1,118 research outputs found
Hidden breakpoints in genome alignments
During the course of evolution, an organism's genome can undergo changes that
affect the large-scale structure of the genome. These changes include gene
gain, loss, duplication, chromosome fusion, fission, and rearrangement. When
gene gain and loss occurs in addition to other types of rearrangement,
breakpoints of rearrangement can exist that are only detectable by comparison
of three or more genomes. An arbitrarily large number of these "hidden"
breakpoints can exist among genomes that exhibit no rearrangements in pairwise
comparisons.
We present an extension of the multichromosomal breakpoint median problem to
genomes that have undergone gene gain and loss. We then demonstrate that the
median distance among three genomes can be used to calculate a lower bound on
the number of hidden breakpoints present. We provide an implementation of this
calculation including the median distance, along with some practical
improvements on the time complexity of the underlying algorithm.
We apply our approach to measure the abundance of hidden breakpoints in
simulated data sets under a wide range of evolutionary scenarios. We
demonstrate that in simulations the hidden breakpoint counts depend strongly on
relative rates of inversion and gene gain/loss. Finally we apply current
multiple genome aligners to the simulated genomes, and show that all aligners
introduce a high degree of error in hidden breakpoint counts, and that this
error grows with evolutionary distance in the simulation. Our results suggest
that hidden breakpoint error may be pervasive in genome alignments.Comment: 13 pages, 4 figure
On pairwise distances and median score of three genomes under DCJ
In comparative genomics, the rearrangement distance between two genomes
(equal the minimal number of genome rearrangements required to transform them
into a single genome) is often used for measuring their evolutionary
remoteness. Generalization of this measure to three genomes is known as the
median score (while a resulting genome is called median genome). In contrast to
the rearrangement distance between two genomes which can be computed in linear
time, computing the median score for three genomes is NP-hard. This inspires a
quest for simpler and faster approximations for the median score, the most
natural of which appears to be the halved sum of pairwise distances which in
fact represents a lower bound for the median score.
In this work, we study relationship and interplay of pairwise distances
between three genomes and their median score under the model of
Double-Cut-and-Join (DCJ) rearrangements. Most remarkably we show that while a
rearrangement may change the sum of pairwise distances by at most 2 (and thus
change the lower bound by at most 1), even the most "powerful" rearrangements
in this respect that increase the lower bound by 1 (by moving one genome
farther away from each of the other two genomes), which we call strong, do not
necessarily affect the median score. This observation implies that the two
measures are not as well-correlated as one's intuition may suggest.
We further prove that the median score attains the lower bound exactly on the
triples of genomes that can be obtained from a single genome with strong
rearrangements. While the sum of pairwise distances with the factor 2/3
represents an upper bound for the median score, its tightness remains unclear.
Nonetheless, we show that the difference of the median score and its lower
bound is not bounded by a constant.Comment: Proceedings of the 10-th Annual RECOMB Satellite Workshop on
Comparative Genomics (RECOMB-CG), 2012. (to appear
Progressive Mauve: Multiple alignment of genomes with gene flux and rearrangement
Multiple genome alignment remains a challenging problem. Effects of
recombination including rearrangement, segmental duplication, gain, and loss
can create a mosaic pattern of homology even among closely related organisms.
We describe a method to align two or more genomes that have undergone
large-scale recombination, particularly genomes that have undergone substantial
amounts of gene gain and loss (gene flux). The method utilizes a novel
alignment objective score, referred to as a sum-of-pairs breakpoint score. We
also apply a probabilistic alignment filtering method to remove erroneous
alignments of unrelated sequences, which are commonly observed in other genome
alignment methods. We describe new metrics for quantifying genome alignment
accuracy which measure the quality of rearrangement breakpoint predictions and
indel predictions. The progressive genome alignment algorithm demonstrates
markedly improved accuracy over previous approaches in situations where genomes
have undergone realistic amounts of genome rearrangement, gene gain, loss, and
duplication. We apply the progressive genome alignment algorithm to a set of 23
completely sequenced genomes from the genera Escherichia, Shigella, and
Salmonella. The 23 enterobacteria have an estimated 2.46Mbp of genomic content
conserved among all taxa and total unique content of 15.2Mbp. We document
substantial population-level variability among these organisms driven by
homologous recombination, gene gain, and gene loss. Free, open-source software
implementing the described genome alignment approach is available from
http://gel.ahabs.wisc.edu/mauve .Comment: Revision dated June 19, 200
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
Principles of genome evolution in the Drosophila melanogaster species group.
That closely related species often differ by chromosomal inversions was discovered by Sturtevant and Plunkett in 1926. Our knowledge of how these inversions originate is still very limited, although a prevailing view is that they are facilitated by ectopic recombination events between inverted repetitive sequences. The availability of genome sequences of related species now allows us to study in detail the mechanisms that generate interspecific inversions. We have analyzed the breakpoint regions of the 29 inversions that differentiate the chromosomes of Drosophila melanogaster and two closely related species, D. simulans and D. yakuba, and reconstructed the molecular events that underlie their origin. Experimental and computational analysis revealed that the breakpoint regions of 59% of the inversions (17/29) are associated with inverted duplications of genes or other nonrepetitive sequences. In only two cases do we find evidence for inverted repetitive sequences in inversion breakpoints. We propose that the presence of inverted duplications associated with inversion breakpoint regions is the result of staggered breaks, either isochromatid or chromatid, and that this, rather than ectopic exchange between inverted repetitive sequences, is the prevalent mechanism for the generation of inversions in the melanogaster species group. Outgroup analysis also revealed evidence for widespread breakpoint recycling. Lastly, we have found that expression domains in D. melanogaster may be disrupted in D. yakuba, bringing into question their potential adaptive significance
Maximum likelihood estimates of pairwise rearrangement distances
Accurate estimation of evolutionary distances between taxa is important for
many phylogenetic reconstruction methods. In the case of bacteria, distances
can be estimated using a range of different evolutionary models, from single
nucleotide polymorphisms to large-scale genome rearrangements. In the case of
sequence evolution models (such as the Jukes-Cantor model and associated
metric) have been used to correct pairwise distances. Similar correction
methods for genome rearrangement processes are required to improve inference.
Current attempts at correction fall into 3 categories: Empirical computational
studies, Bayesian/MCMC approaches, and combinatorial approaches. Here we
introduce a maximum likelihood estimator for the inversion distance between a
pair of genomes, using the group-theoretic approach to modelling inversions
introduced recently. This MLE functions as a corrected distance: in particular,
we show that because of the way sequences of inversions interact with each
other, it is quite possible for minimal distance and MLE distance to
differently order the distances of two genomes from a third. This has obvious
implications for the use of minimal distance in phylogeny reconstruction. The
work also tackles the above problem allowing free rotation of the genome.
Generally a frame of reference is locked, and all computation made accordingly.
This work incorporates the action of the dihedral group so that distance
estimates are free from any a priori frame of reference.Comment: 21 pages, 7 figures. To appear in the Journal of Theoretical Biolog
Limited Lifespan of Fragile Regions in Mammalian Evolution
An important question in genome evolution is whether there exist fragile
regions (rearrangement hotspots) where chromosomal rearrangements are happening
over and over again. Although nearly all recent studies supported the existence
of fragile regions in mammalian genomes, the most comprehensive phylogenomic
study of mammals (Ma et al. (2006) Genome Research 16, 1557-1565) raised some
doubts about their existence. We demonstrate that fragile regions are subject
to a "birth and death" process, implying that fragility has limited
evolutionary lifespan. This finding implies that fragile regions migrate to
different locations in different mammals, explaining why there exist only a few
chromosomal breakpoints shared between different lineages. The birth and death
of fragile regions phenomenon reinforces the hypothesis that rearrangements are
promoted by matching segmental duplications and suggests putative locations of
the currently active fragile regions in the human genome
FPGA Acceleration of Gene Rearrangement Analysis
In this paper we present our work toward FPGA acceleration of phylogenetic reconstruction, a type of analysis that is commonly performed in the fields of systematic biology and comparative genomics. In our initial study, we have targeted a specific application that reconstructs maximum-parsimony (MP) phylogenies for gene-rearrangement data. Like other prevalent applications in computational biology, this application relies on a control-dependent, memory-intensive, and non-arithmetic combinatorial optimization algorithm. To achieve hardware acceleration, we developed an FPGA core design that implements the application\u27s primary bottleneck computation. Because our core is lightweight, we are able to synthesize multiple cores on a single FPGA. By using several cores in parallel, we have achieved a 25X end-to-end application speedup using simulated input data
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