Epistasis machine learning

Mammalian genomes possess multiple enhancers spanning an ultralong distance (>megabases) to modulate important genes, yet it is unclear how these enhancers coordinate to achieve this task. Here, we combine multiplexed CRISPRi screening with machine learning to define quantitative enhancer-enhancer interactions. We find that the ultralong distance enhancer network possesses a nested multi-layer architecture that confers functional robustness of gene expression. Experimental characterization reveals that enhancer epistasis is maintained by three-dimensional chromosomal interactions and BRD4 condensation...

Large-scale measurements linking genetic background to biological function have driven a need for models that can incorporate these data for reliable predictions and insight into the underlying biophysical system. Recent modeling efforts, however, prioritize predictive accuracy at the expense of model interpretability. Here, we present LANTERN (landscape interpretable nonparametric model, https://github.com/usnistgov/lantern), a hierarchical Bayesian model that distills genotype-phenotype landscape (GPL) measurements into a low-dimensional feature space that represents the fundamental biological mechanisms of the system while also enabling straightforward, explainable predictions...

Synthetic biology is a fast-evolving research field that combines biology and engineering principles to develop new biological systems for medical, pharmacological, and industrial applications. Synthetic biologists use iterative "design, build, test, and learn" cycles to efficiently engineer genetic systems that are reliable, reproducible, and predictable. Protein engineering by directed evolution can benefit from such a systematic engineering approach for various reasons. Learning can be carried out before starting, throughout or after finalizing a directed evolution project...

Some rare genetic disorders, such as retinitis pigmentosa or Alport syndrome, are caused by the co-inheritance of DNA variants at two different genetic loci (digenic inheritance). To capture the effects of these disease-causing variants and their possible interactive effects, various statistical methods have been developed in human genetics. Analogous developments have taken place in the field of machine learning, particularly for the field that is now called Big Data. In the past, these two areas have grown independently and have started to converge only in recent years...

Prediction of complex traits based on genome-wide marker information is of central importance for both animal and plant breeding. Numerous models have been proposed for the prediction of complex traits and still considerable effort has been given to improve the prediction accuracy of these models, because various genetics factors like additive, dominance and epistasis effects can influence of the prediction accuracy of such models. Recently machine learning (ML) methods have been widely applied for prediction in both animal and plant breeding programs...

The Apolipoprotein E ( APOE ) genotype has been shown to be the strongest genetic risk factor for Alzheimer's disease (AD). Moreover, both the lipolysis-stimulated lipoprotein receptor (LSR) and the vascular endothelial growth factor A (VEGF-A) are involved in the development of AD. The aim of the study was to develop a prediction model for AD including single nucleotide polymorphisms (SNP) of APOE , LSR and VEGF-A-related variants. The population consisted of 323 individuals (143 AD cases and 180 controls)...

Polygenic risk scores (PRS) aggregating results from genome-wide association studies are the state of the art in the prediction of susceptibility to complex traits or diseases, yet their predictive performance is limited for various reasons, not least of which is their failure to incorporate the effects of gene-gene interactions. Novel machine learning algorithms that use large amounts of data promise to find gene-gene interactions in order to build models with better predictive performance than PRS. Here, we present a data preprocessing step by using data-mining of contextual information to reduce the number of features, enabling machine learning algorithms to identify gene-gene interactions...

Drug-induced liver injury (DILI) is a major cause of drug development failure and drug withdrawal from the market after approval. The identification of human risk factors associated with susceptibility to DILI is of paramount importance. Increasing evidence suggests that genetic variants may lead to inter-individual differences in drug response; however, individual single-nucleotide polymorphisms (SNPs) usually have limited power to predict human phenotypes such as DILI. In this study, we aim to identify appropriate statistical methods to investigate gene-gene and/or gene-environment interactions that impact DILI susceptibility...

Machine learning has been increasingly used for protein engineering. However, because the general sequence contexts they capture are not specific to the protein being engineered, the accuracy of existing machine learning algorithms is rather limited. Here, we report ECNet (evolutionary context-integrated neural network), a deep-learning algorithm that exploits evolutionary contexts to predict functional fitness for protein engineering. This algorithm integrates local evolutionary context from homologous sequences that explicitly model residue-residue epistasis for the protein of interest with the global evolutionary context that encodes rich semantic and structural features from the enormous protein sequence universe...

Drug resistance mutations (DRMs) appear in HIV under treatment pressure. DRMs are commonly transmitted to naive patients. The standard approach to reveal new DRMs is to test for significant frequency differences of mutations between treated and naive patients. However, we then consider each mutation individually and cannot hope to study interactions between several mutations. Here, we aim to leverage the ever-growing quantity of high-quality sequence data and machine learning methods to study such interactions (i...

Directed evolution of proteins often involves a greedy optimization in which the mutation in the highest-fitness variant identified in each round of single-site mutagenesis is fixed. The efficiency of such a single-step greedy walk depends on the order in which beneficial mutations are identified-the process is path dependent. Here, we investigate and optimize a path-independent machine learning-assisted directed evolution (MLDE) protocol that allows in silico screening of full combinatorial libraries. In particular, we evaluate the importance of different protein encoding strategies, training procedures, models, and training set design strategies on MLDE outcome, finding the most important consideration to be the implementation of strategies that reduce inclusion of minimally informative "holes" (protein variants with zero or extremely low fitness) in training data...

Machine learning is helping the interpretation of biological complexity by enabling the inference and classification of cellular, organismal and ecological phenotypes based on large datasets, e.g., from genomic, transcriptomic and metagenomic analyses. A number of available algorithms can help search these datasets to uncover patterns associated with specific traits, including disease-related attributes. While, in many instances, treating an algorithm as a black box is sufficient, it is interesting to pursue an enhanced understanding of how system variables end up contributing to a specific output, as an avenue toward new mechanistic insight...

Genome-wide association studies (GWAS) provide clear insight into understanding genetic variations and environmental influences responsible for various human diseases. Cancer identification through genetic interactions (epistasis) is one of the significant ongoing researches in GWAS. The growth of the cancer cell emerges from multi-locus as well as complex genetic interaction. It is impractical for the physician to detect cancer via manual examination of SNPs interaction. Due to its importance, several computational approaches have been modeled to infer epistasis effects...

(1) Background: Complex genetic relationships, including gene-gene (G × G; epistasis), gene( n ), and gene-environment (G × E) interactions, explain a substantial portion of the heritability in multiple sclerosis (MS). Machine learning and data mining methods are promising approaches for uncovering higher order genetic relationships, but their use in MS have been limited. (2) Methods: Association rule mining (ARM), a combinatorial rule-based machine learning algorithm, was applied to genetic data for non-Latinx MS cases ( n = 207) and controls ( n = 179)...

Complex disease is different from Mendelian disorders. Its development usually involves the interaction of multiple genes or the interaction between genes and the environment (i.e. epistasis). Although the high-throughput sequencing technologies for complex diseases have produced a large amount of data, it is extremely difficult to analyze the data due to the high feature dimension and the combination in the epistasis analysis. In this work, we introduce machine learning methods to effectively reduce the gene dimensionality, retain the key epistatic effects, and effectively characterize the relationship between epistatic effects and complex diseases...

Epistasis detection is a hot topic in bioinformatics due to its relevance to the detection of specific phenotypic traits and gene-gene interactions. Here, we present a step-by-step protocol to apply Epi-GTBN, a machine learning-based method based on genetic algorithm and Bayesian network to effectively mine the epistasis loci. Epi-GTBN utilizes the advantages of genetic algorithm that can achieve a global search and avoid falling into local optima incorporating it into the Bayesian network to obtain the best structure of the model...

To develop medical treatments and prevention, the association between disease and genetic variants needs to be identified. The main goal of genome-wide association study (GWAS) is to discover the underlying reason for vulnerability to disease and utilize this knowledge for the development of prevention and treatment against these diseases. Given the methods available to address the scientific problems involved in the search for epistasis, there is not any standard for detecting epistasis, and this remains a problem due to limited statistical power...

In biology, the term "epistasis" indicates the effect of the interaction of a gene with another gene. A gene can interact with an independently sorted gene, located far away on the chromosome or on an entirely different chromosome, and this interaction can have a strong effect on the function of the two genes. These changes then can alter the consequences of the biological processes, influencing the organism's phenotype. Machine learning is an area of computer science that develops statistical methods able to recognize patterns from data...

RNA structures are dynamic. As a consequence, mutational effects can be hard to rationalize with reference to a single static native structure. We reasoned that deep mutational scanning experiments, which couple molecular function to fitness, should capture mutational effects across multiple conformational states simultaneously. Here, we provide a proof-of-principle that this is indeed the case, using the self-splicing group I intron from Tetrahymena thermophila as a model system. We comprehensively mutagenized two 4-bp segments of the intron...

BACKGROUND: Non-additive interactions among genes are frequently associated with a number of phenotypes, including known complex diseases such as Alzheimer's, diabetes, and cardiovascular disease. Detecting interactions requires careful selection of analytical methods, and some machine learning algorithms are unable or underpowered to detect or model feature interactions that exhibit non-additivity. The Random Forest method is often employed in these efforts due to its ability to detect and model non-additive interactions...