Discriminating among single locus models using small pedigrees

Simulated small pedigrees (2 parents, 4 offspring) were used to illustrate the applications and limitations of a “model choice” approach designed to detect genetic heterogeneity in familial diseases. While it is possible to identify groups of pedigrees which have different genetic causes for quantitative phenotypic trait(s), theoretical limitations on discriminating between 4 single locus models exist for certain pedigree structures. These limitations originate from the overlapping phenotypic predictions of the various genetic models. Such limitations must be carefully considered in the design of genetic studies. Studies aimed at detecting genetic heterogeneity in familial diseases should limit the different genetic models being considered and tailor the sampling strategy to avoid collecting pedigrees which are non-informative for certain comparisons.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/38232/1/1320060307_ftp.pd

Estimating genetic and non-genetic components of variance for fasting glucose levels in pedigrees ascertained through non-insulin dependent diabetes

Fasting glucose levels measured on 337 individuals in 14 pedigrees ascertained through a proband with non-inuslin dependent diabetes were used to estimate genetic and non-genetic components of variance under a multifactorial model of inheritance. In this sample genetic factors were important in controlling variation in basal carbohydrate metabolism, as represented by age-adjusted log-fasting glucose. There was no evidence that arbitrary sib common environments or arbitrary parent common environments accounted for significant portions of the variability in fasting glucose in these data. An arbitrary environment shared by parent and offspring, however, had a marginally significant impact on the likelihood. Parameter estimates obtained from multifactorial models analysed in this manner are sensitive to extreme phenotypic values, however, and caution must be exerciese in estimating total genetic variation. While additive genetic factors did account for a significant proportion of the total variation in fasting glucose, a large proportion remained unexplained.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/66167/1/j.1469-1809.1982.tb01586.x.pd

Potential for La Crosse virus segment reassortment in nature

The evolutionary success of La Crosse virus (LACV, family Bunyaviridae) is due to its ability to adapt to changing conditions through intramolecular genetic changes and segment reassortment. Vertical transmission of LACV in mosquitoes increases the potential for segment reassortment. Studies were conducted to determine if segment reassortment was occurring in naturally infected Aedes triseriatus from Wisconsin and Minnesota in 2000, 2004, 2006 and 2007. Mosquito eggs were collected from various sites in Wisconsin and Minnesota. They were reared in the laboratory and adults were tested for LACV antigen by immunofluorescence assay. RNA was isolated from the abdomen of infected mosquitoes and portions of the small (S), medium (M) and large (L) viral genome segments were amplified by RT-PCR and sequenced. Overall, the viral sequences from 40 infected mosquitoes and 5 virus isolates were analyzed. Phylogenetic and linkage disequilibrium analyses revealed that approximately 25% of infected mosquitoes and viruses contained reassorted genome segments, suggesting that LACV segment reassortment is frequent in nature

Rapid Field Immunoassay for Detecting Antibody to Sin Nombre Virus in Deer Mice

We developed a 1-hour field enzyme immunoassay (EIA) for detecting antibody to Sin Nombre virus in deer mice (Peromyscus maniculatus). The assay specificity and sensitivity were comparable to those of a standard EIA. This test will permit identification of rodents with antibody to this and perhaps other hantaviruses

Resequencing Candidate Genes Implicates Rare Variants in Asthma Susceptibility

Common variation in over 100 genes has been implicated in the risk of developing asthma, but the contribution of rare variants to asthma susceptibility remains largely unexplored. We selected nine genes that showed the strongest signatures of weak purifying selection from among 53 candidate asthma-associated genes, and we sequenced the coding exons and flanking noncoding regions in 450 asthmatic cases and 515 nonasthmatic controls. We observed an overall excess of p values <0.05 (p = 0.02), and rare variants in four genes (AGT, DPP10, IKBKAP, and IL12RB1) contributed to asthma susceptibility among African Americans. Rare variants in IL12RB1 were also associated with asthma susceptibility among European Americans, despite the fact that the majority of rare variants in IL12RB1 were specific to either one of the populations. The combined evidence of association with rare noncoding variants in IL12RB1 remained significant (p = 3.7 × 10−4) after correcting for multiple testing. Overall, the contribution of rare variants to asthma susceptibility was predominantly due to noncoding variants in sequences flanking the exons, although nonsynonymous rare variants in DPP10 and in IL12RB1 were associated with asthma in African Americans and European Americans, respectively. This study provides evidence that rare variants contribute to asthma susceptibility. Additional studies are required for testing whether prioritizing genes for resequencing on the basis of signatures of purifying selection is an efficient means of identifying novel rare variants that contribute to complex disease

Evidence of gene-environment interaction for two genes on chromosome 4 and environmental tobacco smoke in controlling the risk of nonsyndromic cleft palate

Nonsyndromic cleft palate (CP) is one of the most common human birth defects and both genetic and environmental risk factors contribute to its etiology. We conducted a genome-wide association study (GWAS) using 550 CP case-parent trios ascertained in an international consortium. Stratified analysis among trios with different ancestries was performed to test for GxE interactions with common maternal exposures using conditional logistic regression models. While no single nucleotide polymorphism (SNP) achieved genome-wide significance when considered alone, markers in SLC2A9 and the neighboring WDR1 on chromosome 4p16.1 gave suggestive evidence of gene-environment interaction with environmental tobacco smoke (ETS) among 259 Asian trios when the models included a term for GxE interaction. Multiple SNPs in these two genes were associated with increased risk of nonsyndromic CP if the mother was exposed to ETS during the peri-conceptual period (3 months prior to conception through the first trimester). When maternal ETS was considered, fifteen of 135 SNPs mapping to SLC2A9 and 9 of 59 SNPs in WDR1 gave P values approaching genome-wide significance (10-6<P<10-4) in a test for GxETS interaction. SNPs rs3733585 and rs12508991 in SLC2A9 yielded P = 2.26×10-7 in a test for GxETS interaction. SNPs rs6820756 and rs7699512 in WDR1 also yielded P = 1.79×10-7 and P = 1.98×10-7 in a 1 df test for GxE interaction. Although further replication studies are critical to confirming these findings, these results illustrate how genetic associations for nonsyndromic CP can be missed if potential GxE interaction is not taken into account, and this study suggest SLC2A9 and WDR1 should be considered as candidate genes for CP. © 2014 Wu et al

Role of tyrosine 129 in the active site of spinach glycolate oxidase

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/66136/1/j.1432-1033.1993.tb17852.x.pd

Analysis of the low-energy electron-recoil spectrum of the CDMS experiment

We report on the analysis of the low-energy electron-recoil spectrum from the CDMS II experiment using data with an exposure of 443.2 kg-days. The analysis provides details on the observed counting rate and possible background sources in the energy range of 2 - 8.5 keV. We find no significant excess in the counting rate above background, and compare this observation to the recent DAMA results. In the framework of a conversion of a dark matter particle into electromagnetic energy, our 90% confidence level upper limit of 0.246 events/kg/day at 3.15 keV is lower than the total rate above background observed by DAMA by 8.9$\sigma$. In absence of any specific particle physics model to provide the scaling in cross section between NaI and Ge, we assume a Z^2 scaling. With this assumption the observed rate in DAMA differs from the upper limit in CDMS by 6.8$\sigma$. Under the conservative assumption that the modulation amplitude is 6% of the total rate we obtain upper limits on the modulation amplitude a factor of ~2 less than observed by DAMA, constraining some possible interpretations of this modulation.Comment: 4 pages, 3 figure

A Search for WIMPs with the First Five-Tower Data from CDMS

We report first results from the Cryogenic Dark Matter Search (CDMS II) experiment running with its full complement of 30 cryogenic particle detectors at the Soudan Underground Laboratory. This report is based on the analysis of data acquired between October 2006 and July 2007 from 15 Ge detectors (3.75 kg), giving an effective exposure of 121.3 kg-d (averaged over recoil energies 10--100 keV, weighted for a weakly interacting massive particle (WIMP) mass of 60 \gev). A blind analysis, incorporating improved techniques for event reconstruction and data quality monitoring, resulted in zero observed events. This analysis sets an upper limit on the WIMP-nucleon spin-independent cross section of 6.6$\times10^{-44}$ cm$^2$ (4.6$\times10^{-44}$ cm$^2$ when combined with previous CDMS Soudan data) at the 90% confidence level for a WIMP mass of 60 \gev. By providing the best sensitivity for dark matter WIMPs with masses above 42 GeV/c$^2$, this work significantly restricts the parameter space for some of the favored supersymmetric models.Comment: 5 pages, 4 figures, submitted to PRL 28 March 200

Characterization of SuperCDMS 1-inch Ge Detectors

The newly commissioned SuperCDMS Soudan experiment aims to search for WIMP dark matter with a sensitivity to cross sections of 5×10^(−45)cm^2 and larger (90% CL upper limit). This goal is facilitated by a new set of germanium detectors, 2.5 times more massive than the ones used in the CDMS-II experiment, and with a different athermal phonon sensor layout that eliminates radial degeneracy in position reconstruction of high radius events. We present characterization data on these detectors, as well as improved techniques for correcting position-dependent variations in pulse shape across the detector. These improvements provide surface-event discrimination sufficient for a reach of 5×10^(−45)cm^2