Dissecting Complex Traits Using the Drosophila Synthetic Population Resource

For most complex traits we have a poor understanding of the positions, phenotypic effects, and population frequencies of the underlying genetic variants contributing to their variation. Recently, several groups have developed multi-parent advanced intercross mapping panels in different model organisms in an attempt to improve our ability to characterize causative genetic variants. These panels are powerful and are particularly well suited to the dissection of phenotypic variation generated by rare alleles and loci segregating multiple functional alleles. We describe studies using one such panel, the Drosophila Synthetic Population Resource, and the implications for our understanding of the genetic basis of complex traits. In particular, we note that many loci of large effect appear to be multiallelic. If multiallelism is a general rule, analytical approaches designed to identify multiallelic variants should be a priority for both genome wide association studies and multi-parental panels

4-aminopyridine toxicity: a case report and review of the literature.

INTRODUCTION: 4-Aminopyridine (4-AP) selectively blocks voltage-gated potassium channels, prolongs the action potential, increases calcium influx, and subsequently, enhances interneuronal and neuromuscular synaptic transmission. This medication has been studied and used in many disease processes hallmarked by poor neuronal transmission in both the central and peripheral nervous systems including: multiple sclerosis (MS), spinal cord injuries (SCI), botulism, Lambert-Eaton syndrome, and myasthenia gravis. It has also been postulated as a potential treatment of verapamil toxicity and reversal agent for anesthesia-induced neuromuscular blockade. To date, there have been limited reports of either intentional or accidental 4-AP toxicity in humans. Both a case of a patient with 4-AP toxicity and review of the literature are discussed, highlighting commonalities observed in overdose. CASE REPORT: A 37-year-old man with progressive MS presented with diaphoresis, delirium, agitation, and choreathetoid movements after a presumed 4-AP overdose. 4-AP concentration at 6 h was 140 ng/mL. With aggressive benzodiazepine administration and intubation, he recovered uneventfully. DISCUSSION: The commonalities associated with 4-AP toxicity conforms to what is known about its mechanism of action combining cholinergic features including diaphoresis, altered mental status, and seizures with dopamine-related movement abnormalities including tremor, choreoathetosis, and dystonia. Management of patients poisoned by 4-AP centers around good supportive care with definitive airway management and controlling CNS hyperexcitability aggressively with gamma-aminobutyric acid agonist agents. Adjunctive use of dopamine antagonists for extrapyramidal effects after sedation is a treatment possibility. As 4-aminopyridine recently received Federal Drug Administration approval for the treatment of ambulation in patients with MS, physicians should be keenly aware of its presentation, mechanism of action, and management in overdose

Effect of the velopharynx on intraluminal pressures in reconstructed pharynges derived from individuals with and without sleep apnea

The most collapsible part of the upper airway in the majority of individuals is the velopharynx which is the segment positioned behind the soft palate. As such it is an important morphological region for consideration in elucidating the pathogenesis of obstructive sleep apnea (OSA). This study compared steady flow properties during inspiration in the pharynges of nine male subjects with OSA and nine body-mass index (BMI)- and age-matched control male subjects without OSA. The k–ωωSST turbulence model was used to simulate the flow field in subject-specific pharyngeal geometric models reconstructed from anatomical optical coherence tomography (aOCT) data. While analysis of the geometry of reconstructed pharynges revealed narrowing at velopharyngeal level in subjects with OSA, it was not possible to clearly distinguish them from subjects without OSA on the basis of pharyngeal size and shape alone. By contrast, flow simulations demonstrated that pressure fields within the narrowed airway segments were sensitive to small differences in geometry and could lead to significantly different intraluminal pressure characteristics between subjects. The ratio between velopharyngeal and total pharyngeal pressure drops emerged as a relevant flow-based criterion by which subjects with OSA could be differentiated from those without

The Genetic Architecture of Methotrexate Toxicity Is Similar in Drosophila melanogaster and Humans

The severity of the toxic side effects of chemotherapy varies among patients, and much of this variation is likely genetically based. Here, we use the model system Drosophila melanogaster to genetically dissect the toxicity of methotrexate (MTX), a drug used primarily to treat childhood acute lymphoblastic leukemia and rheumatoid arthritis. We use the Drosophila Synthetic Population Resource, a panel of recombinant inbred lines derived from a multiparent advanced intercross, and quantify MTX toxicity as a reduction in female fecundity. We identify three quantitative trait loci (QTL) affecting MTX toxicity; two colocalize with the fly orthologs of human genes believed to mediate MTX toxicity and one is a novel MTX toxicity gene with a human ortholog. A fourth suggestive QTL spans a centromere. Local single-marker association scans of candidate gene exons fail to implicate amino acid variants as the causative single-nucleotide polymorphisms, and we therefore hypothesize the causative variation is regulatory. In addition, the effects at our mapped QTL do not conform to a simple biallelic pattern, suggesting multiple causative factors underlie the QTL mapping results. Consistent with this observation, no single single-nucleotide polymorphism located in or near a candidate gene can explain the QTL mapping signal. Overall, our results validate D. melanogaster as a model for uncovering the genetic basis of chemotoxicity and suggest the genetic basis of MTX toxicity is due to a handful of genes each harboring multiple segregating regulatory factors

Rodenticidal Effects of Zinc Phosphide and Strychnine of Nontarget Species

When three rodenticide treatments—zinc phosphide (prebaited) and strychnine (both with and without prebait)were evaluated, zinc phosphide was the most effective in reducing active burrows of prairie dogs; but, it also resulted in a reduction in deer mouse densities. One month after treatment, counts of fecal pellets of eastern cottontails were greater on areas treated with strychnine without prebait than on sites treated with zinc phosphide. Eight months after treatment, no differences could be detected among rodenticides for either leporid. Horned lark densities were reduced 61% on sites treated with strychnine only

Genetic Dissection of the Drosophila melanogaster Female Head Transcriptome Reveals Widespread Allelic Heterogeneity

Modern genetic mapping is plagued by the “missing heritability” problem, which refers to the discordance between the estimated heritabilities of quantitative traits and the variance accounted for by mapped causative variants. One major potential explanation for the missing heritability is allelic heterogeneity, in which there are multiple causative variants at each causative gene with only a fraction having been identified. The majority of genome-wide association studies (GWAS) implicitly assume that a single SNP can explain all the variance for a causative locus. However, if allelic heterogeneity is prevalent, a substantial amount of genetic variance will remain unexplained. In this paper, we take a haplotype-based mapping approach and quantify the number of alleles segregating at each locus using a large set of 7922 eQTL contributing to regulatory variation in the Drosophila melanogaster female head. Not only does this study provide a comprehensive eQTL map for a major community genetic resource, the Drosophila Synthetic Population Resource, but it also provides a direct test of the allelic heterogeneity hypothesis. We find that 95% of cis-eQTLs and 78% of trans-eQTLs are due to multiple alleles, demonstrating that allelic heterogeneity is widespread in Drosophila eQTL. Allelic heterogeneity likely contributes significantly to the missing heritability problem common in GWAS studies.This work was supported by NIH R01 RR024862/OD010974 to SJM and ADL, an American Recovery and Reinvestment Act (ARRA) administrative supplement to this award, and F32 GM099382 to EGK. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Rodenticidal Effects of Zinc Phosphide and Strychnine of Nontarget Species

When three rodenticide treatments—zinc phosphide (prebaited) and strychnine (both with and without prebait)were evaluated, zinc phosphide was the most effective in reducing active burrows of prairie dogs; but, it also resulted in a reduction in deer mouse densities. One month after treatment, counts of fecal pellets of eastern cottontails were greater on areas treated with strychnine without prebait than on sites treated with zinc phosphide. Eight months after treatment, no differences could be detected among rodenticides for either leporid. Horned lark densities were reduced 61% on sites treated with strychnine only

Lithium in the Intermediate-Age Open Cluster, NGC 3680

High-dispersion spectra centered on the Li 6708 A line have been obtained for 70 potential members of the open cluster NGC 3680, with an emphasis on stars in the turnoff region. A measurable Li abundance has been derived for 53 stars, 39 of which have radial velocities and proper motions consistent with cluster membership. After being transferred to common temperature and abundance scales, previous Li estimates have been combined to generate a sample of 49 members, 40 of which bracket the cluster Li-dip. Spectroscopic elemental analysis of 8 giants and 5 turnoff stars produces [Fe/H] = -0.17 +/- 0.07 (sd) and -0.07 +/- 0.02 (sd), respectively. We also report measurements of Ca, Si and Ni which are consistent with scaled-solar ratios within the errors. Adopting [Fe/H] = -0.08 (Sect. 3.6), Y^2 isochrone comparisons lead to an age of 1.75 +/- 0.10 Gyr and an apparent modulus of (m-M) = 10.30 +/- 0.15 for the cluster, placing the center of the Li-dip at 1.35 +/- 0.03 solar masses. Among the giants, 5 of 9 cluster members are now known to have measurable Li with A(Li) near 1.0. A combined sample of dwarfs in the Hyades and Praesepe is used to delineate the Li-dip profile at 0.7 Gyr and [Fe/H] = +0.15, establishing its center at 1.42 +/- 0.02 solar masses and noting the possible existence of secondary dip on its red boundary. When evolved to the typical age of the clusters NGC 752, IC 4651 and NGC 3680, the Hyades/Praesepe Li-dip profile reproduces the observed morphology of the combined Li-dip within the CMD's of the intermediate-age clusters while implying a metallicity dependence for the central mass of the Li-dip given by Mass = (1.38 +/-0.04) + (0.4 +/- 0.2)[Fe/H]. The implications of the similarity of the Li-dichotomy among giants in NGC 752 and IC 4651 and the disagreement with the pattern among NGC 3680 giants are discussed.Comment: Latex ms. is 56 pages, including 10 figures and 4 tables. Accepted for the Astronomical Journa

WIYN Open Cluster Study. XXXIX. Abundances in NGC 6253 from HYDRA Spectroscopy of the Li 6708 A Region

High-dispersion spectra of 89 potential members of the old, super-metal-rich open cluster, NGC 6253, have been obtained with the HYDRA multi-object spectrograph. Based upon radial-velocity measurements alone, 47 stars at the turnoff of the cluster color-magnitude diagram (CMD) and 18 giants are identified as potential members. Five turnoff stars exhibit evidence of binarity while proper-motion data eliminates two of the dwarfs as members. The mean cluster radial velocity from probable single-star members is -29.4 +/- 1.3 km/sec (sd). A discussion of the current estimates for the cluster reddening, derived independently of potential issues with the BV cluster photometry, lead to an adopted reddening of E(B-V) = 0.22 +/- 0.04. From equivalent width analyses of 38 probable single-star members near the CMD turnoff, the weighted average abundances are found to be [Fe/H] = +0.43 +/- 0.01, [Ni/H] = +0.53 +/- 0.02 and [Si/H] = +0.43 (+0.03,-0.04), where the errors refer to the standard errors of the weighted mean. Weak evidence is found for a possible decline in metallicity with increasing luminosity among stars at the turnoff. We discuss the possibility that our turnoff stars have been affected by microscopic diffusion. For 15 probable single-star members among the giants, spectrum synthesis leads to abundances of +0.46 (+0.02,-0.03) for [Fe/H]. While less than half the age of NGC 6791, NGC 6253 is at least as metal-rich and, within the uncertainties, exhibits the same general abundance pattern as that typified by super-metal-rich dwarfs of the galactic bulge.Comment: 5 Tables, 9 figures, 45 page

Comparison of two- and three-dimensional echocardiography with cineventriculography for measurement of left ventricular volume in patients

AbstractObjectives. We compared two- and three-dimensional echocardiopaphy with cineventriculography for measurement of left ventricular volume in patients.Background. Three-dimensional echocardiography has been shown to be highly accurate and superior to two-dimensional echocardiography in measuring left ventricular volume in vitro. However, there has been little comparison of the two methods in patients.Methods. Two- and three-dimensional echocardiography were performed in 35 patients (mean age 48 years) 1 to 3 h before left ventricular cineventriculography. Three-dimensional echocardiography used an acoustic spatial locator to register image position. Volume was computed using a polyhedral surface reconstruction algorithm based on multiple nonparallel, unevenly spaced short-axis cross sections. Two-dimensional echocardiography used the apical biplane summation of disks method. Single-plane cineventriculographic volumes were calculated using the summation of disks algorithm. The methods were compared by linear regression and a limits of agreement analysis. For the latter, systematic error was assessed by the mean of the deferences (cineventriculography minus echocardiography), and the limits of agreement were defined as ±2 SD from the mean difference.Results. Three-dimensional echocardiographic volumes demonstrated excellent correlation (end-diastole r = 0.97; end-systole r = 0.98) with cineventriculography. Standard errors of the estimate were approximately half those of two-dimensional echocardiography (end-diastole ±11.0 ml vs. ±21.5 ml; end-systole ±10.2 ml vs. ±17.0 ml). By limits of agreement analysis the end-diastolic mean diferences for two- and three-dimensional echocardiography were 21.1 and 12.9 ml, respectively. The limits of agreement (±2 SD) were ±54.0 and ±24.8 ml, respectively. For end-systole, comparable improvement was obtained by three-dimensional echocardiography. Results for ejection fraction by the two methods were similar.Conclusions. Three-dimensional echocardiography correlates highly with cineventriculography for estimation of ventricular volumes in patients and has approximately half the variability of two-dimensional echocardiography for these measurements. On the basis of this study, three-dimensional echocardiography is the preferred echocardiographic technique for measurement of ventricular volume. Three-dimensional echocardiography is equivalent to two-dimensional echocardiography for measuring ejection fraction