Bayesian estimation of a phenotype network structure using reversible jump Markov chain Monte Carlo

<p>In this thesis we aim to estimate the unknown phenotype network structure existing among multiple interacting quantitative traits, assuming the genetic architecture is known. We begin by taking a frequentist approach and implement a score-based greedy hill-climbing search strategy using AICc to estimate an unknown phenotype network structure. This approach was inconsistent and overfitting was common, so we then propose a Bayesian approach that extends on the reversible jump Markov chain Monte Carlo algorithm. Our approach makes use of maximum likelihood estimates in the chain, so we have an efficient sampler using well-tuned proposal distributions. The common approach is to assume uniform priors over all network structures; however, we introduce a prior on the number of edges in the phenotype network structure, which prefers simple models with fewer directed edges. We determine that the relationship between the prior penalty and the joint posterior probability of the true model is not monotonic, there is some interplay between the two. Simulation studies were carried out and our approach is also applied to a published data set. It is determined that larger trait-to-trait effects are required to recover the phenotype network structure; however, mixing is generally slow, a common occurrence with reversible jump Markov chain Monte Carlo methods. We propose the use of a double step to combine two steps that alter the phenotype network structure. This proposes larger steps than the traditional birth and death move types, possibly changing the dimension of the model by more than one. This double step helped the sampler move between different phenotype network structures in simulated data sets.</p>

Bayesian estimation of a phenotype network structure using reversible jump Markov chain Monte Carlo

<p>In this thesis we aim to estimate the unknown phenotype network structure existing among multiple interacting quantitative traits, assuming the genetic architecture is known. We begin by taking a frequentist approach and implement a score-based greedy hill-climbing search strategy using AICc to estimate an unknown phenotype network structure. This approach was inconsistent and overfitting was common, so we then propose a Bayesian approach that extends on the reversible jump Markov chain Monte Carlo algorithm. Our approach makes use of maximum likelihood estimates in the chain, so we have an efficient sampler using well-tuned proposal distributions. The common approach is to assume uniform priors over all network structures; however, we introduce a prior on the number of edges in the phenotype network structure, which prefers simple models with fewer directed edges. We determine that the relationship between the prior penalty and the joint posterior probability of the true model is not monotonic, there is some interplay between the two. Simulation studies were carried out and our approach is also applied to a published data set. It is determined that larger trait-to-trait effects are required to recover the phenotype network structure; however, mixing is generally slow, a common occurrence with reversible jump Markov chain Monte Carlo methods. We propose the use of a double step to combine two steps that alter the phenotype network structure. This proposes larger steps than the traditional birth and death move types, possibly changing the dimension of the model by more than one. This double step helped the sampler move between different phenotype network structures in simulated data sets.</p>

Multiplex gene and phenotype network to characterize shared genetic pathways of epilepsy and autism

It is well established that epilepsy and autism spectrum disorder (ASD) commonly co-occur; however, the underlying biological mechanisms of the co-occurence from their genetic susceptibility are not well understood. Our aim in this study is to characterize genetic modules of subgroups of epilepsy and autism genes that have similar phenotypic manifestations and biological functions. We first integrate a large number of expert-compiled and well-established epilepsy- and ASD-associated genes in a multiplex network, where one layer is connected through protein–protein interaction (PPI) and the other layer through gene-phenotype associations. We identify two modules in the multiplex network, which are significantly enriched in genes associated with both epilepsy and autism as well as genes highly expressed in brain tissues. We find that the first module, which represents the Gene Ontology category of ion transmembrane transport, is more epilepsy-focused, while the second module, representing synaptic signaling, is more ASD-focused. However, because of their enrichment in common genes and association with both epilepsy and ASD phenotypes, these modules point to genetic etiologies and biological processes shared between specific subtypes of epilepsy and ASD. Finally, we use our analysis to prioritize new candidate genes for epilepsy (i.e. ANK2, CACNA1E, CACNA2D3, GRIA2, DLG4) for further validation. The analytical approaches in our study can be applied to similar studies in the future to investigate the genetic connections between different human diseases.

NETMAGE: a humaN-disEase phenoType MAp GEnerator for the Visualization of PheWAS

SummaryGiven genetic associations from a PheWAS, a disease-disease network can be constructed where nodes represent phenotypes and edges represent shared genetic associations between phenotypes. To improve the accessibility of the visualization of shared genetic components across phenotypes, we developed the humaN-disEase phenoType MAp GEnerator (NETMAGE), a web-based tool that produces interactive phenotype network visualizations from summarized PheWAS results. Users can search the map by a variety of attributes, and they can select nodes to view information such as related phenotypes, associated SNPs, and other network statistics. As a test case, we constructed a network using UK BioBank PheWAS summary data. By examining the associations between phenotypes in our map, we can potentially identify novel instances of pleiotropy, where loci influence multiple phenotypic traits. Thus, our tool provides researchers with a means to identify prospective genetic targets for drug design, contributing to the exploration of personalized medicine.Availability and implementationOur service runs at https://hdpm.biomedinfolab.com. Source code can be downloaded at https://github.com/dokyoonkimlab/[email protected] informationSupplementary data and user guide are available at Bioinformatics online.

Pioneering Methods for Enhancing PPI and Phenotype Networks for Candidate Disease Prioritization

The physical contacts of high-specificity between two or more protein molecules constitute Protein-Protein Interactions (PPIs). PPI networks are modeled through graphs where node denotes proteins and edges denote interaction between proteins. The PPI network plays an important role to identify the interesting disease gene candidates. But, the PPI network usually contains false interactions. Many techniques have been proposed to reconstruct PPI network to remove false interactions and improve ranking of candidate disease. Random Walk with Restart on Diffusion profile (RWRDP) and Random Walk on a Reliable Heterogeneous Network (RWRHN) was two among them. In these methods, Gene topological similarity was incorporated with original PPI network to reconstruct new PPI network. Phenotype network was constructed by calculating similarity between gene phenotypes. The reconstructed network and phenotype networks were combined to rank candidate disease genes. However, the PPI reconstruction was fully related with the quality of protein interaction data. In order to enhance the reconstruction of PPI, a Piecewise Linear Regression (PLR) based protein sequence similarity measure and Bat Algorithm based gene expression similarity were proposed with RHN. In this paper, additional measure called Interaction Level Sub cellular Localization Score (ILSLS) is proposed to further reduce the false interaction in the reconstruction of PPI network. ILSLS is the combination of Normalized Sub cellular Localization score (NSL) and Protein Multiple Location Prediction score (PMLP). The proposed work is named as Random Walker on Optimized Trustworthy Heterogeneous Sub Cellular localization aware Network (RW-OTHSN). In order to enhance the ranking of RWOTHSN, phenotype structure is considered while construction phenotype network to rank the candidate disease genes. The phenotype structure is characterized based on h*-sequence model which identify highly discriminative signatures with only a small number of genes. This proposed work is named as Random Walker on Optimized Trustworthy Heterogeneous Sub Cellular localization and Phenotype structure aware Network (RWOTHSPN). The efficiency of the proposed methods are evaluated on PPI network database in terms of Average degree, Relative Frequency for PPI reconstruction, Number of successful predictions, precision and recall for candidate disease gene ranking.

Identifying emerging phenomenon in long temporal phenotyping experiments

Motivation The rapid improvement of phenotyping capability, accuracy and throughput have greatly increased the volume and diversity of phenomics data. A remaining challenge is an efficient way to identify phenotypic patterns to improve our understanding of the quantitative variation of complex phenotypes, and to attribute gene functions. To address this challenge, we developed a new algorithm to identify emerging phenomena from large-scale temporal plant phenotyping experiments. An emerging phenomenon is defined as a group of genotypes who exhibit a coherent phenotype pattern during a relatively short time. Emerging phenomena are highly transient and diverse, and are dependent in complex ways on both environmental conditions and development. Identifying emerging phenomena may help biologists to examine potential relationships among phenotypes and genotypes in a genetically diverse population and to associate such relationships with the change of environments or development. Results We present an emerging phenomenon identification tool called Temporal Emerging Phenomenon Finder (TEP-Finder). Using large-scale longitudinal phenomics data as input, TEP-Finder first encodes the complicated phenotypic patterns into a dynamic phenotype network. Then, emerging phenomena in different temporal scales are identified from dynamic phenotype network using a maximal clique based approach. Meanwhile, a directed acyclic network of emerging phenomena is composed to model the relationships among the emerging phenomena. The experiment that compares TEP-Finder with two state-of-art algorithms shows that the emerging phenomena identified by TEP-Finder are more functionally specific, robust and biologically significant. Availability and implementation The source code, manual and sample data of TEP-Finder are all available at: http://phenomics.uky.edu/TEP-Finder/. Supplementary information Supplementary data are available at Bioinformatics online.

Linking genotypes with multiple phenotypes in single-cell CRISPR screens

CRISPR/Cas9 based functional screening coupled with single-cell RNA-seq (“single-cell CRISPR screening”) unravels gene regulatory networks and enhancer-gene regulations in a large scale. We propose scMAGeCK, a computational framework to systematically identify genes and non-coding elements associated with multiple expression-based phenotypes in single-cell CRISPR screening. scMAGeCK identified genes and enhancers that modulate the expression of a known proliferation marker, MKI67 (Ki-67), a result that resembles the outcome of proliferation-linked CRISPR screening. We further performed single-cell CRISPR screening on mouse embryonic stem cells (mESC), and identified key genes associated with different pluripotency states. scMAGeCK enabled an unbiased construction of genotype-phenotype network, where multiple phenotypes can be regulated by different gene perturbations. Finally, we studied key factors that improve the statistical power of single-cell CRISPR screens, including target gene expression and the number of guide RNAs (gRNAs) per cell. Collectively, scMAGeCK is a novel and effective computational tool to study genotype-phenotype relationships at a single-cell level.