BigFoot: Bayesian Alignment and Phylogenetic Footprinting with MCMC BMC

Background: We have previously combined statistical alignment and phylogenetic footprinting to detect conserved functional elements without assuming a fixed alignment. Considering a probability-weighted distribution of alignments removes sensitivity to alignment errors, properly accommodates regions of alignment uncertainty, and increases the accuracy of functional element prediction. Our method utilized standard dynamic programming hidden markov model algorithms to analyze up to four sequences. Results: We present a novel approach, implemented in the software package BigFoot, for performing phylogenetic footprinting on greater numbers of sequences. We have developed a Markov chain Monte Carlo (MCMC) approach which samples both sequence alignments and locations of slowly evolving regions. We implement our method as an extension of the existing StatAlign software package and test it on well-annotated regions controlling the expression of the even-skipped gene in Drosophila and the α-globin gene in vertebrates. The results exhibit how adding additional sequences to the analysis has the potential to improve the accuracy of functional predictions, and demonstrate how BigFoot outperforms existing alignment-based phylogenetic footprinting techniques. Conclusion: BigFoot extends a combined alignment and phylogenetic footprinting approach to analyze larger amounts of sequence data using MCMC. Our approach is robust to alignment error and uncertainty and can be applied to a variety of biological datasets. The source code and documentation are publicly available for download from http://www.stats.ox.ac.uk/~satija/BigFoot/ </p

Stochastic models of sequence evolution including insertion-deletion events

Comparison of sequences that have descended from a common ancestor based on an explicit stochastic model of substitutions, insertions and deletions has risen to prominence in the last decade. Making statements about the positions of insertions-deletions (abbr. indels) is central in sequence and genome analysis and is called alignment. This statistical approach is harder conceptually and computationally, than competing approaches based on choosing an alignment according to some optimality criteria. But it has major practical advantages in terms of testing evolutionary hypotheses and parameter estimation. Basic dynamic approaches can allow the analysis of up to 4-5 sequences. MCMC techniques can bring this to about 10-15 sequences. Beyond this, different or heuristic approaches must be used. Besides the computational challenges, increasing realism in the underlying models is presently being addressed. A recent development that has been especially fruitful is combining statistical alignment with the problem of sequence annotation, making statements about the function of each nucleotide/amino acid. So far gene finding, protein secondary structure prediction and regulatory signal detection has been tackled within this framework. Much progress can be reported, but clearly major challenges remain if this approach is to be central in the analyses of large incoming sequence data sets

Multiple reference genomes and transcriptomes for Arabidopsis thaliana

Citation: Gan, X., Stegle, O., Behr, J., . . . Mott, R. (2011). Multiple reference genomes and transcriptomes for Arabidopsis thaliana. Nature, 477, 419–423. https://doi.org/10.1038/nature10414Genetic differences between Arabidopsis thaliana accessions underlie the plant’s extensive phenotypic variation, and until now these have been interpreted largely in the context of the annotated reference accession Col-0. Here we report the sequencing, assembly and annotation of the genomes of 18 natural A. thaliana accessions, and their transcriptomes. When assessed on the basis of the reference annotation, one-third of protein-coding genes are predicted to be disrupted in at least one accession. However, re-annotation of each genome revealed that alternative gene models often restore coding potential. Gene expression in seedlings differed for nearly half of expressed genes and was frequently associated with cis variants within 5 kilobases, as were intron retention alternative splicing events. Sequence and expression variation is most pronounced in genes that respond to the biotic environment. Our data further promote evolutionary and functional studies in A. thaliana, especially the MAGIC genetic reference population descended from these accessions