Direct maximum parsimony phylogeny reconstruction from genotype data

<p>Abstract</p> <p>Background</p> <p>Maximum parsimony phylogenetic tree reconstruction from genetic variation data is a fundamental problem in computational genetics with many practical applications in population genetics, whole genome analysis, and the search for genetic predictors of disease. Efficient methods are available for reconstruction of maximum parsimony trees from haplotype data, but such data are difficult to determine directly for autosomal DNA. Data more commonly is available in the form of genotypes, which consist of conflated combinations of pairs of haplotypes from homologous chromosomes. Currently, there are no general algorithms for the direct reconstruction of maximum parsimony phylogenies from genotype data. Hence phylogenetic applications for autosomal data must therefore rely on other methods for first computationally inferring haplotypes from genotypes.</p> <p>Results</p> <p>In this work, we develop the first practical method for computing maximum parsimony phylogenies directly from genotype data. We show that the standard practice of first inferring haplotypes from genotypes and then reconstructing a phylogeny on the haplotypes often substantially overestimates phylogeny size. As an immediate application, our method can be used to determine the minimum number of mutations required to explain a given set of observed genotypes.</p> <p>Conclusion</p> <p>Phylogeny reconstruction directly from unphased data is computationally feasible for moderate-sized problem instances and can lead to substantially more accurate tree size inferences than the standard practice of treating phasing and phylogeny construction as two separate analysis stages. The difference between the approaches is particularly important for downstream applications that require a lower-bound on the number of mutations that the genetic region has undergone.</p

Bayesian Statistical Methods for Genetic Association Studies with Case-Control and Cohort Design

Large-scale genetic association studies are carried out with the hope of discovering single nucleotide polymorphisms involved in the etiology of complex diseases. We propose a coalescent-based model for association mapping which potentially increases the power to detect disease-susceptibility variants in genetic association studies with case-control and cohort design. The approach uses Bayesian partition modelling to cluster haplotypes with similar disease risks by exploiting evolutionary information. We focus on candidate gene regions and we split the chromosomal region of interest into sub-regions or windows of high linkage disequilibrium (LD) therein assuming a perfect phylogeny. The haplotype space is then partitioned into disjoint clusters within which the phenotype-haplotype association is assumed to be the same. The novelty of our approach consists in the fact that the distance used for clustering haplotypes has an evolutionary interpretation, as haplotypes are clustered according to the time to their most recent common mutation. Our approach is fully Bayesian and we develop Markov Chain Monte Carlo algorithms to sample efficiently over the space of possible partitions. We have also developed a Bayesian survival regression model for high-dimension and small sample size settings. We provide a Bayesian variable selection procedure and shrinkage tool by imposing shrinkage priors on the regression coefficients. We have developed a computationally efficient optimization algorithm to explore the posterior surface and find the maximum a posteriori estimates of the regression coefficients. We compare the performance of the proposed methods in simulation studies and using real datasets to both single-marker analyses and recently proposed multi-marker methods and show that our methods perform similarly in localizing the causal allele while yielding lower false positive rates. Moreover, our methods offer computational advantages over other multi-marker approaches

Sequence clustering for genetic mapping of binary traits

Sequence relatedness has potential application to fine-mapping genetic variants contributing to inherited traits. We investigate the utility of genealogical tree-based approaches to fine-map causal variants in three different projects. In the first project, through coalescent simulation, we compare the ability of several popular methods of association mapping to localize causal variants in a sub-region of a candidate genomic region. We consider four broad classes of association methods, which we describe as single-variant, pooled-variant, joint-modelling and tree-based, under an additive genetic-risk model. We also investigate whether differentiating case sequences based on their carrier status for a causal variant can improve fine-mapping. Our results lend support to the potential of tree-based methods for genetic fine-mapping of disease. In the second project, we develop an R package to dynamically cluster a set of single-nucleotide variant sequences. The resulting partition structures provide important insight into the sequence relatedness. In the third project, we investigate the ability of methods based on sequence relatedness to fine-map rare causal variants and compare it to genotypic association methods. Since the true gene genealogy is unknown in reality, we apply the methods developed in the second project to estimate the sequence relatedness. We also pursue the idea of reclassifying case sequences into their carrier status using the idea of genealogical nearest neighbours. We find that method based on sequence relatedness is competitive for fine-mapping rare causal variants. We propose some general recommendations for fine-mapping rare variants in case-control association studies

ISHAPE: new rapid and accurate software for haplotyping

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