A maximum-likelihood method for the estimation of pairwise relatedness in structured populations

A maximum-likelihood estimator for pairwise relatedness is presented for the situation in which the individuals under consideration come from a large outbred subpopulation of the population for which allele frequencies are known. We demonstrate via simulations that a variety of commonly used estimators that do not take this kind of misspecification of allele frequencies into account will systematically overestimate the degree of relatedness between two individuals from a subpopulation. A maximum-likelihood estimator that includes F(ST) as a parameter is introduced with the goal of producing the relatedness estimates that would have been obtained if the subpopulation allele frequencies had been known. This estimator is shown to work quite well, even when the value of F(ST) is misspecified. Bootstrap confidence intervals are also examined and shown to exhibit close to nominal coverage when F(ST) is correctly specified.     

Identification of a novel allosteric GLP-1R antagonist HTL26119 using structure-based drug design

A series of novel allosteric antagonists of the GLP-1 receptor (GLP-1R), exemplified by HTL26119, are described. SBDD approaches were employed to identify HTL26119, exploiting structural understanding of the allosteric binding site of the closely related Glucagon receptor (GCGR) (Jazayeri et al., 2016) and the homology relationships between GCGR and GLP-1R. The region around residue C347^6.36b of the GLP-1R receptor represents a key difference from GCGR and was targeted for selectivity for GLP-1R.     

Genetic relatedness of Escherichia coli isolates in interstitial water from a Lake Huron (Canada) beach

Research was undertaken to characterize Escherichia coli isolates in interstitial water samples of a sandy beach on the southeastern shore of Lake Huron, Ontario, Canada. A survey of the beach area revealed the highest abundance of E. coli in interstitial water of the foreshore beach sand next to the swash zone. Higher concentrations of E. coli (up to 1.6 x 10(6) CFU/100 ml of water) were observed in the interstitial water from the sampling holes on the beach itself compared to lake water and sediment. Repetitive extragenic palindromic PCR (REP-PCR) was used to characterize the genetic diversity of E. coli isolates from interstitial water samples on the beach. E. coli isolates from the same sampling location frequently exhibited the same REP-PCR pattern or were highly similar to each other. In contrast, E. coli isolates from different sampling locations represented populations distinct from each other. This study has identified a unique ecological niche within the foreshore area of the beach where E. coli may survive and possibly multiply outside of host organisms. The results are of interest as increasing concentrations of E. coli in recreational waters are often considered to be an indication of recent fecal pollution.     

Genetic Relatedness of Escherichia coli Isolates in Interstitial Water from a Lake Huron (Canada) Beach

Research was undertaken to characterize Escherichia coli isolates in interstitial water samples of a sandy beach on the southeastern shore of Lake Huron, Ontario, Canada. A survey of the beach area revealed the highest abundance of E. coli in interstitial water of the foreshore beach sand next to the swash zone. Higher concentrations of E. coli (up to 1.6 × 10⁶ CFU/100 ml of water) were observed in the interstitial water from the sampling holes on the beach itself compared to lake water and sediment. Repetitive extragenic palindromic PCR (REP-PCR) was used to characterize the genetic diversity of E. coli isolates from interstitial water samples on the beach. E. coli isolates from the same sampling location frequently exhibited the same REP-PCR pattern or were highly similar to each other. In contrast, E. coli isolates from different sampling locations represented populations distinct from each other. This study has identified a unique ecological niche within the foreshore area of the beach where E. coli may survive and possibly multiply outside of host organisms. The results are of interest as increasing concentrations of E. coli in recreational waters are often considered to be an indication of recent fecal pollution.     

Dominance Genetic Variation Contributes Little to the Missing Heritability for Human Complex Traits

For human complex traits, non-additive genetic variation has been invoked to explain “missing heritability,” but its discovery is often neglected in genome-wide association studies. Here we propose a method of using SNP data to partition and estimate the proportion of phenotypic variance attributed to additive and dominance genetic variation at all SNPs (hSNP2 and δSNP2) in unrelated individuals based on an orthogonal model where the estimate of hSNP2 is independent of that of δSNP2. With this method, we analyzed 79 quantitative traits in 6,715 unrelated European Americans. The estimate of δSNP2 averaged across all the 79 quantitative traits was 0.03, approximately a fifth of that for additive variation (average hSNP2 = 0.15). There were a few traits that showed substantial estimates of δSNP2, none of which were replicated in a larger sample of 11,965 individuals. We further performed genome-wide association analyses of the 79 quantitative traits and detected SNPs with genome-wide significant dominance effects only at the ABO locus for factor VIII and von Willebrand factor. All these results suggest that dominance variation at common SNPs explains only a small fraction of phenotypic variation for human complex traits and contributes little to the missing narrow-sense heritability problem.     

Postcopulatory sexual selection is associated with accelerated evolution of sperm morphology

Rapid diversification of sexual traits is frequently attributed to sexual selection, though explicit tests of this hypothesis remain limited. Spermatozoa exhibit remarkable variability in size and shape, and studies report a correlation between sperm morphology (sperm length and shape) and sperm competition risk or female reproductive tract morphology. However, whether postcopulatory processes (e.g., sperm competition and cryptic female choice) influence the speed of evolutionary diversification in sperm form is unknown. Using passerine birds, we quantified evolutionary rates of sperm length divergence among lineages (i.e., species pairs) and determined whether these rates varied with the level of sperm competition (estimated as relative testes mass). We found that relative testes mass was significantly and positively associated with more rapid phenotypic divergence in sperm midpiece and flagellum lengths, as well as total sperm length. In contrast, there was no association between relative testes mass and rates of evolutionary divergence in sperm head size, and models suggested that head length is evolutionarily constrained. Our results are the first to show an association between the strength of sperm competition and the speed of sperm evolution, and suggest that postcopulatory sexual selection promotes rapid evolutionary diversification of sperm morphology.     

No evidence for root-mediated allelopathy in Centaurea solstitialis, a species in a commonly allelopathic genus

Phytotoxicity bioassays and pot experiments using activated carbon both suggest that Centaurea solstitialis (yellow star-thistle) does not rely on phytotoxic root exudates for invasion of California grasslands. Pot experiments in which five native species were grown in the presence/absence of C. solstitialis and in the presence/absence of activated carbon (fully crossed design) showed that C. solstitialis competitively suppressed native species, but did not inhibit them through allelochemicals. In separate experiments examining the role of root exudates in invasion success, treatment with crude root exudates and chloroform-extracted root exudates from C. solstitialis reduced growth of the model plant Arabidopsis thaliana. However, high concentrations of the exudates (50%, v/v or 500 μg mL⁻¹) were required to inhibit A. thaliana growth and did not result in A. thaliana mortality, suggesting the presence of only a weak growth inhibitor. Moreover, high concentrations of C. solstitialis crude root exudates did not affect the growth of five native grass species often displaced by C. solstitialis invasions in California grasslands. Finally, root exudates collected from C. solstitialis had weaker effects on a native California root parasite, Triphysaria versicolor, than root exudates collected from Zea mays, a species not renowned for its competitive or invasive capabilities. Our results suggest that, while C. solstitialis might possibly “be persuaded to yield a product that is toxic to one species or another” (Population biology of plants, Academic, 1977), we find no evidence that allelopathic root exudates play a role in the competitive success of this invasive.     

Neutralising antibodies block the function of Rh5/Ripr/CyRPA complex during invasion of Plasmodium falciparum into human erythrocytes

An effective vaccine is a priority for malaria control and elimination. The leading candidate in the Plasmodium falciparum blood stage is PfRh5. PfRh5 assembles into trimeric complex with PfRipr and PfCyRPA in the parasite, and this complex is essential for erythrocyte invasion. In this study, we show that antibodies specific for PfRh5 and PfCyRPA prevent trimeric complex formation. We identify the EGF‐7 domain on PfRipr as a neutralising epitope and demonstrate that antibodies against this region act downstream of complex formation to prevent merozoite invasion. Antibodies against the C‐terminal region of PfRipr were more inhibitory than those against either PfRh5 or PfCyRPA alone, and a combination of antibodies against PfCyRPA and PfRipr acted synergistically to reduce invasion. This study supports prioritisation of PfRipr for development as part of a next‐generation antimalarial vaccine.     

The M.ADP.P(i) state is required for helical order in the thick filaments of skeletal muscle

The thick filaments of mammalian and avian skeletal muscle fibers are disordered at low temperature, but become increasingly ordered into an helical structure as the temperature is raised. Wray and colleagues (Schlichting, I., and J. Wray. 1986. J. Muscle Res. Cell Motil. 7:79; Wray, J., R. S. Goody, and K. Holmes. 1986. Adv. Exp. Med. Biol. 226:49-59) interpreted the transition as reflecting a coupling between nucleotide state and global conformation with M.ATP (disordered) being favored at 0 degrees C and M.ADP.P(i) (ordered) at 20 degrees C. However, hitherto this has been limited to a qualitative correlation and the biochemical state of the myosin heads required to obtain the helical array has not been unequivocally identified. In the present study we have critically tested whether the helical arrangement of the myosin heads requires the M.ADP.P(i) state. X-ray diffraction patterns were recorded from skinned rabbit psoas muscle fiber bundles stretched to non-overlap to avoid complications due to interaction with actin. The effect of temperature on the intensities of the myosin-based layer lines and on the phosphate burst of myosin hydrolyzing ATP in solution were examined under closely matched conditions. The results showed that the fraction of myosin mass in the helix closely followed that of the fraction of myosin in the M.ADP.P(i) state. Similar results were found by using a series of nucleoside triphosphates, including CTP and GTP. In addition, fibers treated by N-phenylmaleimide (Barnett, V. A., A. Ehrlich, and M. Schoenberg. 1992. Biophys. J. 61:358-367) so that the myosin was exclusively in the M.ATP state revealed no helical order. Diffraction patterns from muscle fibers in nucleotide-free and in ADP-containing solutions did not show helical structure. All these confirmed that in the presence of nucleotides, the M.NDP.P(i) state is required for helical order. We also found that the spacing of the third meridional reflection of the thick filament is linked to the helical order. The spacing in the ordered M.NDP.P(i) state is 143.4 A, but in the disordered state, it is 144. 2 A. This may be explained by the different interference functions for the myosin heads and the thick filament backbone.     

Detection of pyrogenic toxins of Staphylococcus aureus in sudden infant death syndrome

It has been suggested that pyrogenic toxins of Staphylococcus aureus are involved in the series of events leading to some cases of sudden infant death syndrome (SIDS). The objectives of the study were to screen tissues from SIDS infants for pyrogenic toxins and to compare incidence of identification of these toxins among these infants from different countries. An enzyme-linked immunosorbent assay (ELISA) and a flow cytometry method were used to screen body fluids and frozen or formalin-fixed tissues for pyrogenic toxins of S. aureus, toxic shock syndrome toxin 1 (TSST), staphylococcal enterotoxins A (SEA), B (SEB), and C1 (SEC). Toxins were identified in tissues of 33/62 (53%) SIDS infants from three different countries: Scotland (10/ 19, 56%); France (7/13, 55%); Australia (16/30, 53%). In the Australian series, toxins were identified in only 3/19 (16%) non-SIDS deaths (chi2 = 5.42, P < 0.02). The flow cytometry method was useful for toxin detection in both frozen and fixed tissues, but ELISA was suitable only for frozen tissues or those fixed for less than 12 months. Identification of pyrogenic toxins in > 50% of SIDS infants from three different countries indicated further investigation into the role the toxins play in cot deaths might result in development of additional measures to reduce further the incidence of these infant deaths.