Manycore Algorithms for Genetic Linkage Analysis

Exact algorithms to perform linkage analysis scale exponentially with the size of the input. Beyond a critical point, the amount of work that needs to be done exceeds both available time and memory. In these circumstances, we are forced to either abbreviate the input in some manner or else use an approximation. Approximate methods, like Markov chain Monte Carlo (MCMC), though they make the problem tractable, can take an immense amount of time to converge. The problem of high convergence time is compounded by software which is single-threaded and, as computer processors are manufactured with increasing numbers of physical processing cores, are not designed to take advantage of the available processing power. In this thesis, we will describe our program SwiftLink that embodies our work adapting existing Gibbs samplers to modern computer processor architectures. The processor architectures we target are: multicore processors, that currently feature between 4–8 processor cores, and computer graphics cards (GPUs) that already feature hundreds of processor cores. We implemented parallel versions of the meiosis sampler, that mixes well with tightly linked markers but suffers from irreducibility issues, and the locus sampler which is guaranteed to be irreducible but mixes slowly with tightly linked markers. We evaluate SwiftLink’s performance on real-world datasets of large consanguineous families. We demonstrate that using four processor cores for a single analysis is 3–3.2x faster than the single-threaded implementation of SwiftLink. With respect to the existing MCMC-based programs: it achieves a 6.6–8.7x speedup compared to Morgan and a 66.4– 72.3x speedup compared to Simwalk. Utilising both a multicore processor and a GPU performs 7–7.9x faster than the single-threaded implementation, a 17.6–19x speedup compared to Morgan and a 145.5–192.3x speedup compared to Simwalk

Mutations in the autoregulatory domain of β-tubulin 4a cause hereditary dystonia.

Dystonia type 4 (DYT4) was first described in a large family from Heacham in Norfolk with an autosomal dominantly inherited whispering dysphonia, generalized dystonia, and a characteristic hobby horse ataxic gait. We carried out a genetic linkage analysis in the extended DYT4 family that spanned 7 generations from England and Australia, revealing a single LOD score peak of 6.33 on chromosome 19p13.12-13. Exome sequencing in 2 cousins identified a single cosegregating mutation (p.R2G) in the β-tubulin 4a (TUBB4a) gene that was absent in a large number of controls. The mutation is highly conserved in the β-tubulin autoregulatory MREI (methionine-arginine-glutamic acid-isoleucine) domain, highly expressed in the central nervous system, and extensive in vitro work has previously demonstrated that substitutions at residue 2, specifically R2G, disrupt the autoregulatory capability of the wild-type β-tubulin peptide, affirming the role of the cytoskeleton in dystonia pathogenesis

Autoinflammatory periodic fever, immunodeficiency, and thrombocytopenia (PFIT) caused by mutation in actinregulatory gene WDR1

The importance of actin dynamics in the activation of the inflammasome is becoming increasingly apparent. IL-1β, which is activated by the inflammasome, is known to be central to the pathogenesis of many monogenic autoinflammatory diseases. However, evidence from an autoinflammatory murine model indicates that IL-18, the other cytokine triggered by inflammasome activity, is important in its own right. In this model, autoinflammation was caused by mutation in the actin regulatory gene WDR1 We report a homozygous missense mutation in WDR1 in two siblings causing periodic fevers with immunodeficiency and thrombocytopenia. We found impaired actin dynamics in patient immune cells. Patients had high serum levels of IL-18, without a corresponding increase in IL-18-binding protein or IL-1β, and their cells also secreted more IL-18 but not IL-1β in culture. We found increased caspase-1 cleavage within patient monocytes indicative of increased inflammasome activity. We transfected HEK293T cells with pyrin and wild-type and mutated WDR1 Mutant protein formed aggregates that appeared to accumulate pyrin; this could potentially precipitate inflammasome assembly. We have extended the findings from the mouse model to highlight the importance of WDR1 and actin regulation in the activation of the inflammasome, and in human autoinflammation

Graph Based Automatic Protein Function Annotation Improved by Semantic Similarity

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