An HMM-based Comparative Genomic Framework for Detecting Introgression in Eukaryotes

One outcome of interspecific hybridization and subsequent effects of evolutionary forces is introgression, which is the integration of genetic material from one species into the genome of an individual in another species. The evolution of several groups of eukaryotic species has involved hybridization, and cases of adaptation through introgression have been already established. In this work, we report on a new comparative genomic framework for detecting introgression in genomes, called PhyloNet-HMM, which combines phylogenetic networks, that capture reticulate evolutionary relationships among genomes, with hidden Markov models (HMMs), that capture dependencies within genomes. A novel aspect of our work is that it also accounts for incomplete lineage sorting and dependence across loci. Application of our model to variation data from chromosome 7 in the mouse (Mus musculus domesticus) genome detects a recently reported adaptive introgression event involving the rodent poison resistance gene Vkorc1, in addition to other newly detected introgression regions. Based on our analysis, it is estimated that about 12% of all sites withinchromosome 7 are of introgressive origin (these cover about 18 Mbp of chromosome 7, and over 300 genes). Further, our model detects no introgression in two negative control data sets. Our work provides a powerful framework for systematic analysis of introgression while simultaneously accounting for dependence across sites, point mutations, recombination, and ancestral polymorphism

Integration of Alignment and Phylogeny in the Whole-Genome Era

With the development of new sequencing techniques, whole genomes of many species have become available. This huge amount of data gives rise to new opportunities and challenges. These new sequences provide valuable information on relationships among species, e.g. genome recombination and conservation. One of the principal ways to investigate such information is multiple sequence alignment (MSA). Currently, there is large amount of MSA data on the internet, such as the UCSC genome database, but how to effectively use this information to solve classical and new problems is still an area lacking of exploration. In this thesis, we explored how to use this information in four problems, i.e. sequence orthology search problem, multiple alignment improvement problem, short read mapping problem, and genome rearrangement inference problem. For the first problem, we developed a EM algorithm to iteratively align a query with a multiple alignment database with the information from a phylogeny relating the query species and the species in the multiple alignment. We also infer the query\u27s location in the phylogeny. We showed that by doing alignment and phylogeny inference together, we can improve the accuracies for both problems. For the second problem, we developed an optimization algorithm to iteratively refine the multiple alignment quality. Experiment results showed our algorithm is very stable in term of resulting alignments. The results showed that our method is more accurate than existing methods, i.e. Mafft, Clustal-O, and Mavid, on test data from three sets of species from the UCSC genome database. For the third problem, we developed a model, PhyMap, to align a read to a multiple alignment allowing mismatches and indels. PhyMap computes local alignments of a query sequence against a fixed multiple-genome alignment of closely related species. PhyMap uses a known phylogenetic tree on the species in the multiple alignment to improve the quality of its computed alignments while also estimating the placement of the query on this tree. Both theoretical computation and experiment results show that our model can differentiate between orthologous and paralogous alignments better than other popular short read mapping tools (BWA, BOWTIE and BLAST). For the fourth problem, we gave a simple genome recombination model which can express insertions, deletions, inversions, translocations and inverted translocations on aligned genome segments. We also developed an MCMC algorithm to infer the order of the query segments. We proved that using any Euclidian metrics to measure distance between two sequence orders in the tree optimization goal function will lead to a degenerated solution where the inferred order will be the order of one of the leaf nodes. We also gave a graph-based formulation of the problem which can represent the probability distribution of the order of the query sequences

Methods for Assessing Population Relationships and History Using Genomic Data

Genetic data contain a record of our evolutionary history. The availability of large-scale datasets of human populations from various geographic areas and timescales, coupled with advances in the computational methods to analyze these data, has transformed our ability to use genetic data to learn about our evolutionary past. Here, we review some of the widely used statistical methods to explore and characterize population relationships and history using genomic data. We describe the intuition behind commonly used approaches, their interpretation, and important limitations. For illustration, we apply some of these techniques to genome-wide autosomal data from 929 individuals representing 53 worldwide populations that are part of the Human Genome Diversity Project. Finally, we discuss the new frontiers in genomic methods to learn about population history. In sum, this review highlights the power (and limitations) of DNA to infer features of human evolutionary history, complementing the knowledge gleaned from other disciplines, such as archaeology, anthropology, and linguistics

Genome-wide inference of ancestral recombination graphs

The complex correlation structure of a collection of orthologous DNA sequences is uniquely captured by the "ancestral recombination graph" (ARG), a complete record of coalescence and recombination events in the history of the sample. However, existing methods for ARG inference are computationally intensive, highly approximate, or limited to small numbers of sequences, and, as a consequence, explicit ARG inference is rarely used in applied population genomics. Here, we introduce a new algorithm for ARG inference that is efficient enough to apply to dozens of complete mammalian genomes. The key idea of our approach is to sample an ARG of n chromosomes conditional on an ARG of n-1 chromosomes, an operation we call "threading." Using techniques based on hidden Markov models, we can perform this threading operation exactly, up to the assumptions of the sequentially Markov coalescent and a discretization of time. An extension allows for threading of subtrees instead of individual sequences. Repeated application of these threading operations results in highly efficient Markov chain Monte Carlo samplers for ARGs. We have implemented these methods in a computer program called ARGweaver. Experiments with simulated data indicate that ARGweaver converges rapidly to the true posterior distribution and is effective in recovering various features of the ARG for dozens of sequences generated under realistic parameters for human populations. In applications of ARGweaver to 54 human genome sequences from Complete Genomics, we find clear signatures of natural selection, including regions of unusually ancient ancestry associated with balancing selection and reductions in allele age in sites under directional selection. Preliminary results also indicate that our methods can be used to gain insight into complex features of human population structure, even with a noninformative prior distribution.Comment: 88 pages, 7 main figures, 22 supplementary figures. This version contains a substantially expanded genomic data analysi

Demographic inference from multiple whole genomes using a particle filter for continuous Markov jump processes

Demographic events shape a population's genetic diversity, a process described by the coalescent-with-recombination model that relates demography and genetics by an unobserved sequence of genealogies along the genome. As the space of genealogies over genomes is large and complex, inference under this model is challenging. Formulating the coalescent-with-recombination model as a continuous-time and -space Markov jump process, we develop a particle filter for such processes, and use waypoints that under appropriate conditions allow the problem to be reduced to the discrete-time case. To improve inference, we generalise the Auxiliary Particle Filter for discrete-time models, and use Variational Bayes to model the uncertainty in parameter estimates for rare events, avoiding biases seen with Expectation Maximization. Using real and simulated genomes, we show that past population sizes can be accurately inferred over a larger range of epochs than was previously possible, opening the possibility of jointly analyzing multiple genomes under complex demographic models. Code is available at https://github.com/luntergroup/smcsmc.

The era of the ARG: an empiricist's guide to ancestral recombination graphs

In the presence of recombination, the evolutionary relationships between a set of sampled genomes cannot be described by a single genealogical tree. Instead, the genomes are related by a complex, interwoven collection of genealogies formalized in a structure called an ancestral recombination graph (ARG). An ARG extensively encodes the ancestry of the genome(s) and thus is replete with valuable information for addressing diverse questions in evolutionary biology. Despite its potential utility, technological and methodological limitations, along with a lack of approachable literature, have severely restricted awareness and application of ARGs in empirical evolution research. Excitingly, recent progress in ARG reconstruction and simulation have made ARG-based approaches feasible for many questions and systems. In this review, we provide an accessible introduction and exploration of ARGs, survey recent methodological breakthroughs, and describe the potential for ARGs to further existing goals and open avenues of inquiry that were previously inaccessible in evolutionary genomics. Through this discussion, we aim to more widely disseminate the promise of ARGs in evolutionary genomics and encourage the broader development and adoption of ARG-based inference.Comment: 34 pages, 3 figures, 3 table

Decoding coalescent hidden Markov models in linear time

In many areas of computational biology, hidden Markov models (HMMs) have been used to model local genomic features. In particular, coalescent HMMs have been used to infer ancient population sizes, migration rates, divergence times, and other parameters such as mutation and recombination rates. As more loci, sequences, and hidden states are added to the model, however, the runtime of coalescent HMMs can quickly become prohibitive. Here we present a new algorithm for reducing the runtime of coalescent HMMs from quadratic in the number of hidden time states to linear, without making any additional approximations. Our algorithm can be incorporated into various coalescent HMMs, including the popular method PSMC for inferring variable effective population sizes. Here we implement this algorithm to speed up our demographic inference method diCal, which is equivalent to PSMC when applied to a sample of two haplotypes. We demonstrate that the linear-time method can reconstruct a population size change history more accurately than the quadratic-time method, given similar computation resources. We also apply the method to data from the 1000 Genomes project, inferring a high-resolution history of size changes in the European population.Comment: 18 pages, 5 figures. To appear in the Proceedings of the 18th Annual International Conference on Research in Computational Molecular Biology (RECOMB 2014). The final publication is available at link.springer.co