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

A genome-wide survey of segmental duplications that mediate common human genetic variation of chromosomal architecture.

Recent studies have identified a small number of genomic rearrangements that occur frequently in the general population. Bioinformatics tools are now available for systematic genome-wide surveys of higher-order structures predisposing to such common variations in genomic architecture. Segmental duplications (SDs) constitute up to 5 per cent of the genome and play an important role in generating additional rearrangements and in disease aetiology. We conducted a genome-wide database search for a form of SD, palindromic segmental duplications (PSDs), which consist of paired, inverted duplications, and which predispose to inversions, duplications and deletions. The survey was complemented by a search for SDs in tandem orientation (TSDs) that can mediate duplications and deletions but not inversions. We found more than 230 distinct loci with higher-order genomic structure that can mediate genomic variation, of these about 180 contained a PSD. A number of these sites were previously identified as harbouring common inversions or as being associated with specific genomic diseases characterised by duplication, deletions or inversions. Most of the regions, however, were previously unidentified; their characterisation should identify further common rearrangements and may indicate localisations for additional genomic disorders. The widespread distribution of complex chromosomal architecture suggests a potentially high degree of plasticity of the human genome and could uncover another level of genetic variation within human populations

Microhomology-mediated mechanisms underlie non-recurrent disease-causing microdeletions of the FOXL2 gene or its regulatory domain

Genomic disorders are often caused by recurrent copy number variations (CNVs), with nonallelic homologous recombination (NAHR) as the underlying mechanism. Recently, several microhomology-mediated repair mechanisms-such as microhomology-mediated end-joining (MMEJ), fork stalling and template switching (FoSTeS), microhomology-mediated break-induced replication (MMBIR), serial replication slippage (SRS), and break-induced SRS (BISRS)-were described in the etiology of non-recurrent CNVs in human disease. In addition, their formation may be stimulated by genomic architectural features. It is, however, largely unexplored to what extent these mechanisms contribute to rare, locus-specific pathogenic CNVs. Here, fine-mapping of 42 microdeletions of the FOXL2 locus, encompassing FOXL2 (32) or its regulatory domain (10), serves as a model for rare, locus-specific CNVs implicated in genetic disease. These deletions lead to blepharophimosis syndrome (BPES), a developmental condition affecting the eyelids and the ovary. For breakpoint mapping we used targeted array-based comparative genomic hybridization (aCGH), quantitative PCR (qPCR), long-range PCR, and Sanger sequencing of the junction products. Microhomology, ranging from 1 bp to 66 bp, was found in 91.7% of 24 characterized breakpoint junctions, being significantly enriched in comparison with a random control sample. Our results show that microhomology-mediated repair mechanisms underlie at least 50% of these microdeletions. Moreover, genomic architectural features, like sequence motifs, non-B DNA conformations, and repetitive elements, were found in all breakpoint regions. In conclusion, the majority of these microdeletions result from microhomology-mediated mechanisms like MMEJ, FoSTeS, MMBIR, SRS, or BISRS. Moreover, we hypothesize that the genomic architecture might drive their formation by increasing the susceptibility for DNA breakage or promote replication fork stalling. Finally, our locus-centered study, elucidating the etiology of a large set of rare microdeletions involved in a monogenic disorder, can serve as a model for other clustered, non-recurrent microdeletions in genetic disease

Canonical, Stable, General Mapping using Context Schemes

Motivation: Sequence mapping is the cornerstone of modern genomics. However, most existing sequence mapping algorithms are insufficiently general. Results: We introduce context schemes: a method that allows the unambiguous recognition of a reference base in a query sequence by testing the query for substrings from an algorithmically defined set. Context schemes only map when there is a unique best mapping, and define this criterion uniformly for all reference bases. Mappings under context schemes can also be made stable, so that extension of the query string (e.g. by increasing read length) will not alter the mapping of previously mapped positions. Context schemes are general in several senses. They natively support the detection of arbitrary complex, novel rearrangements relative to the reference. They can scale over orders of magnitude in query sequence length. Finally, they are trivially extensible to more complex reference structures, such as graphs, that incorporate additional variation. We demonstrate empirically the existence of high performance context schemes, and present efficient context scheme mapping algorithms. Availability and Implementation: The software test framework created for this work is available from https://registry.hub.docker.com/u/adamnovak/sequence-graphs/. Contact: [email protected] Supplementary Information: Six supplementary figures and one supplementary section are available with the online version of this article.Comment: Submission for Bioinformatic

Discovery of large genomic inversions using long range information.

BackgroundAlthough many algorithms are now available that aim to characterize different classes of structural variation, discovery of balanced rearrangements such as inversions remains an open problem. This is mainly due to the fact that breakpoints of such events typically lie within segmental duplications or common repeats, which reduces the mappability of short reads. The algorithms developed within the 1000 Genomes Project to identify inversions are limited to relatively short inversions, and there are currently no available algorithms to discover large inversions using high throughput sequencing technologies.ResultsHere we propose a novel algorithm, VALOR, to discover large inversions using new sequencing methods that provide long range information such as 10X Genomics linked-read sequencing, pooled clone sequencing, or other similar technologies that we commonly refer to as long range sequencing. We demonstrate the utility of VALOR using both pooled clone sequencing and 10X Genomics linked-read sequencing generated from the genome of an individual from the HapMap project (NA12878). We also provide a comprehensive comparison of VALOR against several state-of-the-art structural variation discovery algorithms that use whole genome shotgun sequencing data.ConclusionsIn this paper, we show that VALOR is able to accurately discover all previously identified and experimentally validated large inversions in the same genome with a low false discovery rate. Using VALOR, we also predicted a novel inversion, which we validated using fluorescent in situ hybridization. VALOR is available at https://github.com/BilkentCompGen/VALOR

Transcription as a Threat to Genome Integrity

Genomes undergo different types of sporadic alterations, including DNA damage, point mutations, and genome rearrangements, that constitute the basis for evolution. However, these changes may occur at high levels as a result of cell pathology and trigger genome instability, a hallmark of cancer and a number of genetic diseases. In the last two decades, evidence has accumulated that transcription constitutes an important natural source of DNA metabolic errors that can compromise the integrity of the genome. Transcription can create the conditions for high levels of mutations and recombination by its ability to open the DNA structure and remodel chromatin, making it more accessible to DNA insulting agents, and by its ability to become a barrier to DNA replication. Here we review the molecular basis of such events from a mechanistic perspective with particular emphasis on the role of transcription as a genome instability determinant

Mutations as Levy flights

Data from a long time evolution experiment with Escherichia Coli and from a large study on copy number variations in subjects with european ancestry are analyzed in order to argue that mutations can be described as Levy flights in the mutation space. These Levy flights have at least two components: random single-base substitutions and large DNA rearrangements. From the data, we get estimations for the time rates of both events and the size distribution function of large rearrangements