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1.  Efficient Whole-Genome Association Mapping using Local Phylogenies for Unphased Genotype Data 
Bioinformatics (Oxford, England)  2008;24(19):2215-2221.
Motivation
Recent advances in genotyping technology has made data acquisition for whole-genome association study cost effective, and a current active area of research is developing efficient methods to analyze such large-scale data sets. Most sophisticated association mapping methods that are currently available take phased haplotype data as input. However, phase information is not readily available from sequencing methods and inferring the phase via computational approaches is time-consuming, taking days to phase a single chromosome.
Results
In this paper, we devise an efficient method for scanning unphased whole-genome data for association. Our approach combines a recently found linear-time algorithm for phasing genotypes on trees with a recently proposed tree-based method for association mapping. From unphased genotype data, our algorithm builds local phylogenies along the genome, and scores each tree according to the clustering of cases and controls. We assess the performance of our new method on both simulated and real biological data sets.
doi:10.1093/bioinformatics/btn406
PMCID: PMC2553438  PMID: 18667442
2.  Whole genome association mapping by incompatibilities and local perfect phylogenies 
BMC Bioinformatics  2006;7:454.
Background
With current technology, vast amounts of data can be cheaply and efficiently produced in association studies, and to prevent data analysis to become the bottleneck of studies, fast and efficient analysis methods that scale to such data set sizes must be developed.
Results
We present a fast method for accurate localisation of disease causing variants in high density case-control association mapping experiments with large numbers of cases and controls. The method searches for significant clustering of case chromosomes in the "perfect" phylogenetic tree defined by the largest region around each marker that is compatible with a single phylogenetic tree. This perfect phylogenetic tree is treated as a decision tree for determining disease status, and scored by its accuracy as a decision tree. The rationale for this is that the perfect phylogeny near a disease affecting mutation should provide more information about the affected/unaffected classification than random trees. If regions of compatibility contain few markers, due to e.g. large marker spacing, the algorithm can allow the inclusion of incompatibility markers in order to enlarge the regions prior to estimating their phylogeny. Haplotype data and phased genotype data can be analysed. The power and efficiency of the method is investigated on 1) simulated genotype data under different models of disease determination 2) artificial data sets created from the HapMap ressource, and 3) data sets used for testing of other methods in order to compare with these. Our method has the same accuracy as single marker association (SMA) in the simplest case of a single disease causing mutation and a constant recombination rate. However, when it comes to more complex scenarios of mutation heterogeneity and more complex haplotype structure such as found in the HapMap data our method outperforms SMA as well as other fast, data mining approaches such as HapMiner and Haplotype Pattern Mining (HPM) despite being significantly faster. For unphased genotype data, an initial step of estimating the phase only slightly decreases the power of the method. The method was also found to accurately localise the known susceptibility variants in an empirical data set – the ΔF508 mutation for cystic fibrosis – where the susceptibility variant is already known – and to find significant signals for association between the CYP2D6 gene and poor drug metabolism, although for this dataset the highest association score is about 60 kb from the CYP2D6 gene.
Conclusion
Our method has been implemented in the Blossoc (BLOck aSSOCiation) software. Using Blossoc, genome wide chip-based surveys of 3 million SNPs in 1000 cases and 1000 controls can be analysed in less than two CPU hours.
doi:10.1186/1471-2105-7-454
PMCID: PMC1624851  PMID: 17042942
3.  Direct maximum parsimony phylogeny reconstruction from genotype data 
BMC Bioinformatics  2007;8:472.
Background
Maximum parsimony phylogenetic tree reconstruction from genetic variation data is a fundamental problem in computational genetics with many practical applications in population genetics, whole genome analysis, and the search for genetic predictors of disease. Efficient methods are available for reconstruction of maximum parsimony trees from haplotype data, but such data are difficult to determine directly for autosomal DNA. Data more commonly is available in the form of genotypes, which consist of conflated combinations of pairs of haplotypes from homologous chromosomes. Currently, there are no general algorithms for the direct reconstruction of maximum parsimony phylogenies from genotype data. Hence phylogenetic applications for autosomal data must therefore rely on other methods for first computationally inferring haplotypes from genotypes.
Results
In this work, we develop the first practical method for computing maximum parsimony phylogenies directly from genotype data. We show that the standard practice of first inferring haplotypes from genotypes and then reconstructing a phylogeny on the haplotypes often substantially overestimates phylogeny size. As an immediate application, our method can be used to determine the minimum number of mutations required to explain a given set of observed genotypes.
Conclusion
Phylogeny reconstruction directly from unphased data is computationally feasible for moderate-sized problem instances and can lead to substantially more accurate tree size inferences than the standard practice of treating phasing and phylogeny construction as two separate analysis stages. The difference between the approaches is particularly important for downstream applications that require a lower-bound on the number of mutations that the genetic region has undergone.
doi:10.1186/1471-2105-8-472
PMCID: PMC2222657  PMID: 18053244
4.  Linkage disequilibrium mapping via cladistic analysis of phase-unknown genotypes and inferred haplotypes in the Genetic Analysis Workshop 14 simulated data 
BMC Genetics  2005;6(Suppl 1):S100.
We recently described a method for linkage disequilibrium (LD) mapping, using cladistic analysis of phased single-nucleotide polymorphism (SNP) haplotypes in a logistic regression framework. However, haplotypes are often not available and cannot be deduced with certainty from the unphased genotypes. One possible two-stage approach is to infer the phase of multilocus genotype data and analyze the resulting haplotypes as if known. Here, haplotypes are inferred using the expectation-maximization (EM) algorithm and the best-guess phase assignment for each individual analyzed. However, inferring haplotypes from phase-unknown data is prone to error and this should be taken into account in the subsequent analysis. An alternative approach is to analyze the phase-unknown multilocus genotypes themselves. Here we present a generalization of the method for phase-known haplotype data to the case of unphased SNP genotypes. Our approach is designed for high-density SNP data, so we opted to analyze the simulated dataset. The marker spacing in the initial screen was too large for our method to be effective, so we used the answers provided to request further data in regions around the disease loci and in null regions. Power to detect the disease loci, accuracy in localizing the true site of the locus, and false-positive error rates are reported for the inferred-haplotype and unphased genotype methods. For this data, analyzing inferred haplotypes outperforms analysis of genotypes. As expected, our results suggest that when there is little or no LD between a disease locus and the flanking region, there will be no chance of detecting it unless the disease variant itself is genotyped.
doi:10.1186/1471-2156-6-S1-S100
PMCID: PMC1866839  PMID: 16451556
5.  Haplotype inference from unphased SNP data in heterozygous polyploids based on SAT 
BMC Genomics  2008;9:356.
Background
Haplotype inference based on unphased SNP markers is an important task in population genetics. Although there are different approaches to the inference of haplotypes in diploid species, the existing software is not suitable for inferring haplotypes from unphased SNP data in polyploid species, such as the cultivated potato (Solanum tuberosum). Potato species are tetraploid and highly heterozygous.
Results
Here we present the software SATlotyper which is able to handle polyploid and polyallelic data. SATlo-typer uses the Boolean satisfiability problem to formulate Haplotype Inference by Pure Parsimony. The software excludes existing haplotype inferences, thus allowing for calculation of alternative inferences. As it is not known which of the multiple haplotype inferences are best supported by the given unphased data set, we use a bootstrapping procedure that allows for scoring of alternative inferences. Finally, by means of the bootstrapping scores, it is possible to optimise the phased genotypes belonging to a given haplotype inference. The program is evaluated with simulated and experimental SNP data generated for heterozygous tetraploid populations of potato. We show that, instead of taking the first haplotype inference reported by the program, we can significantly improve the quality of the final result by applying additional methods that include scoring of the alternative haplotype inferences and genotype optimisation. For a sub-population of nineteen individuals, the predicted results computed by SATlotyper were directly compared with results obtained by experimental haplotype inference via sequencing of cloned amplicons. Prediction and experiment gave similar results regarding the inferred haplotypes and phased genotypes.
Conclusion
Our results suggest that Haplotype Inference by Pure Parsimony can be solved efficiently by the SAT approach, even for data sets of unphased SNP from heterozygous polyploids. SATlotyper is freeware and is distributed as a Java JAR file. The software can be downloaded from the webpage of the GABI Primary Database at . The application of SATlotyper will provide haplotype information, which can be used in haplotype association mapping studies of polyploid plants.
doi:10.1186/1471-2164-9-356
PMCID: PMC2566320  PMID: 18667059
6.  Inferring haplotypes and parental genotypes in larger full sib-ships and other pedigrees with missing or erroneous genotype data 
BMC Genetics  2012;13:85.
Background
In many contexts, pedigrees for individuals are known even though not all individuals have been fully genotyped. In one extreme case, the genotypes for a set of full siblings are known, with no knowledge of parental genotypes. We propose a method for inferring phased haplotypes and genotypes for all individuals, even those with missing data, in such pedigrees, allowing a multitude of classic and recent methods for linkage and genome analysis to be used more efficiently.
Results
By artificially removing the founder generation genotype data from a well-studied simulated dataset, the quality of reconstructed genotypes in that generation can be verified. For the full structure of repeated matings with 15 offspring per mating, 10 dams per sire, 99.89% of all founder markers were phased correctly, given only the unphased genotypes for offspring. The accuracy was reduced only slightly, to 99.51%, when introducing a 2% error rate in offspring genotypes. When reduced to only 5 full-sib offspring in a single sire-dam mating, the corresponding percentage is 92.62%, which compares favorably with 89.28% from the leading Merlin package. Furthermore, Merlin is unable to handle more than approximately 10 sibs, as the number of states tracked rises exponentially with family size, while our approach has no such limit and handles 150 half-sibs with ease in our experiments.
Conclusions
Our method is able to reconstruct genotypes for parents when genotype data is only available for offspring individuals, as well as haplotypes for all individuals. Compared to the Merlin package, we can handle larger pedigrees and produce superior results, mainly due to the fact that Merlin uses the Viterbi algorithm on the state space to infer the genotype sequence. Tracking of haplotype and allele origin can be used in any application where the marker set does not directly influence genotype variation influencing traits. Inference of genotypes can also reduce the effects of genotyping errors and missing data. The cnF2freq codebase implementing our approach is available under a BSD-style license.
doi:10.1186/1471-2156-13-85
PMCID: PMC3562206  PMID: 23046532
Haplotyping; Phasing; Genotype inference; Nuclear family data; Hidden Markov models
7.  HaploRec: efficient and accurate large-scale reconstruction of haplotypes 
BMC Bioinformatics  2006;7:542.
Background
Haplotypes extracted from human DNA can be used for gene mapping and other analysis of genetic patterns within and across populations. A fundamental problem is, however, that current practical laboratory methods do not give haplotype information. Estimation of phased haplotypes of unrelated individuals given their unphased genotypes is known as the haplotype reconstruction or phasing problem.
Results
We define three novel statistical models and give an efficient algorithm for haplotype reconstruction, jointly called HaploRec. HaploRec is based on exploiting local regularities conserved in haplotypes: it reconstructs haplotypes so that they have maximal local coherence. This approach – not assuming statistical dependence for remotely located markers – has two useful properties: it is well-suited for sparse marker maps, such as those used in gene mapping, and it can actually take advantage of long maps.
Conclusion
Our experimental results with simulated and real data show that HaploRec is a powerful method for the large scale haplotyping needed in association studies. With sample sizes large enough for gene mapping it appeared to be the best compared to all other tested methods (Phase, fastPhase, PL-EM, Snphap, Gerbil; simulated data), with small samples it was competitive with the best available methods (real data). HaploRec is several orders of magnitude faster than Phase and comparable to the other methods; the running times are roughly linear in the number of subjects and the number of markers. HaploRec is publicly available at .
doi:10.1186/1471-2105-7-542
PMCID: PMC1766938  PMID: 17187677
8.  Investigation of Inversion Polymorphisms in the Human Genome Using Principal Components Analysis 
PLoS ONE  2012;7(7):e40224.
Despite the significant advances made over the last few years in mapping inversions with the advent of paired-end sequencing approaches, our understanding of the prevalence and spectrum of inversions in the human genome has lagged behind other types of structural variants, mainly due to the lack of a cost-efficient method applicable to large-scale samples. We propose a novel method based on principal components analysis (PCA) to characterize inversion polymorphisms using high-density SNP genotype data. Our method applies to non-recurrent inversions for which recombination between the inverted and non-inverted segments in inversion heterozygotes is suppressed due to the loss of unbalanced gametes. Inside such an inversion region, an effect similar to population substructure is thus created: two distinct “populations” of inversion homozygotes of different orientations and their 1∶1 admixture, namely the inversion heterozygotes. This kind of substructure can be readily detected by performing PCA locally in the inversion regions. Using simulations, we demonstrated that the proposed method can be used to detect and genotype inversion polymorphisms using unphased genotype data. We applied our method to the phase III HapMap data and inferred the inversion genotypes of known inversion polymorphisms at 8p23.1 and 17q21.31. These inversion genotypes were validated by comparing with literature results and by checking Mendelian consistency using the family data whenever available. Based on the PCA-approach, we also performed a preliminary genome-wide scan for inversions using the HapMap data, which resulted in 2040 candidate inversions, 169 of which overlapped with previously reported inversions. Our method can be readily applied to the abundant SNP data, and is expected to play an important role in developing human genome maps of inversions and exploring associations between inversions and susceptibility of diseases.
doi:10.1371/journal.pone.0040224
PMCID: PMC3392271  PMID: 22808122
9.  inPHAP: Interactive visualization of genotype and phased haplotype data 
BMC Bioinformatics  2014;15:200.
Background
To understand individual genomes it is necessary to look at the variations that lead to changes in phenotype and possibly to disease. However, genotype information alone is often not sufficient and additional knowledge regarding the phase of the variation is needed to make correct interpretations. Interactive visualizations, that allow the user to explore the data in various ways, can be of great assistance in the process of making well informed decisions. But, currently there is a lack for visualizations that are able to deal with phased haplotype data.
Results
We present inPHAP, an interactive visualization tool for genotype and phased haplotype data. inPHAP features a variety of interaction possibilities such as zooming, sorting, filtering and aggregation of rows in order to explore patterns hidden in large genetic data sets. As a proof of concept, we apply inPHAP to the phased haplotype data set of Phase 1 of the 1000 Genomes Project. Thereby, inPHAP’s ability to show genetic variations on the population as well as on the individuals level is demonstrated for several disease related loci.
Conclusions
As of today, inPHAP is the only visual analytical tool that allows the user to explore unphased and phased haplotype data interactively. Due to its highly scalable design, inPHAP can be applied to large datasets with up to 100 GB of data, enabling users to visualize even large scale input data. inPHAP closes the gap between common visualization tools for unphased genotype data and introduces several new features, such as the visualization of phased data. inPHAP is available for download at http://bit.ly/1iJgKmX.
doi:10.1186/1471-2105-15-200
PMCID: PMC4083868  PMID: 25002076
Genotype data; Phased haplotype data; Interactive visualization; 1000 genomes project
10.  HapTree: A Novel Bayesian Framework for Single Individual Polyplotyping Using NGS Data 
PLoS Computational Biology  2014;10(3):e1003502.
As the more recent next-generation sequencing (NGS) technologies provide longer read sequences, the use of sequencing datasets for complete haplotype phasing is fast becoming a reality, allowing haplotype reconstruction of a single sequenced genome. Nearly all previous haplotype reconstruction studies have focused on diploid genomes and are rarely scalable to genomes with higher ploidy. Yet computational investigations into polyploid genomes carry great importance, impacting plant, yeast and fish genomics, as well as the studies of the evolution of modern-day eukaryotes and (epi)genetic interactions between copies of genes. In this paper, we describe a novel maximum-likelihood estimation framework, HapTree, for polyploid haplotype assembly of an individual genome using NGS read datasets. We evaluate the performance of HapTree on simulated polyploid sequencing read data modeled after Illumina sequencing technologies. For triploid and higher ploidy genomes, we demonstrate that HapTree substantially improves haplotype assembly accuracy and efficiency over the state-of-the-art; moreover, HapTree is the first scalable polyplotyping method for higher ploidy. As a proof of concept, we also test our method on real sequencing data from NA12878 (1000 Genomes Project) and evaluate the quality of assembled haplotypes with respect to trio-based diplotype annotation as the ground truth. The results indicate that HapTree significantly improves the switch accuracy within phased haplotype blocks as compared to existing haplotype assembly methods, while producing comparable minimum error correction (MEC) values. A summary of this paper appears in the proceedings of the RECOMB 2014 conference, April 2–5.
Author Summary
While human and other eukaryotic genomes typically contain two copies of every chromosome, plants, yeast and fish such as salmon can have strictly more than two copies of each chromosome. By running standard genotype calling tools, it is possible to accurately identify the number of “wild type” and “mutant” alleles (A, C, G, or T) for each single-nucleotide polymorphism (SNP) site. However, in the case of two heterozygous SNP sites, genotype calling tools cannot determine whether “mutant” alleles from different SNP loci are on the same or different chromosomes. While the former would be healthy, in many cases the latter can cause loss of function; it is therefore necessary to identify the phase—the copies of a chromosome on which the mutant alleles occur—in addition to the genotype. This necessitates efficient algorithms to obtain accurate and comprehensive phase information directly from the next-generation-sequencing read data in higher ploidy species. We introduce an efficient statistical method for this task and show that our method significantly outperforms previous ones, in both accuracy and speed, for phasing triploid and higher ploidy genomes. Our method performs well on human diploid genomes as well, as demonstrated by our improved phasing of the well known NA12878 (1000 Genomes Project).
doi:10.1371/journal.pcbi.1003502
PMCID: PMC3967924  PMID: 24675685
11.  Lep-MAP: fast and accurate linkage map construction for large SNP datasets 
Bioinformatics  2013;29(24):3128-3134.
Motivation: Current high-throughput sequencing technologies allow cost-efficient genotyping of millions of single nucleotide polymorphisms (SNPs) for hundreds of samples. However, the tools that are currently available for constructing linkage maps are not well suited for large datasets. Linkage maps of large datasets would be helpful in de novo genome assembly by facilitating comprehensive genome validation and refinement by enabling chimeric scaffold detection, as well as in family-based linkage and association studies, quantitative trait locus mapping, analysis of genome synteny and other complex genomic data analyses.
Results: We describe a novel tool, called Lepidoptera-MAP (Lep-MAP), for constructing accurate linkage maps with ultradense genome-wide SNP data. Lep-MAP is fast and memory efficient and largely automated, requiring minimal user interaction. It uses simultaneously data on multiple outbred families and can increase linkage map accuracy by taking into account achiasmatic meiosis, a special feature of Lepidoptera and some other taxa with no recombination in one sex (no recombination in females in Lepidoptera). We demonstrate that Lep-MAP outperforms other methods on real and simulated data. We construct a genome-wide linkage map of the Glanville fritillary butterfly (Melitaea cinxia) with over 40 000 SNPs. The data were generated with a novel in-house SOLiD restriction site-associated DNA tag sequencing protocol, which is described in the online supplementary material.
Availability and implementation: Java source code under GNU general public license with the compiled classes and the datasets are available from http://sourceforge.net/users/lep-map.
Contact: pasi.rastas@helsinki.fi
Supplementary information: Supplementary data are available at Bioinformatics online.
doi:10.1093/bioinformatics/btt563
PMCID: PMC4433499  PMID: 24078685
12.  Viral diversity and clonal evolution from unphased genomic data 
BMC Genomics  2014;15(Suppl 6):S17.
Background
Clonal expansion is a process in which a single organism reproduces asexually, giving rise to a diversifying population. It is pervasive in nature, from within-host pathogen evolution to emergent infectious disease outbreaks. Standard phylogenetic tools rely on full-length genomes of individual pathogens or population consensus sequences (phased genotypes).
Although high-throughput sequencing technologies are able to sample population diversity, the short sequence reads inherent to them preclude assessing whether two reads originate from the same clone (unphased genotypes). This obstacle severely limits the application of phylogenetic methods and investigation of within-host dynamics of acute infections using this rich data source.
Methods
We introduce two measures of diversity to study the evolution of clonal populations using unphased genomic data, which eliminate the need to construct full-length genomes. Our method follows a maximum likelihood approach to estimate evolutionary rates and times to the most recent common ancestor, based on a relaxed molecular clock model; independent of a growth model. Deviations from neutral evolution indicate the presence of selection and bottleneck events.
Results
We evaluated our methods in silico and then compared it against existing approaches with the well-characterized 2009 H1N1 influenza pandemic. We then applied our method to high-throughput genomic data from marburgvirus-infected non-human primates and inferred the time of infection and the intra-host evolutionary rate, and identified purifying selection in viral populations.
Conclusions
Our method has the power to make use of minor variants present in less than 1% of the population and capture genomic diversification within days of infection, making it an ideal tool for the study of acute RNA viral infection dynamics.
doi:10.1186/1471-2164-15-S6-S17
PMCID: PMC4240099  PMID: 25573168
Clonal evolution; Evolutionary dynamics; Viral genomic diversity; Marburgvirus
13.  Efficient and Accurate Construction of Genetic Linkage Maps from the Minimum Spanning Tree of a Graph 
PLoS Genetics  2008;4(10):e1000212.
Genetic linkage maps are cornerstones of a wide spectrum of biotechnology applications, including map-assisted breeding, association genetics, and map-assisted gene cloning. During the past several years, the adoption of high-throughput genotyping technologies has been paralleled by a substantial increase in the density and diversity of genetic markers. New genetic mapping algorithms are needed in order to efficiently process these large datasets and accurately construct high-density genetic maps. In this paper, we introduce a novel algorithm to order markers on a genetic linkage map. Our method is based on a simple yet fundamental mathematical property that we prove under rather general assumptions. The validity of this property allows one to determine efficiently the correct order of markers by computing the minimum spanning tree of an associated graph. Our empirical studies obtained on genotyping data for three mapping populations of barley (Hordeum vulgare), as well as extensive simulations on synthetic data, show that our algorithm consistently outperforms the best available methods in the literature, particularly when the input data are noisy or incomplete. The software implementing our algorithm is available in the public domain as a web tool under the name MSTmap.
Author Summary
Genetic linkage maps are cornerstones of a wide spectrum of biotechnology applications. In recent years, new high-throughput genotyping technologies have substantially increased the density and diversity of genetic markers, creating new algorithmic challenges for computational biologists. In this paper, we present a novel algorithmic method to construct genetic maps based on a new theoretical insight. Our approach outperforms the best methods available in the scientific literature, particularly when the input data are noisy or incomplete.
doi:10.1371/journal.pgen.1000212
PMCID: PMC2556103  PMID: 18846212
14.  A haplotype inference algorithm for trios based on deterministic sampling 
BMC Genetics  2010;11:78.
Background
In genome-wide association studies, thousands of individuals are genotyped in hundreds of thousands of single nucleotide polymorphisms (SNPs). Statistical power can be increased when haplotypes, rather than three-valued genotypes, are used in analysis, so the problem of haplotype phase inference (phasing) is particularly relevant. Several phasing algorithms have been developed for data from unrelated individuals, based on different models, some of which have been extended to father-mother-child "trio" data.
Results
We introduce a technique for phasing trio datasets using a tree-based deterministic sampling scheme. We have compared our method with publicly available algorithms PHASE v2.1, BEAGLE v3.0.2 and 2SNP v1.7 on datasets of varying number of markers and trios. We have found that the computational complexity of PHASE makes it prohibitive for routine use; on the other hand 2SNP, though the fastest method for small datasets, was significantly inaccurate. We have shown that our method outperforms BEAGLE in terms of speed and accuracy for small to intermediate dataset sizes in terms of number of trios for all marker sizes examined. Our method is implemented in the "Tree-Based Deterministic Sampling" (TDS) package, available for download at http://www.ee.columbia.edu/~anastas/tds
Conclusions
Using a Tree-Based Deterministic sampling technique, we present an intuitive and conceptually simple phasing algorithm for trio data. The trade off between speed and accuracy achieved by our algorithm makes it a strong candidate for routine use on trio datasets.
doi:10.1186/1471-2156-11-78
PMCID: PMC2939632  PMID: 20727218
15.  Linkage disequilibrium based genotype calling from low-coverage shotgun sequencing reads 
BMC Bioinformatics  2011;12(Suppl 1):S53.
Background
Recent technology advances have enabled sequencing of individual genomes, promising to revolutionize biomedical research. However, deep sequencing remains more expensive than microarrays for performing whole-genome SNP genotyping.
Results
In this paper we introduce a new multi-locus statistical model and computationally efficient genotype calling algorithms that integrate shotgun sequencing data with linkage disequilibrium (LD) information extracted from reference population panels such as Hapmap or the 1000 genomes project. Experiments on publicly available 454, Illumina, and ABI SOLiD sequencing datasets suggest that integration of LD information results in genotype calling accuracy comparable to that of microarray platforms from sequencing data of low-coverage. A software package implementing our algorithm, released under the GNU General Public License, is available at http://dna.engr.uconn.edu/software/GeneSeq/.
Conclusions
Integration of LD information leads to significant improvements in genotype calling accuracy compared to prior LD-oblivious methods, rendering low-coverage sequencing as a viable alternative to microarrays for conducting large-scale genome-wide association studies.
doi:10.1186/1471-2105-12-S1-S53
PMCID: PMC3044311  PMID: 21342586
16.  Inference of the Haplotype Effect in a Matched Case-Control Study Using Unphased Genotype Data* 
Typically locus specific genotype data do not contain information regarding the gametic phase of haplotypes, especially when an individual is heterozygous at more than one locus among a large number of linked polymorphic loci. Thus, studying disease-haplotype association using unphased genotype data is essentially a problem of handling a missing covariate in a case-control design. There are several methods for estimating a disease-haplotype association parameter in a matched case-control study. Here we propose a conditional likelihood approach for inference regarding the disease-haplotype association using unphased genotype data arising from a matched case-control study design. The proposed method relies on a logistic disease risk model and a Hardy-Weinberg equilibrium (HWE) among the control population only. We develop an expectation and conditional maximization (ECM) algorithm for jointly estimating the haplotype frequency and the disease-haplotype association parameter(s). We apply the proposed method to analyze the data from the Alpha-Tocopherol, Beta-Carotene Cancer prevention study, and a matched case-control study of breast cancer patients conducted in Israel. The performance of the proposed method is evaluated via simulation studies.
doi:10.2202/1557-4679.1079
PMCID: PMC2835450  PMID: 20231916
17.  Multinomial logistic regression approach to haplotype association analysis in population-based case-control studies 
BMC Genetics  2006;7:43.
Background
The genetic association analysis using haplotypes as basic genetic units is anticipated to be a powerful strategy towards the discovery of genes predisposing human complex diseases. In particular, the increasing availability of high-resolution genetic markers such as the single-nucleotide polymorphisms (SNPs) has made haplotype-based association analysis an attractive alternative to single marker analysis.
Results
We consider haplotype association analysis under the population-based case-control study design. A multinomial logistic model is proposed for haplotype analysis with unphased genotype data, which can be decomposed into a prospective logistic model for disease risk as well as a model for the haplotype-pair distribution in the control population. Environmental factors can be readily incorporated and hence the haplotype-environment interaction can be assessed in the proposed model. The maximum likelihood estimation with unphased genotype data can be conveniently implemented in the proposed model by applying the EM algorithm to a prospective multinomial logistic regression model and ignoring the case-control design. We apply the proposed method to the hypertriglyceridemia study and identifies 3 haplotypes in the apolipoprotein A5 gene that are associated with increased risk for hypertriglyceridemia. A haplotype-age interaction effect is also identified. Simulation studies show that the proposed estimator has satisfactory finite-sample performances.
Conclusion
Our results suggest that the proposed method can serve as a useful alternative to existing methods and a reliable tool for the case-control haplotype-based association analysis.
doi:10.1186/1471-2156-7-43
PMCID: PMC1559715  PMID: 16907993
18.  SNPAnalyzer 2.0: A web-based integrated workbench for linkage disequilibrium analysis and association analysis 
BMC Bioinformatics  2008;9:290.
Background
Since the completion of the HapMap project, huge numbers of individual genotypes have been generated from many kinds of laboratories. The efforts of finding or interpreting genetic association between disease and SNPs/haplotypes have been on-going widely. So, the necessity of the capability to analyze huge data and diverse interpretation of the results are growing rapidly.
Results
We have developed an advanced tool to perform linkage disequilibrium analysis, and genetic association analysis between disease and SNPs/haplotypes in an integrated web interface. It comprises of four main analysis modules: (i) data import and preprocessing, (ii) haplotype estimation, (iii) LD blocking and (iv) association analysis. Hardy-Weinberg Equilibrium test is implemented for each SNPs in the data preprocessing. Haplotypes are reconstructed from unphased diploid genotype data, and linkage disequilibrium between pairwise SNPs is computed and represented by D', r2 and LOD score. Tagging SNPs are determined by using the square of Pearson's correlation coefficient (r2). If genotypes from two different sample groups are available, diverse genetic association analyses are implemented using additive, codominant, dominant and recessive models. Multiple verified algorithms and statistics are implemented in parallel for the reliability of the analysis.
Conclusion
SNPAnalyzer 2.0 performs linkage disequilibrium analysis and genetic association analysis in an integrated web interface using multiple verified algorithms and statistics. Diverse analysis methods, capability of handling huge data and visual comparison of analysis results are very comprehensive and easy-to-use.
doi:10.1186/1471-2105-9-290
PMCID: PMC2453143  PMID: 18570686
19.  Using 2k + 2 bubble searches to find single nucleotide polymorphisms in k-mer graphs 
Bioinformatics  2014;31(5):642-646.
Motivation: Single nucleotide polymorphism (SNP) discovery is an important preliminary for understanding genetic variation. With current sequencing methods, we can sample genomes comprehensively. SNPs are found by aligning sequence reads against longer assembled references. De Bruijn graphs are efficient data structures that can deal with the vast amount of data from modern technologies. Recent work has shown that the topology of these graphs captures enough information to allow the detection and characterization of genetic variants, offering an alternative to alignment-based methods. Such methods rely on depth-first walks of the graph to identify closing bifurcations. These methods are conservative or generate many false-positive results, particularly when traversing highly inter-connected (complex) regions of the graph or in regions of very high coverage.
Results: We devised an algorithm that calls SNPs in converted De Bruijn graphs by enumerating 2k + 2 cycles. We evaluated the accuracy of predicted SNPs by comparison with SNP lists from alignment-based methods. We tested accuracy of the SNP calling using sequence data from 16 ecotypes of Arabidopsis thaliana and found that accuracy was high. We found that SNP calling was even across the genome and genomic feature types. Using sequence-based attributes of the graph to train a decision tree allowed us to increase accuracy of SNP calls further. Together these results indicate that our algorithm is capable of finding SNPs accurately in complex sub-graphs and potentially comprehensively from whole genome graphs.
Availability and implementation: The source code for a C++ implementation of our algorithm is available under the GNU Public Licence v3 at: https://github.com/danmaclean/2kplus2. The datasets used in this study are available at the European Nucleotide Archive, reference ERP00565, http://www.ebi.ac.uk/ena/data/view/ERP000565
Contact: dan.maclean@tsl.ac.uk
Supplementary information: Supplementary data are available at Bioinformatics online.
doi:10.1093/bioinformatics/btu706
PMCID: PMC4341063  PMID: 25344498
20.  HTreeQA: Using Semi-Perfect Phylogeny Trees in Quantitative Trait Loci Study on Genotype Data 
G3: Genes|Genomes|Genetics  2012;2(2):175-189.
With the advances in high-throughput genotyping technology, the study of quantitative trait loci (QTL) has emerged as a promising tool to understand the genetic basis of complex traits. Methodology development for the study of QTL recently has attracted significant research attention. Local phylogeny-based methods have been demonstrated to be powerful tools for uncovering significant associations between phenotypes and single-nucleotide polymorphism markers. However, most existing methods are designed for homozygous genotypes, and a separate haplotype reconstruction step is often needed to resolve heterozygous genotypes. This approach has limited power to detect nonadditive genetic effects and imposes an extensive computational burden. In this article, we propose a new method, HTreeQA, that uses a tristate semi-perfect phylogeny tree to approximate the perfect phylogeny used in existing methods. The semi-perfect phylogeny trees are used as high-level markers for association study. HTreeQA uses the genotype data as direct input without phasing. HTreeQA can handle complex local population structures. It is suitable for QTL mapping on any mouse populations, including the incipient Collaborative Cross lines. Applied HTreeQA, significant QTLs are found for two phenotypes of the PreCC lines, white head spot and running distance at day 5/6. These findings are consistent with known genes and QTL discovered in independent studies. Simulation studies under three different genetic models show that HTreeQA can detect a wider range of genetic effects and is more efficient than existing phylogeny-based approaches. We also provide rigorous theoretical analysis to show that HTreeQA has a lower error rate than alternative methods.
doi:10.1534/g3.111.001768
PMCID: PMC3284325  PMID: 22384396
phylogeny; quantitative trait loci (QTL); Mouse Collaborative Cross; Mouse Genetic Resource
21.  PRIMAL: Fast and Accurate Pedigree-based Imputation from Sequence Data in a Founder Population 
PLoS Computational Biology  2015;11(3):e1004139.
Founder populations and large pedigrees offer many well-known advantages for genetic mapping studies, including cost-efficient study designs. Here, we describe PRIMAL (PedigRee IMputation ALgorithm), a fast and accurate pedigree-based phasing and imputation algorithm for founder populations. PRIMAL incorporates both existing and original ideas, such as a novel indexing strategy of Identity-By-Descent (IBD) segments based on clique graphs. We were able to impute the genomes of 1,317 South Dakota Hutterites, who had genome-wide genotypes for ~300,000 common single nucleotide variants (SNVs), from 98 whole genome sequences. Using a combination of pedigree-based and LD-based imputation, we were able to assign 87% of genotypes with >99% accuracy over the full range of allele frequencies. Using the IBD cliques we were also able to infer the parental origin of 83% of alleles, and genotypes of deceased recent ancestors for whom no genotype information was available. This imputed data set will enable us to better study the relative contribution of rare and common variants on human phenotypes, as well as parental origin effect of disease risk alleles in >1,000 individuals at minimal cost.
Author Summary
The recent availability of whole genome and whole exome sequencing allows genetic studies of human diseases and traits at an unprecedented resolution, although their cost limits the size of the studied sample. To overcome this limitation and design cost-efficient studies, we developed a two step method: sequencing of relatively few members of a well-characterized founder population followed by pedigree-based whole genome imputation of many other individuals with genome-wide genotype data. We show that by sequencing only 98 Hutterites, we can impute 7 million variants in an additional 1,317 Hutterites with >99% accuracy and an average call rate of 87%. Furthermore, parental origin was assigned to 83% of the alleles. Such studies in the Hutterites and other founder populations should yield new insights into the genetic architecture of common diseases, gene expression traits, and clinically relevant biomarkers of disease, and ultimately provide outstanding opportunities for personalized medicine in these well-characterized populations.
doi:10.1371/journal.pcbi.1004139
PMCID: PMC4348507  PMID: 25735005
22.  A combined long-range phasing and long haplotype imputation method to impute phase for SNP genotypes 
Background
Knowing the phase of marker genotype data can be useful in genome-wide association studies, because it makes it possible to use analysis frameworks that account for identity by descent or parent of origin of alleles and it can lead to a large increase in data quantities via genotype or sequence imputation. Long-range phasing and haplotype library imputation constitute a fast and accurate method to impute phase for SNP data.
Methods
A long-range phasing and haplotype library imputation algorithm was developed. It combines information from surrogate parents and long haplotypes to resolve phase in a manner that is not dependent on the family structure of a dataset or on the presence of pedigree information.
Results
The algorithm performed well in both simulated and real livestock and human datasets in terms of both phasing accuracy and computation efficiency. The percentage of alleles that could be phased in both simulated and real datasets of varying size generally exceeded 98% while the percentage of alleles incorrectly phased in simulated data was generally less than 0.5%. The accuracy of phasing was affected by dataset size, with lower accuracy for dataset sizes less than 1000, but was not affected by effective population size, family data structure, presence or absence of pedigree information, and SNP density. The method was computationally fast. In comparison to a commonly used statistical method (fastPHASE), the current method made about 8% less phasing mistakes and ran about 26 times faster for a small dataset. For larger datasets, the differences in computational time are expected to be even greater. A computer program implementing these methods has been made available.
Conclusions
The algorithm and software developed in this study make feasible the routine phasing of high-density SNP chips in large datasets.
doi:10.1186/1297-9686-43-12
PMCID: PMC3068938  PMID: 21388557
23.  Application of the Linux cluster for exhaustive window haplotype analysis using the FBAT and Unphased programs 
BMC Bioinformatics  2008;9(Suppl 6):S10.
Background
Genetic association studies have been used to map disease-causing genes. A newly introduced statistical method, called exhaustive haplotype association study, analyzes genetic information consisting of different numbers and combinations of DNA sequence variations along a chromosome. Such studies involve a large number of statistical calculations and subsequently high computing power. It is possible to develop parallel algorithms and codes to perform the calculations on a high performance computing (HPC) system. However, most existing commonly-used statistic packages for genetic studies are non-parallel versions. Alternatively, one may use the cutting-edge technology of grid computing and its packages to conduct non-parallel genetic statistical packages on a centralized HPC system or distributed computing systems. In this paper, we report the utilization of a queuing scheduler built on the Grid Engine and run on a Rocks Linux cluster for our genetic statistical studies.
Results
Analysis of both consecutive and combinational window haplotypes was conducted by the FBAT (Laird et al., 2000) and Unphased (Dudbridge, 2003) programs. The dataset consisted of 26 loci from 277 extended families (1484 persons). Using the Rocks Linux cluster with 22 compute-nodes, FBAT jobs performed about 14.4–15.9 times faster, while Unphased jobs performed 1.1–18.6 times faster compared to the accumulated computation duration.
Conclusion
Execution of exhaustive haplotype analysis using non-parallel software packages on a Linux-based system is an effective and efficient approach in terms of cost and performance.
doi:10.1186/1471-2105-9-S6-S10
PMCID: PMC2423433  PMID: 18541045
24.  Joint amalgamation of most parsimonious reconciled gene trees 
Bioinformatics  2014;31(6):841-848.
Motivation: Traditionally, gene phylogenies have been reconstructed solely on the basis of molecular sequences; this, however, often does not provide enough information to distinguish between statistically equivalent relationships. To address this problem, several recent methods have incorporated information on the species phylogeny in gene tree reconstruction, leading to dramatic improvements in accuracy. Although probabilistic methods are able to estimate all model parameters but are computationally expensive, parsimony methods—generally computationally more efficient—require a prior estimate of parameters and of the statistical support.
Results: Here, we present the Tree Estimation using Reconciliation (TERA) algorithm, a parsimony based, species tree aware method for gene tree reconstruction based on a scoring scheme combining duplication, transfer and loss costs with an estimate of the sequence likelihood. TERA explores all reconciled gene trees that can be amalgamated from a sample of gene trees. Using a large scale simulated dataset, we demonstrate that TERA achieves the same accuracy as the corresponding probabilistic method while being faster, and outperforms other parsimony-based methods in both accuracy and speed. Running TERA on a set of 1099 homologous gene families from complete cyanobacterial genomes, we find that incorporating knowledge of the species tree results in a two thirds reduction in the number of apparent transfer events.
Availability and implementation: The algorithm is implemented in our program TERA, which is freely available from http://mbb.univ-montp2.fr/MBB/download_sources/16__TERA.
Contact: celine.scornavacca@univ-montp2.fr, ssolo@angel.elte.hu
Supplementary information: Supplementary data are available at Bioinformatics online.
doi:10.1093/bioinformatics/btu728
PMCID: PMC4380024  PMID: 25380957
25.  Correcting population stratification in genetic association studies using a phylogenetic approach 
Bioinformatics  2010;26(6):798-806.
Motivation: The rapid development of genotyping technology and extensive cataloguing of single nucleotide polymorphisms (SNPs) across the human genome have made genetic association studies the mainstream for gene mapping of complex human diseases. For many diseases, the most practical approach is the population-based design with unrelated individuals. Although having the advantages of easier sample collection and greater power than family-based designs, unrecognized population stratification in the study samples can lead to both false-positive and false-negative findings and might obscure the true association signals if not appropriately corrected.
Methods: We report PHYLOSTRAT, a new method that corrects for population stratification by combining phylogeny constructed from SNP genotypes and principal coordinates from multi-dimensional scaling (MDS) analysis. This hybrid approach efficiently captures both discrete and admixed population structures.
Results: By extensive simulations, the analysis of a synthetic genome-wide association dataset created using data from the Human Genome Diversity Project, and the analysis of a lactase-height dataset, we show that our method can correct for population stratification more efficiently than several existing population stratification correction methods, including EIGENSTRAT, a hybrid approach based on MDS and clustering, and STRATSCORE , in terms of requiring fewer random SNPs for inference of population structure. By combining the flexibility and hierarchical nature of phylogenetic trees with the advantage of representing admixture using MDS, our hybrid approach can capture the complex population structures in human populations effectively.
Software Availability: Codes can be downloaded from http://people.pcbi.upenn.edu/∼lswang/phylostrat/
Contact: mingyao@upenn.edu; iswang@upenn.edu.
Supplementary information: Supplementary data are available at Bioinformatics online.
doi:10.1093/bioinformatics/btq025
PMCID: PMC2832820  PMID: 20097913

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