the likely impact of the potential contributions from protein-ligand interactions, we are able to attribute the anomalous ΔC_p for the nucleotides largely to a change in the conformation of the domain structure and local motion in the lid region of N-Hsp90 with the concomitant exposure of hydrophobic amino acid side chains.     

Novel inhibitors of the αvβ3 integrin—lead identification strategy

A novel approach to inhibition of the αvβ3 integrin is described, which uses compounds designed to generate nM potency without using the arginine binding site.     

Hierarchical metapopulation structure in a highly mobile marine predator: the southern Australian coastal bottlenose dolphin (<Emphasis Type="Italic">Tursiops</Emphasis> cf. <Emphasis Type="Italic">australis</Emphasis>)

Little is known about the population ecology of the recently described bottlenose dolphin species Tursiops australis. The classification of this species is still under debate, but this putative species is thought to be comprised of small and genetically distinct populations (including sub-populations under increasing anthropogenic threats) and is likely endemic to coastal southern Australia. Mitochondrial DNA (mtDNA) control region sequences and microsatellite loci were used to assess genetic variation and hierarchical population structure of coastal T. cf. australis across a range of spatial scales and environmental discontinuities between southern Western Australia (WA) and central South Australia (SA). Overall, genetic diversity was similar to that typically found for bottlenose dolphins, although very low mtDNA diversity was found in Gulf St. Vincent (GSV) dolphins. We found historical genetic subdivision and likely differences in colonisation between GSV and Spencer Gulf, outer- and inner-gulf locations, and SA/WA and previously identified Victorian/Tasmanian populations. A hierarchical metapopulation structure was revealed along southern Australia, with at least six genetic populations occurring between Esperance, WA and southern Tasmania. In addition, fine-scale genetic subdivision was observed within each SA/WA population. In general, contemporary migration was limited throughout southern Australia, but an important gene flow pathway was identified eastward along the Great Australian Bight. Management strategies that promote gene flow among populations should be implemented to assist with the maintenance of the inferred metapopulation structure. Further research into the population ecology of this species is needed to facilitate well-informed management decisions.     

C. elegans Eats Its Own Intestine to Make Yolk Leading to Multiple Senescent Pathologies

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Estimating the Frequency Distribution of Crossovers during Meiosis from Recombination Data

Estimation of tetrad crossover frequency distributions from genetic recombination data is a classic problem dating back to Weinstein (1936, Genetics 21, 155-199). But a number of important issues, such as how to specify the maximum number of crossovers, how to construct confidence intervals for crossover probabilities, and how to obtain correct p-values for hypothesis tests, have never been adequately addressed. In this article, we obtain some properties of the maximum likelihood estimate (MLE) for crossover probabilities that imply guidelines for choosing the maximum number of crossovers. We give these results for both normal meiosis and meiosis with nondisjunction. We also develop an accelerated EM algorithm to find the MLE more efficiently. We propose bootstrap-based methods to find confidence intervals and p-values and conduct simulation studies to check the validity of the bootstrap approach.     

Transfer Ribonucleic Acid Synthetase Activity Associated with Avian Myeloblastosis Virus

Avian myeloblastosis virions purified by conventional techniques were shown to be associated with or to contain transfer ribonucleic acid synthetase activity. Arginine, tryptophan, cystine, and lysine synthetase activities were observed.