4,937 research outputs found
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MPRAnalyze: statistical framework for massively parallel reporter assays.
Massively parallel reporter assays (MPRAs) can measure the regulatory function of thousands of DNA sequences in a single experiment. Despite growing popularity, MPRA studies are limited by a lack of a unified framework for analyzing the resulting data. Here we present MPRAnalyze: a statistical framework for analyzing MPRA count data. Our model leverages the unique structure of MPRA data to quantify the function of regulatory sequences, compare sequences' activity across different conditions, and provide necessary flexibility in an evolving field. We demonstrate the accuracy and applicability of MPRAnalyze on simulated and published data and compare it with existing methods
Pathway-Based Genomics Prediction using Generalized Elastic Net.
We present a novel regularization scheme called The Generalized Elastic Net (GELnet) that incorporates gene pathway information into feature selection. The proposed formulation is applicable to a wide variety of problems in which the interpretation of predictive features using known molecular interactions is desired. The method naturally steers solutions toward sets of mechanistically interlinked genes. Using experiments on synthetic data, we demonstrate that pathway-guided results maintain, and often improve, the accuracy of predictors even in cases where the full gene network is unknown. We apply the method to predict the drug response of breast cancer cell lines. GELnet is able to reveal genetic determinants of sensitivity and resistance for several compounds. In particular, for an EGFR/HER2 inhibitor, it finds a possible trans-differentiation resistance mechanism missed by the corresponding pathway agnostic approach
Methods for Joint Normalization and Comparison of Hi-C data
The development of chromatin conformation capture technology has opened new avenues of study into the 3D structure and function of the genome. Chromatin structure is known to influence gene regulation, and differences in structure are now emerging as a mechanism of regulation between, e.g., cell differentiation and disease vs. normal states. Hi-C sequencing technology now provides a way to study the 3D interactions of the chromatin over the whole genome. However, like all sequencing technologies, Hi-C suffers from several forms of bias stemming from both the technology and the DNA sequence itself. Several normalization methods have been developed for normalizing individual Hi-C datasets, but little work has been done on developing joint normalization methods for comparing two or more Hi-C datasets. To make full use of Hi-C data, joint normalization and statistical comparison techniques are needed to carry out experiments to identify regions where chromatin structure differs between conditions.
We develop methods for the joint normalization and comparison of two Hi-C datasets, which we then extended to more complex experimental designs. Our normalization method is novel in that it makes use of the distance-dependent nature of chromatin interactions. Our modification of the Minus vs. Average (MA) plot to the Minus vs. Distance (MD) plot allows for a nonparametric data-driven normalization technique using loess smoothing. Additionally, we present a simple statistical method using Z-scores for detecting differentially interacting regions between two datasets. Our initial method was published as the Bioconductor R package HiCcompare [http://bioconductor.org/packages/HiCcompare/](http://bioconductor.org/packages/HiCcompare/).
We then further extended our normalization and comparison method for use in complex Hi-C experiments with more than two datasets and optional covariates. We extended the normalization method to jointly normalize any number of Hi-C datasets by using a cyclic loess procedure on the MD plot. The cyclic loess normalization technique can remove between dataset biases efficiently and effectively even when several datasets are analyzed at one time. Our comparison method implements a generalized linear model-based approach for comparing complex Hi-C experiments, which may have more than two groups and additional covariates. The extended methods are also available as a Bioconductor R package [http://bioconductor.org/packages/multiHiCcompare/](http://bioconductor.org/packages/multiHiCcompare/). Finally, we demonstrate the use of HiCcompare and multiHiCcompare in several test cases on real data in addition to comparing them to other similar methods (https://doi.org/10.1002/cpbi.76)
Iterative Random Forests to detect predictive and stable high-order interactions
Genomics has revolutionized biology, enabling the interrogation of whole
transcriptomes, genome-wide binding sites for proteins, and many other
molecular processes. However, individual genomic assays measure elements that
interact in vivo as components of larger molecular machines. Understanding how
these high-order interactions drive gene expression presents a substantial
statistical challenge. Building on Random Forests (RF), Random Intersection
Trees (RITs), and through extensive, biologically inspired simulations, we
developed the iterative Random Forest algorithm (iRF). iRF trains a
feature-weighted ensemble of decision trees to detect stable, high-order
interactions with same order of computational cost as RF. We demonstrate the
utility of iRF for high-order interaction discovery in two prediction problems:
enhancer activity in the early Drosophila embryo and alternative splicing of
primary transcripts in human derived cell lines. In Drosophila, among the 20
pairwise transcription factor interactions iRF identifies as stable (returned
in more than half of bootstrap replicates), 80% have been previously reported
as physical interactions. Moreover, novel third-order interactions, e.g.
between Zelda (Zld), Giant (Gt), and Twist (Twi), suggest high-order
relationships that are candidates for follow-up experiments. In human-derived
cells, iRF re-discovered a central role of H3K36me3 in chromatin-mediated
splicing regulation, and identified novel 5th and 6th order interactions,
indicative of multi-valent nucleosomes with specific roles in splicing
regulation. By decoupling the order of interactions from the computational cost
of identification, iRF opens new avenues of inquiry into the molecular
mechanisms underlying genome biology
Predicting whole genome protein interaction networks from primary sequence data in model and non-model organisms using ENTS
Background
The large-scale identification of physical protein-protein interactions (PPIs) is an important step toward understanding how biological networks evolve and generate emergent phenotypes. However, experimental identification of PPIs is a laborious and error-prone process, and current methods of PPI prediction tend to be highly conservative or require large amounts of functional data that may not be available for newly-sequenced organisms. Results
In this study we demonstrate a random-forest based technique, ENTS, for the computational prediction of protein-protein interactions based only on primary sequence data. Our approach is able to efficiently predict interactions on a whole-genome scale for any eukaryotic organism, using pairwise combinations of conserved domains and predicted subcellular localization of proteins as input features. We present the first predicted interactome for the forest tree Populus trichocarpa in addition to the predicted interactomes for Saccharomyces cerevisiae, Homo sapiens, Mus musculus, and Arabidopsis thaliana. Comparing our approach to other PPI predictors, we find that ENTS performs comparably to or better than a number of existing approaches, including several that utilize a variety of functional information for their predictions. We also find that the predicted interactions are biologically meaningful, as indicated by similarity in functional annotations and enrichment of co-expressed genes in public microarray datasets. Furthermore, we demonstrate some of the biological insights that can be gained from these predicted interaction networks. We show that the predicted interactions yield informative groupings of P. trichocarpa metabolic pathways, literature-supported associations among human disease states, and theory-supported insight into the evolutionary dynamics of duplicated genes in paleopolyploid plants. Conclusion
We conclude that the ENTS classifier will be a valuable tool for the de novoannotation of genome sequences, providing initial clues about regulatory and metabolic network topology, and revealing relationships that are not immediately obvious from traditional homology-based annotations
Identification of novel risk loci, causal insights, and heritable risk for Parkinson's disease: a meta-analysis of genome-wide association studies
Background: Genome-wide association studies (GWAS) in Parkinson's disease have increased the scope of biological knowledge about the disease over the past decade. We aimed to use the largest aggregate of GWAS data to identify novel risk loci and gain further insight into the causes of Parkinson's disease. /
Methods: We did a meta-analysis of 17 datasets from Parkinson's disease GWAS available from European ancestry samples to nominate novel loci for disease risk. These datasets incorporated all available data. We then used these data to estimate heritable risk and develop predictive models of this heritability. We also used large gene expression and methylation resources to examine possible functional consequences as well as tissue, cell type, and biological pathway enrichments for the identified risk factors. Additionally, we examined shared genetic risk between Parkinson's disease and other phenotypes of interest via genetic correlations followed by Mendelian randomisation. /
Findings: Between Oct 1, 2017, and Aug 9, 2018, we analysed 7·8 million single nucleotide polymorphisms in 37 688 cases, 18 618 UK Biobank proxy-cases (ie, individuals who do not have Parkinson's disease but have a first degree relative that does), and 1·4 million controls. We identified 90 independent genome-wide significant risk signals across 78 genomic regions, including 38 novel independent risk signals in 37 loci. These 90 variants explained 16–36% of the heritable risk of Parkinson's disease depending on prevalence. Integrating methylation and expression data within a Mendelian randomisation framework identified putatively associated genes at 70 risk signals underlying GWAS loci for follow-up functional studies. Tissue-specific expression enrichment analyses suggested Parkinson's disease loci were heavily brain-enriched, with specific neuronal cell types being implicated from single cell data. We found significant genetic correlations with brain volumes (false discovery rate-adjusted p=0·0035 for intracranial volume, p=0·024 for putamen volume), smoking status (p=0·024), and educational attainment (p=0·038). Mendelian randomisation between cognitive performance and Parkinson's disease risk showed a robust association (p=8·00 × 10−7). /
Interpretation: These data provide the most comprehensive survey of genetic risk within Parkinson's disease to date, to the best of our knowledge, by revealing many additional Parkinson's disease risk loci, providing a biological context for these risk factors, and showing that a considerable genetic component of this disease remains unidentified. These associations derived from European ancestry datasets will need to be followed-up with more diverse data. /
Funding: The National Institute on Aging at the National Institutes of Health (USA), The Michael J Fox Foundation, and The Parkinson's Foundation (see appendix for full list of funding sources)
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Methods in functional data analysis and functional genomics
This thesis has two overall themes, both of which involve the word functional, albeit in different contexts. The theme that motivates two of the chapters is the development of methods that enable a deeper understanding of the variability of functional data. The theme of the final chapter is the development of methods that enable a deeper understanding of the landscape of functionality across the human genome in different human tissues.
The first chapter of this thesis provides a framework for quantifying the variability of functional data and for analyzing the factors that affect this variability. We extend functional principal components analysis by modeling the variance of principal component scores. We pose a Bayesian model, which we estimate using variational Bayes methods. We illustrate our model with an application to a kinematic dataset of two-dimensional planar reaching motions by healthy subjects, showing the effect of learning on motion variability.
The second chapter of this thesis provides an alternative method for decomposing functional data that follows a Poisson distribution. Classical methods pose a latent Gaussian process that is then linked to the observed data via a logarithmic link function. We pose an alternative model that draws on ideas from non-negative matrix factorization, in which we constrain both scores and spline coefficient vectors for the functional prototypes to be non-negative. We impose smoothness on the functional prototypes. We estimate our model using the method of alternating minimization. We illustrate our model with an application to a dataset of accelerometer readings from elderly healthy Americans.
The third chapter of this thesis focuses on functional genomics, rather than functional data analysis. Here we pose a method for unsupervised clustering of functional genomics data. Our method is non-parametric, allowing for flexible modeling of the functional genomics data without binarization. We estimate our model using variational Bayes methods, and illustrate it by calculating genome-wide functional scores (based on a partition of our clusters into functional and non-functional clusters) for 127 different human tissues. We show that these genome-wide and tissue-specific functional scores provide state-of-the-art functional prediction
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