517 research outputs found
Learning mutational graphs of individual tumour evolution from single-cell and multi-region sequencing data
Background. A large number of algorithms is being developed to reconstruct
evolutionary models of individual tumours from genome sequencing data. Most
methods can analyze multiple samples collected either through bulk multi-region
sequencing experiments or the sequencing of individual cancer cells. However,
rarely the same method can support both data types.
Results. We introduce TRaIT, a computational framework to infer mutational
graphs that model the accumulation of multiple types of somatic alterations
driving tumour evolution. Compared to other tools, TRaIT supports multi-region
and single-cell sequencing data within the same statistical framework, and
delivers expressive models that capture many complex evolutionary phenomena.
TRaIT improves accuracy, robustness to data-specific errors and computational
complexity compared to competing methods.
Conclusions. We show that the application of TRaIT to single-cell and
multi-region cancer datasets can produce accurate and reliable models of
single-tumour evolution, quantify the extent of intra-tumour heterogeneity and
generate new testable experimental hypotheses
Vestige: Maximum likelihood phylogenetic footprinting
BACKGROUND: Phylogenetic footprinting is the identification of functional regions of DNA by their evolutionary conservation. This is achieved by comparing orthologous regions from multiple species and identifying the DNA regions that have diverged less than neutral DNA. Vestige is a phylogenetic footprinting package built on the PyEvolve toolkit that uses probabilistic molecular evolutionary modelling to represent aspects of sequence evolution, including the conventional divergence measure employed by other footprinting approaches. In addition to measuring the divergence, Vestige allows the expansion of the definition of a phylogenetic footprint to include variation in the distribution of any molecular evolutionary processes. This is achieved by displaying the distribution of model parameters that represent partitions of molecular evolutionary substitutions. Examination of the spatial incidence of these effects across regions of the genome can identify DNA segments that differ in the nature of the evolutionary process. RESULTS: Vestige was applied to a reference dataset of the SCL locus from four species and provided clear identification of the known conserved regions in this dataset. To demonstrate the flexibility to use diverse models of molecular evolution and dissect the nature of the evolutionary process Vestige was used to footprint the Ka/Ks ratio in primate BRCA1 with a codon model of evolution. Two regions of putative adaptive evolution were identified illustrating the ability of Vestige to represent the spatial distribution of distinct molecular evolutionary processes. CONCLUSION: Vestige provides a flexible, open platform for phylogenetic footprinting. Underpinned by the PyEvolve toolkit, Vestige provides a framework for visualising the signatures of evolutionary processes across the genome of numerous organisms simultaneously. By exploiting the maximum-likelihood statistical framework, the complex interplay between mutational processes, DNA repair and selection can be evaluated both spatially (along a sequence alignment) and temporally (for each branch of the tree) providing visual indicators to the attributes and functions of DNA sequences
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Statistical Inference under the Multispecies Coalescent: Methods and Theory
The rising availability of genome-scale data for a large number of species has allowed for more in-depth studies of the genetics between species using increasingly sophisticated methods. The accumulation of pairwise differences between individuals are indicative of how diverged they are in time. The multi-species coalescent (MSC) has been the most popular framework with which to model the dynamics of the coalescent process in the presence of species barriers, such as a tree structure. Modelling using the MSC in the presence of increasing amounts of data (loci and species) while maintaining feasible computational times is the main focus of many emerging methods.In this dissertation, I explore the use of the MSC in 3 different ways, using classical and novel statistical analysis to provide insight into species divergence parameters. I begin by constructing a novel statistical method for inferring species tree divergence times and population size parameters for any given tree topology from sequence data. The program COAL-PHYRE, presented here, makes use of the MSC marginally between individuals, as I demonstrate that pairwise information within the MSC is sufficient to learn times and population sizes on a tree. My focus then shifts to the derivation of the covariance between pairs of coalescence times and its application to studying average pairwise differences and the commonly used statistic, Fst. I confirm that estimates of Fst are biased, and quantify the effect of not accounting for this bias in different applications. I conclude by continuing to study the covariance between coalescence times and its use in inferring species tree topologies. I define a metric based on these statistics which, when paired with the minimum spanning tree algorithm, provides estimates of species tree topologies. I provide partial proofs of statistical consistency of the approach
Evolutionary genomics : statistical and computational methods
This open access book addresses the challenge of analyzing and understanding the evolutionary dynamics of complex biological systems at the genomic level, and elaborates on some promising strategies that would bring us closer to uncovering of the vital relationships between genotype and phenotype. After a few educational primers, the book continues with sections on sequence homology and alignment, phylogenetic methods to study genome evolution, methodologies for evaluating selective pressures on genomic sequences as well as genomic evolution in light of protein domain architecture and transposable elements, population genomics and other omics, and discussions of current bottlenecks in handling and analyzing genomic data. Written for the highly successful Methods in Molecular Biology series, chapters include the kind of detail and expert implementation advice that lead to the best results. Authoritative and comprehensive, Evolutionary Genomics: Statistical and Computational Methods, Second Edition aims to serve both novices in biology with strong statistics and computational skills, and molecular biologists with a good grasp of standard mathematical concepts, in moving this important field of study forward
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