Motivation: The enormous amount of short reads generated by the new DNA sequencing technologies call for the development of fast and accurate read alignment programs. A first generation of hash table-based methods has been developed, including MAQ, which is accurate, feature rich and fast enough to align short reads from a single individual. However, MAQ does not support gapped alignment for single-end reads, which makes it unsuitable for alignment of longer reads where indels may occur frequently. The speed of MAQ is also a concern when the alignment is scaled up to the resequencing of hundreds of individuals.

Results: We implemented Burrows-Wheeler Alignment tool (BWA), a new read alignment package that is based on backward search with Burrows–Wheeler Transform (BWT), to efficiently align short sequencing reads against a large reference sequence such as the human genome, allowing mismatches and gaps. BWA supports both base space reads, e.g. from Illumina sequencing machines, and color space reads from AB SOLiD machines. Evaluations on both simulated and real data suggest that BWA is ~10–20× faster than MAQ, while achieving similar accuracy. In addition, BWA outputs alignment in the new standard SAM (Sequence Alignment/Map) format. Variant calling and other downstream analyses after the alignment can be achieved with the open source SAMtools software package.

Availability: http://maq.sourceforge.net 

Contact: [email protected]

/pdf/fast-and-accurate-short-read-alignment-with-burrows-wheeler-43uqhgr33c.pdf

Fast and accurate short read alignment with Burrows–Wheeler transform

Bowtie is an ultrafast, memory-efficient alignment program for aligning short DNA sequence reads to large genomes. For the human genome, Burrows-Wheeler indexing allows Bowtie to align more than 25 million reads per CPU hour with a memory footprint of approximately 1.3 gigabytes. Bowtie extends previous Burrows-Wheeler techniques with a novel quality-aware backtracking algorithm that permits mismatches. Multiple processor cores can be used simultaneously to achieve even greater alignment speeds. Bowtie is open source http://bowtie.cbcb.umd.edu.

/pdf/ultrafast-and-memory-efficient-alignment-of-short-dna-3mrm42jmnc.pdf

Ultrafast and memory-efficient alignment of short DNA sequences to the human genome

The human genome encodes the blueprint of life, but the function of the vast majority of its nearly three billion bases is unknown. The Encyclopedia of DNA Elements (ENCODE) project has systematically mapped regions of transcription, transcription factor association, chromatin structure and histone modification. These data enabled us to assign biochemical functions for 80% of the genome, in particular outside of the well-studied protein-coding regions. Many discovered candidate regulatory elements are physically associated with one another and with expressed genes, providing new insights into the mechanisms of gene regulation. The newly identified elements also show a statistical correspondence to sequence variants linked to human disease, and can thereby guide interpretation of this variation. Overall, the project provides new insights into the organization and regulation of our genes and genome, and is an expansive resource of functional annotations for biomedical research.

/pdf/an-integrated-encyclopedia-of-dna-elements-in-the-human-52ukbi8ats.pdf

An integrated encyclopedia of DNA elements in the human genome

Machine Learning is the study of methods for programming computers to learn. Computers are applied to a wide range of tasks, and for most of these it is relatively easy for programmers to design and implement the necessary software. However, there are many tasks for which this is difficult or impossible. These can be divided into four general categories. First, there are problems for which there exist no human experts. For example, in modern automated manufacturing facilities, there is a need to predict machine failures before they occur by analyzing sensor readings. Because the machines are new, there are no human experts who can be interviewed by a programmer to provide the knowledge necessary to build a computer system. A machine learning system can study recorded data and subsequent machine failures and learn prediction rules. Second, there are problems where human experts exist, but where they are unable to explain their expertise. This is the case in many perceptual tasks, such as speech recognition, hand-writing recognition, and natural language understanding. Virtually all humans exhibit expert-level abilities on these tasks, but none of them can describe the detailed steps that they follow as they perform them. Fortunately, humans can provide machines with examples of the inputs and correct outputs for these tasks, so machine learning algorithms can learn to map the inputs to the outputs. Third, there are problems where phenomena are changing rapidly. In finance, for example, people would like to predict the future behavior of the stock market, of consumer purchases, or of exchange rates. These behaviors change frequently, so that even if a programmer could construct a good predictive computer program, it would need to be rewritten frequently. A learning program can relieve the programmer of this burden by constantly modifying and tuning a set of learned prediction rules. Fourth, there are applications that need to be customized for each computer user separately. Consider, for example, a program to filter unwanted electronic mail messages. Different users will need different filters. It is unreasonable to expect each user to program his or her own rules, and it is infeasible to provide every user with a software engineer to keep the rules up-to-date. A machine learning system can learn which mail messages the user rejects and maintain the filtering rules automatically. Machine learning addresses many of the same research questions as the fields of statistics, data mining, and psychology, but with differences of emphasis. Statistics focuses on understanding the phenomena that have generated the data, often with the goal of testing different hypotheses about those phenomena. Data mining seeks to find patterns in the data that are understandable by people. Psychological studies of human learning aspire to understand the mechanisms underlying the various learning behaviors exhibited by people (concept learning, skill acquisition, strategy change, etc.).

Machine learning

We present Model-based Analysis of ChIP-Seq data, MACS, which analyzes data generated by short read sequencers such as Solexa's Genome Analyzer. MACS empirically models the shift size of ChIP-Seq tags, and uses it to improve the spatial resolution of predicted binding sites. MACS also uses a dynamic Poisson distribution to effectively capture local biases in the genome, allowing for more robust predictions. MACS compares favorably to existing ChIP-Seq peak-finding algorithms, and is freely available.

/pdf/model-based-analysis-of-chip-seq-macs-11m6g885d3.pdf

Model-based Analysis of ChIP-Seq (MACS)

We present an algorithm for computing a maximum agreement subtree of two unrooted evolutionary trees. It takes O(n^{1.5} log n) time for trees with unbounded degrees, matching the best known time complexity for the rooted case. Our algorithm allows the input trees to be mixed trees, i.e., trees that may contain directed and undirected edges at the same time. Our algorithm adopts a recursive strategy exploiting a technique called label compression. The backbone of this technique is an algorithm that computes the maximum weight matchings over many subgraphs of a bipartite graph as fast as it takes to compute a single matching.

Cavity Matchings, Label Compressions, and Unrooted Evolutionary Trees

Insertions are one of the major types of structural variations and are defined as the addition of 50 nucleotides or more into a DNA sequence. Several methods exist to detect insertions from next-generation sequencing short read data, but they generally have low sensitivity. Our contribution is two-fold. First, we introduce INSurVeyor, a fast, sensitive and precise method that detects insertions from next-generation sequencing paired-end data. Using publicly available benchmark datasets (both human and non-human), we show that INSurVeyor is not only more sensitive than any individual caller we tested, but also more sensitive than all of them combined. Furthermore, for most types of insertions, INSurVeyor is almost as sensitive as long reads callers. Second, we provide state-of-the-art catalogues of insertions for 1047 Arabidopsis Thaliana genomes from the 1001 Genomes Project and 3202 human genomes from the 1000 Genomes Project, both generated with INSurVeyor. We show that they are more complete and precise than existing resources, and important insertions are missed by existing methods. 

/pdf/insurveyor-improving-insertion-calling-from-short-read-17iur6ar.pdf

INSurVeyor: improving insertion calling from short read sequencing data

Based on the experiments on 35 pairs of virus genomes using three software tools (MUMmer-3, MaxMinCluster, MSS), we show that using anchors with mismatches does increase the effectiveness of locating conserved regions ( about 10% more conserved gene regions are located, while maintaining a high sensitivity) . To generate a more comprehensive set of anchors with mismatches is not trivial for long sequences due to the time and memory limitation. We propose two practical algorithms for generating this anchor set. One aims at speeding up the process, the other aims at saving memory. Experimental results show that both algorithms are faster (6 times and 5 times, respectively) than a straightforward suffix tree based appr oach.

/pdf/allowing-mismatches-in-anchors-for-wholw-genome-alignment-4z3n7l488e.pdf

Allowing mismatches in anchors for wholw genome alignment: Generation and effectiveness

In silico motif finding algorithms are often used for discovering protein-DNA binding sites in a set of regulatory sequences. Current algorithms mainly address motif discovery in short sequences. Analyzing long sequences can be quite challenging not only due to increasing time and memory requirements of the algorithm, but also decreasing accuracy. However, in case the motif is localized in a short interval of the long sequences relative to an anchor point, it is tenable to detect it easily by restricting the search to that interval. But the region of localization of the motif is not known a priori. This paper reports an algorithm called LocalMotif to detect localized motifs in long regulatory sequences. A novel score function predicts the region of localization of the motif. This score is combined with other scoring measures including Z-score and relative entropy to detect the motif. The algorithm is optimized for fast processing of long regulatory sequences. Tests on simulated and real datasets confirm that LocalMotif accurately determines the region of localization of motifs and automatically discovers the biologically relevant motifs, which can be detected by other motif finding algorithms only when the search is restricted to the relevant interval.

LocalMotif - An In-Silico Tool for Detecting Localized Motifs in Regulatory Sequences

Consider a set of labels $L$ and a set of trees ${\mathcal T} = \{{\mathcal T}^{(1), {\mathcal T}^{(2), ..., {\mathcal T}^{(k) \$ where each tree ${\mathcal T}^{(i)$ is distinctly leaf-labeled by some subset of $L$. One fundamental problem is to find the biggest tree (denoted as supertree) to represent $\mathcal T}$ which minimizes the disagreements with the trees in ${\mathcal T}$ under certain criteria. This problem finds applications in phylogenetics, database, and data mining. In this paper, we focus on two particular supertree problems, namely, the maximum agreement supertree problem (MASP) and the maximum compatible supertree problem (MCSP). These two problems are known to be NP-hard for $k \geq 3$. This paper gives the first polynomial time algorithms for both MASP and MCSP when both $k$ and the maximum degree $D$ of the trees are constant.

Wing-Kin Sung

Papers

Cavity Matchings, Label Compressions, and Unrooted Evolutionary Trees

INSurVeyor: improving insertion calling from short read sequencing data

Allowing mismatches in anchors for wholw genome alignment: Generation and effectiveness

LocalMotif - An In-Silico Tool for Detecting Localized Motifs in Regulatory Sequences

Fixed Parameter Polynomial Time Algorithms for Maximum Agreement and Compatible Supertrees