Genetic Variation and Population Substructure in Outbred CD-1 Mice: Implications for Genome-Wide Association Studies

Outbred laboratory mouse populations are widely used in biomedical research. Since little is known about the degree of genetic variation present in these populations, they are not widely used for genetic studies. Commercially available outbred CD-1 mice are drawn from an extremely large breeding population that has accumulated many recombination events, which is desirable for genome-wide association studies. We therefore examined the degree of genome-wide variation within CD-1 mice to investigate their suitability for genetic studies. The CD-1 mouse genome displays patterns of linkage disequilibrium and heterogeneity similar to wild-caught mice. Population substructure and phenotypic differences were observed among CD-1 mice obtained from different breeding facilities. Differences in genetic variation among CD-1 mice from distinct facilities were similar to genetic differences detected between closely related human populations, consistent with a founder effect. This first large-scale genetic analysis of the outbred CD-1 mouse strain provides important considerations for the design and analysis of genetic studies in CD-1 mice.</p

Getting DNA twist rigidity from single molecule experiments

We use an elastic rod model with contact to study the extension versus rotation diagrams of single supercoiled DNA molecules. We reproduce quantitatively the supercoiling response of overtwisted DNA and, using experimental data, we get an estimation of the effective supercoiling radius and of the twist rigidity of B-DNA. We find that unlike the bending rigidity, the twist rigidity of DNA seems to vary widely with the nature and concentration of the salt buffer in which it is immerged

Gauge vortex dynamics at finite mass of bosonic fields

The simple derivation of the string equation of motion adopted in the nonrelativistic case is presented, paying the special attention to the effects of finite masses of bosonic fields of an Abelian Higgs model. The role of the finite mass effects in the evaluation of various topological characteristics of the closed strings is discussed. The rate of the dissipationless helicity change is calculated. It is demonstrated how the conservation of the sum of the twisting and writhing numbers of the string is recovered despite the changing helicity.Comment: considerably revised to include errata to journal versio

Custom stems for femoral deformity in patients less than 40 years of age: 70 hips followed for an average of 14 years

Background and purpose Femoral deformity associated with osteoarthritis is a challenge for both the surgeon and the implant. Many of the patients with these deformities are young. Standard implants can be difficult to fit into these femurs. We prospectively evaluated the outcome of custom uncemented femoral stems in young patients

Relativistic quantum model of confinement and the current quark masses

We consider a relativistic quantum model of confined massive spinning quarks and antiquarks which describes leading Regge trajectories of mesons. The quarks are described by the Dirac equations and the gluon contribution is approximated by the Nambu-Goto straight-line string. The string tension and the current quark masses are the main parameters of the model. Additional parameters are phenomenological constants which approximate nonstring short-range contributions. Comparison of the measured meson masses with the model predictions allows one to determine the current quark masses (in MeV) to be $m_s = 227 \pm 5,~ m_c = 1440 \pm 10,~ m_b = 4715 \pm 20$. The chiral $SU_3$ model[23] makes it possible to estimate from here the $u$- and $d$-quark masses to be $m_u = 6.2 \pm 0.2$~ Mev and $m_d = 11.1 \pm 0.4$ Mev.Comment: 15 pages, LATEX, 2 tables. (submitted to Phys.Rev.D

Population Genetic Study of the Brain-Derived Neurotrophic Factor (BDNF) Gene

Genetic variants in the brain-derived neurotrophic factor (BDNF) gene, predominantly the functional Val66Met polymorphism, have been associated with risk of bipolar disorder and other psychiatric disorders. However, not all studies support these findings, and overall the evidence for the association of BDNF with disease risk is weak. As differences in population genetic structure between patient samples could cause discrepant or spurious association results, we investigated this possibility by carrying out population genetic analyses of the BDNF genomic region. Substantial variation was detected in BDNF coding region single-nucleotide polymorphism (SNP) allele and haplotype frequencies between 58 global populations, with the derived Met allele of Val66Met ranging in frequency from 0 to 72% across populations. FST analyses to assess diversity in the HapMap populations determined that the Val66Met FST value was at the 99.8th percentile among all SNPs in the genome. As the BDNF population genetic differences may be due to local selection, we performed the long-range haplotype test for selection using 68 SNPs spanning the BDNF genomic region in 12 European-derived pedigrees. Evidence for positive selection was found for a high-frequency Val-carrying haplotype, with a relative extended haplotype homozygosity value above the 99th percentile compared with HapMap data $(P=4.6 \times 10^{−4})$. In conclusion, we observed considerable BDNF allele and haplotype diversity among global populations and evidence for positive selection at the BDNF locus. These phenomena can have a profound impact on the detection of disease susceptibility genes and must be considered in gene association studies of BDNF.Organismic and Evolutionary BiologyOther Research Uni

An evaluation and comparison of conservation guidelines for an at-risk migratory songbird

For at-risk wildlife species, it is important to consider conservation within the process of adaptive management. Golden-winged Warblers (Vermivora chrysoptera) are Neotropical migratory songbirds that are experiencing long-term population declines due in part to the loss of early-successional nesting habitat. Recently-developed Golden-winged Warbler habitat management guidelines are being implemented by USDA: Natural Resource Conservation Service (2014) and its partners through the Working Lands For Wildlife (WLFW) program. During 2012–2014, we studied the nesting ecology of Golden-winged Warblers in managed habitats of the eastern US that conformed to WLFW conservation practices. We evaluated five NRCS “management scenarios” with respect to nesting success and attainment of recommended nest site vegetation conditions outlined in the Golden-winged Warbler breeding habitat guidelines. Using estimates of territory density, pairing rate, nest survival, and clutch size, we also estimated fledglingproductivity (number of fledglings/ha) for each management scenario. In general, Golden-winged Warbler nest survival declined as each breeding season advanced, but nest survival was similar across management scenarios. Within each management scenario, vegetation variables had little influence on nest survival. Still, percent Rubus cover and density of \u3e2 m tall shrubs were relevant in some management scenarios. All five management scenarios rarely attained recommended levels of nest site vegetation conditions for Golden-winged, yet nest survival was high. Fledgling productivity estimates for each management scenario ranged from 2.1 to 8.6 fledglings/10 hectares. Our results indicate that targeted habitat management for Golden-winged Warblers using a variety of management techniques on private lands has the capability to yield high nest survival and fledgling productivity, and thus have the potential to contribute to the species recovery

Association and Mutation Analyses of 16p11.2 Autism Candidate Genes

Background: Autism is a complex childhood neurodevelopmental disorder with a strong genetic basis. Microdeletion or duplication of a ∼500–700-kb genomic rearrangement on 16p11.2 that contains 24 genes represents the second most frequent chromosomal disorder associated with autism. The role of common and rare 16p11.2 sequence variants in autism etiology is unknown.Methodology/Principal Findings: To identify common 16p11.2 variants with a potential role in autism, we performed association studies using existing data generated from three microarray platforms: Affymetrix 5.0 (777 families), Illumina 550 K (943 families), and Affymetrix 500 K (60 families). No common variants were identified that were significantly associated with autism. To look for rare variants, we performed resequencing of coding and promoter regions for eight candidate genes selected based on their known expression patterns and functions. In total, we identified 26 novel variants in autism: 13 exonic (nine non-synonymous, three synonymous, and one untranslated region) and 13 promoter variants. We found a significant association between autism and a coding variant in the seizure-related gene SEZ6L2 (12/1106 autism vs. 3/1161 controls; p = 0.018). Sez6l2 expression in mouse embryos was restricted to the spinal cord and brain. SEZ6L2 expression in human fetal brain was highest in post-mitotic cortical layers, hippocampus, amygdala, and thalamus. Association analysis of SEZ6L2 in an independent sample set failed to replicate our initial findings.Conclusions/Significance: We have identified sequence variation in at least one candidate gene in 16p11.2 that may represent a novel genetic risk factor for autism. However, further studies are required to substantiate these preliminary findings.</p