HLODs, trait models, and ascertainment: implications of admixture for parameter estimation and linkage detection

Maximizing the homogeneity lod is known to be an appropriate procedure for estimating parameters of the trait model in an approximately 'ascertainment assumption free' (AAF) manner. We have investigated whether this same property also holds for the heterogeneity lod (HLOD). We show that, when the genetic models at linked and unlinked loci differ, HLODs are not AAF, and maximizing the HLOD yields parameter estimates that are for all practical purposes meaningless; indeed, the admixture parameter alpha does not even measure the proportion of linked families within the sample, as is commonly supposed. In spite of this, our results confirm a large body of evidence supporting the use of HLODs as robust tools for linkage detection, and suggest further that maximizing the HLOD over both alpha and parameters of the trait model can improve accuracy in estimation of the recombination fraction theta;. These findings have important implications for the optimal handling of nuisance parameters in linkage analysis, particularly when evaluating the evidence for or against linkage based on multiple independent heterogeneous sets of data.     

A major susceptibility locus for specific language impairment is located on 13q21

Children who fail to develop language normally-in the absence of explanatory factors such as neurological disorders, hearing impairment, or lack of adequate opportunity-are clinically described as having specific language impairment (SLI). SLI has a prevalence of approximately 7% in children entering school and is associated with later difficulties in learning to read. Research indicates that genetic factors are important in the etiology of SLI. Studies have consistently demonstrated that SLI aggregates in families. Increased monozygotic versus dizygotic twin concordance rates indicate that heredity, not just shared environment, is the cause of the familial clustering. We have collected five pedigrees of Celtic ancestry that segregate SLI, and we have conducted genomewide categorical linkage analysis, using model-based LOD score techniques. Analysis was conducted under both dominant and recessive models by use of three phenotypic classifications: clinical diagnosis, language impairment (spoken language quotient <85) and reading discrepancy (nonverbal IQ minus non-word reading >15). Chromosome 13 yielded a maximum multipoint LOD score of 3.92 under the recessive reading discrepancy model. Simulation to correct for multiple models and multiple phenotypes indicated that the genomewide empirical P value is <.01. As an alternative measure, we also computed the posterior probability of linkage (PPL), obtaining a PPL of 53% in the same region. One other genomic region yielded suggestive results on chromosome 2 (multipoint LOD score 2.86, genomic P value <.06 under the recessive language impairment model). Our findings underscore the utility of traditional LOD-score-based methods in finding genes for complex diseases, specifically, SLI.     

Likelihood of attending bowel screening after a negative genetic test result: the possible influence of health professionals

This study was undertaken to determine the extent to which the reported likelihood of attending future bowel screening following negative genetic testing results for familial adenomatous polyposis (FAP) varies between the type of health professional providing care and the country of testing. The study subjects were 103 unaffected adults at risk for FAP who received negative results following predictive DNA testing. Our study indicates that the reported likelihood of attending bowel screening was higher in those given results by nongenetics physicians, rather than by genetics professionals; the reported likelihood of attending bowel screening under these circumstances was also higher in the UK than in Australia. Both of these results were affected by the perceived chances of developing FAP, and, in the case of the country of testing, by the perceived accuracy of the genetic test result and the perceived seriousness of the disease. How and what health professionals communicate with patients about genetic testing may explain the differences between type of health professional and country of testing and attitudes toward bowel screening. If this is the case, training in communication may change patients' perceptions and, in turn, their behavioral intentions and actions following a negative test result.     

Apoptotic pathways: involvement of lysosomal proteases

Apoptosis or programmed cell death is the major mechanism used by multicellular organisms to remove infected, excessive and potentially dangerous cells. Cysteine proteases from the caspase family play a crucial role in the process. However, there is increasing evidence that lysosomal proteases are also involved in apoptosis. In this review various lysosomal proteases and their potential contribution to propagation of apoptosis are discussed.     

alpha2-Adrenoceptors control the release of noradrenaline but not neuropeptide Y from perivascular nerve terminals

Neuropeptide Y (NPY) and noradrenaline (NA) are co-transmitters at many sympathetic synapses, but it is not yet clear if their release is independently regulated. To address this question, we quantified the electrically evoked release of these co-transmitters from perivascular nerve terminals to the mesenteric circulation in control and drug-treated rats. 6-Hydroxydopamine reduced the tissue content and the electrically evoked release of ir-NPY and NA as well as the rise in perfusion pressure. A 0.001 mg/kg reserpine reduced the content of ir-NPY and NA, but did not modify their release nor altered the rise in perfusion pressure elicited by the electrical stimuli. However, 0.1mg/kg reserpine reduced both the content and release of NA but decreased only the content but not the release of ir-NPY; the rise in perfusion pressure was halved. Clonidine did not affect the release of ir-NPY while it lowered the outflow of NA, not altering the rise in perfusion pressure elicited by the electrical stimuli. Yohimbine, did not modify the release of ir-NPY but increased the NA outflow, it antagonized the clonidine effect. Therefore, presynaptic alpha2-adrenoceptors modulate the release of NA but not NPY, implying separate regulatory mechanisms.     

Major proteins of bovine seminal plasma bind to the low-density lipoprotein fraction of hen's egg yolk

Over the past 60 years, egg yolk (EY) has been routinely used in both liquid semen extenders and those used to cryopreserve sperm. However, the mechanism by which EY protects sperm during liquid storage or from freezing damage is unknown. Bovine seminal plasma contains a family of proteins designated BSP-A1/-A2, BSP-A3, and BSP-30-kDa (collectively called BSP proteins). These proteins are secretory products of seminal vesicles that are acquired by sperm at ejaculation, modifying the sperm membrane by inducing cholesterol efflux. Because cholesterol efflux is time and concentration dependent, continuous exposure to seminal plasma (SP) that contains BSP proteins may be detrimental to the sperm membrane, which may adversely affect the ability of sperm to be preserved. In this article, we show that the BSP proteins bind to the low-density fraction (LDF), a lipoprotein component of the EY extender. The binding is rapid, specific, saturable, and stable even after freeze-thawing of semen. Furthermore, LDF has a very high capacity for BSP protein binding. The binding of BSP proteins to LDF may prevent their detrimental effect on sperm membrane, and this may be crucial for sperm storage. Thus, we propose that the sequestration of BSP proteins of SP by LDF may represent the major mechanism of sperm protection by EY.