Single Individual Haplotyping Research Articles

Estimating Haplotype Structure and Frequencies: A Bayesian Approach to Unknown Design in Pooled Genomic Data.

The estimation of haplotype structure and frequencies provides crucial information about the composition of genomes. Techniques, such as single-individual haplotyping, aim to reconstruct individual haplotypes from diploid genome sequencing data. However, our focus is distinct. We address the challenge of reconstructing haplotype structure and frequencies from pooled sequencing samples where multiple individuals are sequenced simultaneously. A frequentist method to address this issue has recently been proposed. In contrast to this and other methods that compute point estimates, our proposed Bayesian hierarchical model delivers a posterior that permits us to also quantify uncertainty. Since matching permutations in both haplotype structure and corresponding frequency matrix lead to the same reconstruction of their product, we introduce an order-preserving shrinkage prior that ensures identifiability with respect to permutations. For inference, we introduce a blocked Gibbs sampler that enforces the required constraints. In a simulation study, we assessed the performance of our method. Furthermore, by using our approach on two distinct sets of real data, we demonstrate that our Bayesian approach can reconstruct the dominant haplotypes in a challenging, high-dimensional set-up.

On the complexity of haplotyping a microbial community.

MotivationPopulation-level genetic variation enables competitiveness and niche specialization in microbial communities. Despite the difficulty in culturing many microbes from an environment, we can still study these communities by isolating and sequencing DNA directly from an environment (metagenomics). Recovering the genomic sequences of all isoforms of a given gene across all organisms in a metagenomic sample would aid evolutionary and ecological insights into microbial ecosystems with potential benefits for medicine and biotechnology. A significant obstacle to this goal arises from the lack of a computationally tractable solution that can recover these sequences from sequenced read fragments. This poses a problem analogous to reconstructing the two sequences that make up the genome of a diploid organism (i.e. haplotypes) but for an unknown number of individuals and haplotypes.ResultsThe problem of single individual haplotyping was first formalized by Lancia et al. in 2001. Now, nearly two decades later, we discuss the complexity of ‘haplotyping’ metagenomic samples, with a new formalization of Lancia et al.’s data structure that allows us to effectively extend the single individual haplotype problem to microbial communities. This work describes and formalizes the problem of recovering genes (and other genomic subsequences) from all individuals within a complex community sample, which we term the metagenomic individual haplotyping problem. We also provide software implementations for a pairwise single nucleotide variant (SNV) co-occurrence matrix and greedy graph traversal algorithm.Availability and implementationOur reference implementation of the described pairwise SNV matrix (Hansel) and greedy haplotype path traversal algorithm (Gretel) is open source, MIT licensed and freely available online at github.com/samstudio8/hansel and github.com/samstudio8/gretel, respectively.

A Graph Auto-Encoder for Haplotype Assembly and Viral Quasispecies Reconstruction

Reconstructing components of a genomic mixture from data obtained by means of DNA sequencing is a challenging problem encountered in a variety of applications including single individual haplotyping and studies of viral communities. High-throughput DNA sequencing platforms oversample mixture components to provide massive amounts of reads whose relative positions can be determined by mapping the reads to a known reference genome; assembly of the components, however, requires discovery of the reads' origin – an NP-hard problem that the existing methods struggle to solve with the required level of accuracy. In this paper, we present a learning framework based on a graph auto-encoder designed to exploit structural properties of sequencing data. The algorithm is a neural network which essentially trains to ignore sequencing errors and infers the posterior probabilities of the origin of sequencing reads. Mixture components are then reconstructed by finding consensus of the reads determined to originate from the same genomic component. Results on realistic synthetic as well as experimental data demonstrate that the proposed framework reliably assembles haplotypes and reconstructs viral communities, often significantly outperforming state-of-the-art techniques. Source codes, datasets and supplementary document are available at https://github.com/WuLoli/GAEseq.

Fast single individual haplotyping method using GPGPU

BackgroundMost bioinformatic tools for next generation sequencing (NGS) data are computationally intensive, requiring a large amount of computational power for processing and analysis. Here the utility of graphic processing units (GPUs) for NGS data computation is assessed. MethodIn a previous study, we developed a probabilistic evolutionary algorithm with toggling for haplotyping (PEATH) method based on the estimation of distribution algorithm and toggling heuristic. Here, we parallelized the PEATH method (PEATH/G) using general-purpose computing on GPU (GPGPU). ResultsThe PEATH/G runs approximately 46.8 times and 25.4 times faster than PEATH on the NA12878 fosmid-sequencing dataset and the HuRef dataset, respectively, with an NVIDIA GeForce GTX 1660Ti. Moreover, the PEATH/G is approximately 13.3 times faster on the fosmid-sequencing dataset, even with an inexpensive conventional GPGPU (NVIDIA GeForce GTX 950). ConclusionsPEATH/G can be a practical single individual haplotyping tool in terms of both its accuracy and speed. GPGPU can help reduce the running time of NGS analysis tools.

Matrix Completion and Performance Guarantees for Single Individual Haplotyping

Single individual haplotyping is an NP-hard problem that emerges when attempting to reconstruct an organism's inherited genetic variations using data typically generated by high-throughput DNA sequencing platforms. Genomes of diploid organisms, including humans, are organized into homologous pairs of chromosomes that differ from each other in a relatively small number of variant positions. Haplotypes are ordered sequences of the nucleotides in the variant positions of the chromosomes in a homologous pair; for diploids, haplotypes associated with a pair of chromosomes may be conveniently represented by means of complementary binary sequences. In this paper, we consider a binary matrix factorization formulation of the single individual haplotyping problem and efficiently solve it by means of alternating minimization. We analyze the convergence properties of the alternating minimization algorithm and establish theoretical bounds for the achievable haplotype reconstruction error. The proposed technique is shown to outperform existing methods when applied to synthetic as well as real-world Fosmid-based HapMap NA12878 datasets.

PEATH: single-individual haplotyping by a probabilistic evolutionary algorithm with toggling.

Single-individual haplotyping (SIH) is critical in genomic association studies and genetic diseases analysis. However, most genomic analysis studies do not perform haplotype-phasing analysis due to its complexity. Several computational methods have been developed to solve the SIH problem, but these approaches have not generated sufficiently reliable haplotypes. Here, we propose a novel SIH algorithm, called PEATH (Probabilistic Evolutionary Algorithm with Toggling for Haplotyping), to achieve more accurate and reliable haplotyping. The proposed PEATH method was compared to the most recent algorithms in terms of the phased length, N50 length, switch error rate and minimum error correction. The PEATH algorithm consistently provides the best phase and N50 lengths, as long as possible, given datasets. In addition, verification of the simulation data demonstrated that the PEATH method outperforms other methods on high noisy data. Additionally, the experimental results of a real dataset confirmed that the PEATH method achieved comparable or better accuracy. Source code of PEATH is available at https://github.com/jcna99/PEATH. jkrhee@catholic.ac.kr or sooyong.shin@gmail.com. Supplementary data are available at Bioinformatics online.

AROHap: An effective algorithm for single individual haplotype reconstruction based on asexual reproduction optimization

In this paper, a method for single individual haplotype (SIH) reconstruction using Asexual reproduction optimization (ARO) is proposed. Haplotypes, as a set of genetic variations in each chromosome, contain vital information such as the relationship between human genome and diseases. Finding haplotypes in diploid organisms is a challenging task. Experimental methods are expensive and require special equipment. In SIH problem, we encounter with several fragments and each fragment covers some parts of desired haplotype. The main goal is bi-partitioning of the fragments with minimum error correction (MEC). This problem is addressed as NP-hard and several attempts have been made in order to solve it using heuristic methods. The current method, AROHap, has two main phases. In the first phase, most of the fragments are clustered based on a practical metric distance. In the second phase, ARO algorithm as a fast convergence bio-inspired method is used to improve the initial bi-partitioning of the fragments in the previous step. AROHap is implemented with several benchmark datasets. The experimental results demonstrate that satisfactory results were obtained, proving that AROHap can be used for SIH reconstruction problem.

H-PoP and H-PoPG: heuristic partitioning algorithms for single individual haplotyping of polyploids.

Some economically important plants including wheat and cotton have more than two copies of each chromosome. With the decreasing cost and increasing read length of next-generation sequencing technologies, reconstructing the multiple haplotypes of a polyploid genome from its sequence reads becomes practical. However, the computational challenge in polyploid haplotyping is much greater than that in diploid haplotyping, and there are few related methods. This article models the polyploid haplotyping problem as an optimal poly-partition problem of the reads, called the Polyploid Balanced Optimal Partition model. For the reads sequenced from a k-ploid genome, the model tries to divide the reads into k groups such that the difference between the reads of the same group is minimized while the difference between the reads of different groups is maximized. When the genotype information is available, the model is extended to the Polyploid Balanced Optimal Partition with Genotype constraint problem. These models are all NP-hard. We propose two heuristic algorithms, H-PoP and H-PoPG, based on dynamic programming and a strategy of limiting the number of intermediate solutions at each iteration, to solve the two models, respectively. Extensive experimental results on simulated and real data show that our algorithms can solve the models effectively, and are much faster and more accurate than the recent state-of-the-art polyploid haplotyping algorithms. The experiments also show that our algorithms can deal with long reads and deep read coverage effectively and accurately. Furthermore, H-PoP might be applied to help determine the ploidy of an organism. https://github.com/MinzhuXie/H-PoPG CONTACT: xieminzhu@hotmail.comSupplementary information: Supplementary data are available at Bioinformatics online.

Algorithmic approaches for the single individual haplotyping problem

Since its introduction in 2001, the Single Individual Haplotyping problem has received an ever-increasing attention from the scientific community. In this paper we survey, in the form of an annotated bibliography, the developments in the study of the problem from its origin until our days.

Combinatorial pooled sequencing: experiment design and decoding

Owing to rapid advances in the next‐generation sequencing technology, the cost of DNA sequencing has been reduced by over several orders of magnitude. However, genomic sequencing of individuals at the population scale is still restricted to a few model species due to the huge challenge of constructing libraries for thousands of samples. Meanwhile, pooled sequencing provides a cost‐effective alternative to sequencing individuals separately, which could vastly reduce the time and cost for DNA library preparation. Technological improvements, together with the broad range of biological research questions that require large sample sizes, mean that pooled sequencing will continue to complement the sequencing of individual genomes and become increasingly important in the foreseeable future. However, simply mixing samples together for sequencing makes it impossible to identify reads that belongs to each sample. Barcoding technology could help to solve this problem, nonetheless, currently, barcoding every sample is costly especially for large‐scale samples. An alternative to barcoding is combinatorial pooled sequencing which employs pooling pattern rather than short DNA barcodes to encode each sample. In combinatorial pooled sequencing, samples are mixed into few pools according to a carefully designed pooling strategy which allows the sequencing data to be decoded to identify the reads that belongs to the sample that are unique or rare in the population. In this review, we mainly survey the experiment design and decoding procedure for the combinatorial pooled sequencing applied in rare variant and rare haplotype carriers screening, complex genome assembling and single individual haplotyping.

LGH: A Fast and Accurate Algorithm for Single Individual Haplotyping Based on a Two-Locus Linkage Graph.

Phased haplotype information is crucial in our complete understanding of differences between individuals at the genetic level. Given a collection of DNA fragments sequenced from a homologous pair of chromosomes, the problem of single individual haplotyping (SIH) aims to reconstruct a pair of haplotypes using a computer algorithm. In this paper, we encode the information of aligned DNA fragments into a two-locus linkage graph and approach the SIH problem by vertex labeling of the graph. In order to find a vertex labeling with the minimum sum of weights of incompatible edges, we develop a fast and accurate heuristic algorithm. It starts with detecting error-tolerant components by an adapted breadth-first search. A proper labeling of vertices is then identified for each component, with which sequencing errors are further corrected and edge weights are adjusted accordingly. After contracting each error-tolerant component into a single vertex, the above procedure is iterated on the resulting condensed linkage graph until error-tolerant components are no longer detected. The algorithm finally outputs a haplotype pair based on the vertex labeling. Extensive experiments on simulated and real data show that our algorithm is more accurate and faster than five existing algorithms for single individual haplotyping.

FastHap: fast and accurate single individual haplotype reconstruction using fuzzy conflict graphs

Motivation: Understanding exact structure of an individual’s haplotype plays a significant role in various fields of human genetics. Despite tremendous research effort in recent years, fast and accurate haplotype reconstruction remains as an active research topic, mainly owing to the computational challenges involved. Existing haplotype assembly algorithms focus primarily on improving accuracy of the assembly, making them computationally challenging for applications on large high-throughput sequence data. Therefore, there is a need to develop haplotype reconstruction algorithms that are not only accurate but also highly scalable.Results: In this article, we introduce FastHap, a fast and accurate haplotype reconstruction approach, which is up to one order of magnitude faster than the state-of-the-art haplotype inference algorithms while also delivering higher accuracy than these algorithms. FastHap leverages a new similarity metric that allows us to precisely measure distances between pairs of fragments. The distance is then used in building the fuzzy conflict graphs of fragments. Given that optimal haplotype reconstruction based on minimum error correction is known to be NP-hard, we use our fuzzy conflict graphs to develop a fast heuristic for fragment partitioning and haplotype reconstruction.Availability: An implementation of FastHap is available for sharing on request.Contact: sepideh@cs.ucla.edu

Integrating dilution-based sequencing and population genotypes for single individual haplotyping.

BackgroundHaplotype information is useful for many genetic analyses and haplotypes are usually inferred using computational approaches. Among such approaches, the importance of single individual haplotyping (SIH), which infers individual haplotypes from sequence fragments, has been increasing with the advent of novel sequencing techniques, such as dilution-based sequencing. These techniques could produce virtual long read fragments by separating DNA fragments into multiple low-concentration aliquots, sequencing and mapping each aliquot, and merging clustered short reads. Although these experimental techniques are sophisticated, they have the problem of producing chimeric fragments whose left and right parts match different chromosomes. In our previous research, we found that chimeric fragments significantly decrease the accuracy of SIH. Although chimeric fragments can be removed by using haplotypes which are determined from pedigree genotypes, pedigree genotypes are generally not available. The length of reads cluster and heterozygous calls were also used to detect chimeric fragments. Although some chimeric fragments will be removed with these features, considerable number of chimeric fragments will be undetected because of the dispersion of the length and the absence of SNPs in the overlapped regions. For these reasons, a general method to detect and remove chimeric fragments is needed.ResultsIn this paper, we propose a general method to detect chimeric fragments. The basis of our method is that a chimeric fragment would correspond to an artificial recombinant haplotype and would differ from biological haplotypes. To detect differences from biological haplotypes, we integrated statistical phasing, which is a haplotype inference approach from population genotypes, into our method. We applied our method to two datasets and detected chimeric fragments with high AUC. AUC values of our method are higher than those of just using cluster length and heterozygous calls. We then used multiple SIH algorithm to compare the accuracy of SIH before and after removing the chimeric fragment candidates. The accuracy of assembled haplotypes increased significantly after removing chimeric fragment candidates.ConclusionsOur method is useful for detecting chimeric fragments and improving SIH accuracy. The Ruby script is available at https://sites.google.com/site/hmatsu1226/software/csp.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2164-15-733) contains supplementary material, which is available to authorized users.

Accurate single individual haplotyping based on HuRef dataset using HapSAT algorithm

Studying haplotypes is an important approach for investigation of genetic variations in the human genome because they contain a lot of information related to these types of variations. The haplotype assembly problem is to reconstruct two haplotypes for an individual using a set of aligned single nucleotide polymorphism (SNP) fragments from the two haplotypes (related to a particular chromosome). This problem is recognised as an NP–hard problem due to possible sequencing errors. Therefore, in practice, heuristic algorithms are used for finding satisfactory solutions to this problem. In this paper, an optimised reimplementation of HapSAT algorithm has been used to find haplotypes for HuRef dataset. Finding more accurate haplotypes based on this dataset is of considerable importance, because HuRef haplotypes are widely used in some researches (in biology, medicine, and pharmacy). Since the HapSAT algorithm provides significantly superior results compared to previously proposed algorithms, assembled haplotypes using HapSAT algorithm will be very useful for future researches.

MixSIH: a mixture model for single individual haplotyping

BackgroundHaplotype information is useful for various genetic analyses, including genome-wide association studies. Determining haplotypes experimentally is difficult and there are several computational approaches that infer haplotypes from genomic data. Among such approaches, single individual haplotyping or haplotype assembly, which infers two haplotypes of an individual from aligned sequence fragments, has been attracting considerable attention. To avoid incorrect results in downstream analyses, it is important not only to assemble haplotypes as long as possible but also to provide means to extract highly reliable haplotype regions. Although there are several efficient algorithms for solving haplotype assembly, there are no efficient method that allow for extracting the regions assembled with high confidence.ResultsWe develop a probabilistic model, called MixSIH, for solving the haplotype assembly problem. The model has two mixture components representing two haplotypes. Based on the optimized model, a quality score is defined, which we call the 'minimum connectivity' (MC) score, for each segment in the haplotype assembly. Because existing accuracy measures for haplotype assembly are designed to compare the efficiency between the algorithms and are not suitable for evaluating the quality of the set of partially assembled haplotype segments, we develop an accuracy measure based on the pairwise consistency and evaluate the accuracy on the simulation and real data. By using the MC scores, our algorithm can extract highly accurate haplotype segments. We also show evidence that an existing experimental dataset contains chimeric read fragments derived from different haplotypes, which significantly degrade the quality of assembled haplotypes.ConclusionsWe develop a novel method for solving the haplotype assembly problem. We also define the quality score which is based on our model and indicates the accuracy of the haplotypes segments. In our evaluation, MixSIH has successfully extracted reliable haplotype segments. The C++ source code of MixSIH is available at https://sites.google.com/site/hmatsu1226/software/mixsih.

Using genetic algorithm in reconstructing single individual haplotype with minimum error correction

Discovering ways to reconstruct reliable Single Individual Haplotypes (SIHs) becomes one of the core issues in the whole-genome research nowadays as previous research showed that haplotypes contain more information than individual Singular Nucleotide Polymorphisms (SNPs). Although with advances in high-throughput sequencing technologies obtaining sequence information is becoming easier in today’s laboratories, obtained sequences from current technologies always contain inevitable sequence errors and missing information. The SIH reconstruction problem can be formulated as bi-partitioning the input SNP fragment matrix into paternal and maternal sections to achieve minimum error correction (MEC) time; the problem that is proved to be NP-hard. Several heuristics or greedy algorithms have already been designed and implemented to solve this problem, most of them however (1) do not have the ability to handle data sets with high error rates and/or (2) can only handle binary input matrices. In this study, we introduce a Genetic Algorithm (GA) based method, named GAHap, to reconstruct SIHs with lowest MEC times. GAHap is equipped with a well-designed fitness function to obtain better reconstruction rates. GAHap is also compared with existing methods to show its ability in generating highly reliable solutions.

A fast and accurate algorithm for single individual haplotyping

BackgroundDue to the difficulty in separating two (paternal and maternal) copies of a chromosome, most published human genome sequences only provide genotype information, i.e., the mixed information of the underlying two haplotypes. However, phased haplotype information is needed to completely understand complex genetic polymorphisms and to increase the power of genome-wide association studies for complex diseases. With the rapid development of DNA sequencing technologies, reconstructing a pair of haplotypes from an individual's aligned DNA fragments by computer algorithms (i.e., Single Individual Haplotyping) has become a practical haplotyping approach.ResultsIn the paper, we combine two measures "errors corrected" and "fragments cut" and propose a new optimization model, called Balanced Optimal Partition (BOP), for single individual haplotyping. The model generalizes two existing models, Minimum Error Correction (MEC) and Maximum Fragments Cut (MFC), and could be made either model by using some extreme parameter values. To solve the model, we design a heuristic dynamic programming algorithm H-BOP. By limiting the number of intermediate solutions at each iteration to an appropriately chosen small integer k, H-BOP is able to solve the model efficiently.ConclusionsExtensive experimental results on simulated and real data show that when k = 8, H-BOP is generally faster and more accurate than a recent state-of-art algorithm ReFHap in haplotype reconstruction. The running time of H-BOP is linearly dependent on some of the key parameters controlling the input size and H-BOP scales well to large input data. The code of H-BOP is available to the public for free upon request to the corresponding author.

Fosmid-based whole genome haplotyping of a HapMap trio child: evaluation of Single Individual Haplotyping techniques

Determining the underlying haplotypes of individual human genomes is an essential, but currently difficult, step toward a complete understanding of genome function. Fosmid pool-based next-generation sequencing allows genome-wide generation of 40-kb haploid DNA segments, which can be phased into contiguous molecular haplotypes computationally by Single Individual Haplotyping (SIH). Many SIH algorithms have been proposed, but the accuracy of such methods has been difficult to assess due to the lack of real benchmark data. To address this problem, we generated whole genome fosmid sequence data from a HapMap trio child, NA12878, for which reliable haplotypes have already been produced. We assembled haplotypes using eight algorithms for SIH and carried out direct comparisons of their accuracy, completeness and efficiency. Our comparisons indicate that fosmid-based haplotyping can deliver highly accurate results even at low coverage and that our SIH algorithm, ReFHap, is able to efficiently produce high-quality haplotypes. We expanded the haplotypes for NA12878 by combining the current haplotypes with our fosmid-based haplotypes, producing near-to-complete new gold-standard haplotypes containing almost 98% of heterozygous SNPs. This improvement includes notable fractions of disease-related and GWA SNPs. Integrated with other molecular biological data sets, this phase information will advance the emerging field of diploid genomics.

New results for the Longest Haplotype Reconstruction problem

The haplotyping problem has emerged in recent years as one of the most relevant problems in Computational Biology. In particular, in the Single Individual Haplotyping (SIH) problem, starting from a matrix of incomplete haplotype fragments, the goal is the reconstruction of the two complete haplotypes of an individual. In this paper we consider one of the variants of the Single Individual Haplotyping problem, the Longest Haplotyping Reconstruction (LHR) problem. We prove that the LHR problem is NP-hard even in the restricted case when the input matrix is error-free. Furthermore, we investigate the approximation complexity of the problem, and we show that the problem cannot be approximated within factor 2logδnm for any constant δ<1, unless NP⊆DTIME[2polylognm]. Finally, we exhibit a fixed-parameter algorithm for the LHR problem, where the parameter is the size of the two reconstructed haplotypes.

A parthenogenetic algorithm for single individual SNP haplotyping

The minimum error correction (MEC) model is one of the important computational models for single individual single nucleotide polymorphism (SNP) haplotyping. Due to the NP-hardness of the model, Qian et al. presented a particle swarm optimization (PSO) algorithm to solve it, and the particle code length is equal to the number of SNP fragments. However, there are hundreds and thousands of SNP fragments in practical applications. The PSO algorithm based on this kind of long particle code cannot obtain high reconstruction rate efficiently. In this paper, a practical heuristic algorithm PGA-MEC based on parthenogenetic algorithm (PGA) is presented to solve the model. A kind of short chromosome code and an effective recombination operator are designed for the algorithm. The reconstruction rate of PGA-MEC algorithm is higher than that of PSO algorithm and the running time of PGA-MEC algorithm is shorter than that of PSO algorithm, which are proved by a number of experiments.