MapperPlus: Agnostic clustering of high-dimension data for precision medicine.

One of the goals of precision medicine is to classify patients into subgroups that differ in their susceptibility and response to a disease, thereby enabling tailored treatments for each subgroup. Therefore, there is a great need to identify distinctive clusters of patients from patient data. There are three key challenges to three key challenges of patient stratification: 1) the unknown number of clusters, 2) the need for assessing cluster validity, and 3) the clinical interpretability. We developed MapperPlus, a novel unsupervised clustering pipeline, that directly addresses these challenges. It extends the topological Mapper technique and blends it with two random-walk algorithms to automatically detect disjoint subgroups in patient data. We demonstrate that MapperPlus outperforms traditional agnostic clustering methods in key accuracy/performance metrics by testing its performance on publicly available medical and non-medical data set. We also demonstrate the predictive power of MapperPlus in a medical dataset of pediatric stem cell transplant patients where a number of cluster is unknown. Here, MapperPlus stratifies the patient population into clusters with distinctive survival rates. The MapperPlus software is open-source and publicly available.

Sparse Epistatic Patterns in the Evolution of Terpene Synthases.

We explore sequence determinants of enzyme activity and specificity in a major enzyme family of terpene synthases. Most enzymes in this family catalyze reactions that produce cyclic terpenes-complex hydrocarbons widely used by plants and insects in diverse biological processes such as defense, communication, and symbiosis. To analyze the molecular mechanisms of emergence of terpene cyclization, we have carried out in-depth examination of mutational space around (E)-ß-farnesene synthase, an Artemisia annua enzyme which catalyzes production of a linear hydrocarbon chain. Each mutant enzyme in our synthetic libraries was characterized biochemically, and the resulting reaction rate data were used as input to the Michaelis-Menten model of enzyme kinetics, in which free energies were represented as sums of one-amino-acid contributions and two-amino-acid couplings. Our model predicts measured reaction rates with high accuracy and yields free energy landscapes characterized by relatively few coupling terms. As a result, the Michaelis-Menten free energy landscapes have simple, interpretable structure and exhibit little epistasis. We have also developed biophysical fitness models based on the assumption that highly fit enzymes have evolved to maximize the output of correct products, such as cyclic products or a specific product of interest, while minimizing the output of byproducts. This approach results in nonlinear fitness landscapes that are considerably more epistatic. Overall, our experimental and computational framework provides focused characterization of evolutionary emergence of novel enzymatic functions in the context of microevolutionary exploration of sequence space around naturally occurring enzymes.