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Most genetic association studies focus on common variants, but rare genetic variants can play major roles in influencing complex traits.\cite{Pritchard_2001,Schork_2009}. The rare susceptibility variants identified through sequencing have potential to explain some of the ’missing heritability’ of complex traits \cite{Eichler_2010}. However, standard methods to test for association with single genetic variants are underpowered for rare variants unless sample sizes are very large \cite{Lee_2014}. The lack of power of single-variant approaches holds in fine-mapping as well as genome-wide association studies. #
In this report, we are concerned with fine-mapping a genomic region that has been sequenced in cases and controls to identify disease-risk loci. A number of methods have been developed to evaluate the disease association for both single-variant and multiple-variants in a genomic region. Besides single-variant methods, we consider three broad classes of methods for analysing sequence data: pooled-variant, joint-modelling and tree-based methods. Pooled-variant methods evaluate the cumulative effects of multiple genetic variants in a genomic region. The score statistics from marginal models of the trait association with individual variants are collapsed into a single test statistic, either by combining the information for multiple variants into a single genetic score or by evaluating the distribution of the pooled score statistics of individual variants \cite{Lee_2014}. Joint-modeling methods identify the joint effect of multiple genetic variants simultaneously. These methods can assess whether a variant carries any further information about the trait beyond what is explained by the other variants. When trait-influencing variants are in low linkage disequilibrium, this approach may be more powerful than pooling test statistics for marginal associations across variants \cite{Cho_2010}. A local genealogical tree represents the ancestry of the sample of haplotypes at each locus in the genomic region being fine-mapped. Haplotypes carrying the same disease risk alleles are expected to be related and cluster on the genealogical tree at a disease risk locus. Tree-based methods assess whether trait values co-cluster with the ancestral tree for the haplotypes (e.g., \citeNP{Bardel_2005}). \citeNP{Mailund_2006} has developed a method to reconstruct and score genealogies according to the case-control clusters.
In practice true trees are unknown. However, cluster statistics based on true trees represent a best case for detecting association as tree uncertainty is eliminated. Burkett et al. use known trees to assess the effectiveness of such a tree-based approach for detection of rare, disease-risk variants in a candidate genomic region under various models of disease risk in a haploid population. They found that Mantel statistics computed on the known trees outperform popular methods for detecting rare variants associated with disease. Following Burkett et al., we use clustering tests based on true trees as benchmarks against which to compare the popular association methods. However, unlike Burkett et al., who focus on detection of disease risk variants, we here focus on localization of association signal in the candidate genomic region. Moreover, we use a diploid disease model instead of a haploid disease model.
In this article, we compare the performance of selected rare-variant association methods for fine-mapping a disease locus. Our investigation focus on the localization of association signal to between 950kbp − 1050kbp within a 2Mb candidate genomic region. To motivate our study, we use variant data simulated from coalescent trees. Our work on localization of association signal extends that of Burkett et al., which investigated the ability to detect association signal in the candidate region, without regard to localization. To illustrate ideas, we start by working through a particular example dataset as a case study for insight into selected association methods. we next perform a simulation study involving 200 sequencing datasets and score which association method localizes best, overall. Our results indicate that the potential of ancestral tree-based approach for localizing the association signal.
Renewable And Sustainable Energy Reviews Template
Non Baryonic Dark Matter with a Concentration on Cold Dark Matter from Supersymmetry
Ever since astronomers have been studying galaxies and their mass/luminosity relationship, there is clearly something wrong. There is a missing luminosity problem - there is a lot of non-luminous (about 90%) matter in a galaxy. Possible dark matter candidates come from cold dark matter, warm dark matter, hot dark matter, and axions. After years of research, astronomers and physicists can rule out warm and hot dark matter, but cold dark matter and axions are both extremely probable candidates of dark matter. In this report, I will explain about all the different candidates of dark matter and their implications.
edx Phot1x report template (2016/11)
This is the final report for the Mach-Zehnder interferometer device with both simulated results and experimental results. The pdf of this report can be found at https://upload.siepic.ubc.ca/uploads/EBeam_JamesClay.pdf
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C-terminus:helix region interactions
N-terminus:helix region interactions
strong interactions of residues within the 15-24 region that stabilize the helix
interactions between residues 40-35, 33-27, and 3-9
lactam bridge between Asp23 and a Lys residue that we substituted for Val40
covalent linkage prevents interaction of the C-terminus with the core helix
predicted to preclude formation of the stable dimer state formed through concerted collapse of two monomers and produce distinct assembly behavior
\label{fig:peptide_association_scheme_v9.pdf}
displayed no dimer band, but an intense monomer band
a band migrating below monomer
suggesting that structure 3 is capable of forming two conformers in SDS-PAGE, one with an Mr consistent with wild type Aβ40 and one with a smaller Mr of ≈3500.
\label{fig:sdspage}
structure 3 spectrum contained a large -7/2 dimer (formed from -4 and -3 monomers) peak
suggesting that self association of structure 3 produces a dimer structure unique from that formed by wild type Aβ40
“collision cross section” (σ) value for structure 3 was larger than that of wild type Aβ40 (620 vs 607 Å2)
supporting the explanation that structure 3 forms a unique conformer
\label{fig:Spectral_Overlay}
an immediate monotonic increase in fluorescence that plateaued at 12 days at a level that was ≈1/2 that of Aβ40
appears to self-associate without a substantial lag phase (<<1 days)
appears to produce aggregates that display substantially less β-sheet than do wild type assemblies
\label{fig:LMM-tht}
far fewer fibrils
a number of structures not seen with WT Aβ40, including short worm-like structures, longer worm-like structures, and fibrils with prominent helical twists
multifilar rod-like structures
some of the rod-like structures had “sausage-link” morphologies with the links occurring at intervals of ≈270 nm
\label{fig:em}