Efficiency and Power as a Function of Sequence Coverage, SNP Array Density, and Imputation

High coverage whole genome sequencing provides near complete information about genetic variation. However, other technologies can be more efficient in some settings by (a) reducing redundant coverage within samples and (b) exploiting patterns of genetic variation across samples. To characterize as many samples as possible, many genetic studies therefore employ lower coverage sequencing or SNP array genotyping coupled to statistical imputation. To compare these approaches individually and in conjunction, we developed a statistical framework to estimate genotypes jointly from sequence reads, array intensities, and imputation. In European samples, we find similar sensitivity (89%) and specificity (99.6%) from imputation with either 1× sequencing or 1 M SNP arrays. Sensitivity is increased, particularly for low-frequency polymorphisms (MAF <5%), when low coverage sequence reads are added to dense genome-wide SNP arrays — the converse, however, is not true. At sites where sequence reads and array intensities produce different sample genotypes, joint analysis reduces genotype errors and identifies novel error modes. Our joint framework informs the use of next-generation sequencing in genome wide association studies and supports development of improved methods for genotype calling

Disorder-induced Majorana metal in interacting non-Abelian anyon systems

We demonstrate that a thermal metal of Majorana fermions forms in a two-dimensional system of interacting non-Abelian (Ising) anyons in the presence of moderate disorder. This bulk metallic phase arises in the $\nu=5/2$ quantum Hall state when disorder pins the anyonic quasiparticles. More generally, it naturally occurs for various proposed systems supporting Majorana fermion zero modes when disorder induces the random pinning of a finite density of vortices. This includes all two-dimensional topological superconductors in so-called symmetry class D. A distinct experimental signature of the thermal metal phase is the presence of bulk heat transport down to zero temperature.Comment: 4 pages, 6 figure

Spectroscopy, Interactions and Level Splittings in Au Nanoparticles

We have measured the electronic energy spectra of nm-scale Au particles using a new tunneling spectroscopy configuration. The particle diameters ranged from 5nm to 9nm, and at low energies the spectrum is discrete, as expected by the electron-in-a-box model. The density of tunneling resonances increases rapidly with energy, and at higher energies the resonances overlap forming broad resonances. Near the Thouless energy, the broad resonances merge into a continuum. The tunneling resonances display Zeeman splitting in a magnetic field. Surprisingly, the g-factors (~0.3) of energy levels in Au nano-particles are much smaller than the g-factor (2.1) in bulk gold

The breakdown of the Nagaoka phase in the 2D t-J model

In the limit of weak exchange, J, at low hole concentration, the ground state of the 2D t-J model is believed to be ferromagnetic. We study the leading instability of this Nagaoka state, which emerges with increasing J. Both exact diagonalization of small clusters, and a semiclassical analytical calculation of larger systems show that above a certain critical value of the exchange, Nagaoka's state is unstable to phase separation. In a finite-size system a bubble of antiferromagnetic Mott insulator appears in the ground state above this threshold. The size of this bubble depends on the hole concentration and scales as a power of the system size, N

The Role of CD 133+ Cells in a Recurrent Embryonal Tumor with Abundant Neuropil and True Rosettes ( ETANTR )

Embryonal tumor with abundant neuropil and true rosettes ( ETANTR ) is a recently described embryonal neoplasm of the central nervous system, consisting of a well‐circumscribed embryonal tumor of infancy with mixed features of ependymoblastoma (multilayer ependymoblastic rosettes and pseudorosettes) and neuroblastoma (neuroblastic rosettes) in the presence of neuropil‐like islands. We present the case of a young child with a very aggressive tumor that rapidly recurred after gross total resection, chemotherapy and radiation. Prominent vascular sclerosis and circumscribed tumor led to the diagnosis of malignant astroblastoma; however, rapid recurrence and progression of this large tumor after gross total resection prompted review of the original pathology. ETANTR is histologically distinct with focal glial fibrillary acid protein ( GFAP ) and synaptophysin expression in the presence of neuronal and ependymoblastic rosettes with focal neuropil islands. These architectural features, combined with unique chromosome 19q13.42 amplification, confirmed the diagnosis. In this report, we describe tumor stem cell ( TSC ) marker CD 133, CD 15 and nestin alterations in ETANTR before and after chemotherapy. We found that TSC marker CD 133 was richly expressed after chemotherapy in recurrent ETANTR , while CD 15 is depleted compared with that expressed in the original tumor, suggesting that CD 133+ cells likely survived initial treatment, further contributing to formation of the recurrent tumor.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/102077/1/bpa12079.pd

Bistability in the Tunnelling Current through a Ring of NN Coupled Quantum Dots

We study bistability in the electron transport through a ring of N coupled quantum dots with two orbitals in each dot. One orbital is localized (called b orbital) and coupling of the b orbitals in any two dots is negligible; the other is delocalized in the plane of the ring (called d orbital), due to coupling of the d orbitals in the neighboring dots, as described by a tight-binding model. The d orbitals thereby form a band with finite width. The b and d orbitals are connected to the source and drain electrodes with a voltage bias V, allowing the electron tunnelling. Tunnelling current is calculated by using a nonequilibrium Green function method recently developed to treat nanostructures with multiple energy levels. We find a bistable effect in the tunnelling current as a function of bias V, when the size N>50; this effect scales with the size N and becomes sizable at N~100. The temperature effect on bistability is also discussed. In comparison, mean-field treatment tends to overestimate the bistable effect.Comment: Published in JPSJ; minor typos correcte

The Case for Selection at CCR5-Δ32

The C-C chemokine receptor 5, 32 base-pair deletion (CCR5-Δ32) allele confers strong resistance to infection by the AIDS virus HIV. Previous studies have suggested that CCR5-Δ32 arose within the past 1,000 y and rose to its present high frequency (5%–14%) in Europe as a result of strong positive selection, perhaps by such selective agents as the bubonic plague or smallpox during the Middle Ages. This hypothesis was based on several lines of evidence, including the absence of the allele outside of Europe and long-range linkage disequilibrium at the locus. We reevaluated this evidence with the benefit of much denser genetic maps and extensive control data. We find that the pattern of genetic variation at CCR5-Δ32 does not stand out as exceptional relative to other loci across the genome. Moreover using newer genetic maps, we estimated that the CCR5-Δ32 allele is likely to have arisen more than 5,000 y ago. While such results can not rule out the possibility that some selection may have occurred at C-C chemokine receptor 5 (CCR5), they imply that the pattern of genetic variation seen atCCR5-Δ32 is consistent with neutral evolution. More broadly, the results have general implications for the design of future studies to detect the signs of positive selection in the human genome

Common Variants in 40 Genes Assessed for Diabetes Incidence and Response to Metformin and Lifestyle Intervention in the Diabetes Prevention Program

OBJECTIVE: Genome-wide association studies have begun to elucidate the genetic architecture of type 2 diabetes. We examined whether single nucleotide polymorphisms (SNPs) identified through targeted complementary approaches affect diabetes incidence in the at-risk population of the Diabetes Prevention Program (DPP) and whether they influence a response to preventive interventions. RESEARCH DESIGN AND METHODS: We selected SNPs identified by prior genome-wide association studies for type 2 diabetes and related traits, or capturing common variation in 40 candidate genes previously associated with type 2 diabetes, implicated in monogenic diabetes, encoding type 2 diabetes drug targets or drug-metabolizing/transporting enzymes, or involved in relevant physiological processes. We analyzed 1,590 SNPs for association with incident diabetes and their interaction with response to metformin or lifestyle interventions in 2,994 DPP participants. We controlled for multiple hypothesis testing by assessing false discovery rates. RESULTS: We replicated the association of variants in the metformin transporter gene $SLC47A1$ with metformin response and detected nominal interactions in the AMP kinase (AMPK) gene $STK11$, the AMPK subunit genes $PRKAA1$ and $PRKAA2$, and a missense SNP in $SLC22A1$, which encodes another metformin transporter. The most significant association with diabetes incidence occurred in the AMPK subunit gene $PRKAG2$ (hazard ratio 1.24, 95% CI 1.09–1.40, P = 7 × 10$^{−4}$). Overall, there were nominal associations with diabetes incidence at 85 SNPs and nominal interactions with the metformin and lifestyle interventions at 91 and 69 mostly nonoverlapping SNPs, respectively. The lowest $P$ values were consistent with experiment-wide 33% false discovery rates. CONCLUSIONS: We have identified potential genetic determinants of metformin response. These results merit confirmation in independent samples

Genetic modulation of lipid profiles following lifestyle modification or metformin treatment: The Diabetes Prevention Program

Weight-loss interventions generally improve lipid profiles and reduce cardiovascular disease risk, but effects are variable and may depend on genetic factors. We performed a genetic association analysis of data from 2,993 participants in the Diabetes Prevention Program to test the hypotheses that a genetic risk score (GRS) based on deleterious alleles at 32 lipid-associated single-nucleotide polymorphisms modifies the effects of lifestyle and/or metformin interventions on lipid levels and nuclear magnetic resonance (NMR) lipoprotein subfraction size and number. Twenty-three loci previously associated with fasting LDL-C, HDL-C, or triglycerides replicated (P = 0.04–1×10−17). Except for total HDL particles (r = −0.03, P = 0.26), all components of the lipid profile correlated with the GRS (partial |r| = 0.07–0.17, P = 5×10−5–1×10−19). The GRS was associated with higher baseline-adjusted 1-year LDL cholesterol levels (β = +0.87, SEE±0.22 mg/dl/allele, P = 8×10−5, Pinteraction = 0.02) in the lifestyle intervention group, but not in the placebo (β = +0.20, SEE±0.22 mg/dl/allele, P = 0.35) or metformin (β = −0.03, SEE±0.22 mg/dl/allele, P = 0.90; Pinteraction = 0.64) groups. Similarly, a higher GRS predicted a greater number of baseline-adjusted small LDL particles at 1 year in the lifestyle intervention arm (β = +0.30, SEE±0.012 ln nmol/L/allele, P = 0.01, Pinteraction = 0.01) but not in the placebo (β = −0.002, SEE±0.008 ln nmol/L/allele, P = 0.74) or metformin (β = +0.013, SEE±0.008 nmol/L/allele, P = 0.12; Pinteraction = 0.24) groups. Our findings suggest that a high genetic burden confers an adverse lipid profile and predicts attenuated response in LDL-C levels and small LDL particle number to dietary and physical activity interventions aimed at weight loss