Quantitative Analysis of Genetic and Neuronal Multi-Perturbation Experiments

Abstract

Perturbation studies, in which functional performance is measured after deletion, mutation, or lesion of elements of a biological system, have been traditionally employed in many fields in biology. The vast majority of these studies have been qualitative and have employed single perturbations, often resulting in little phenotypic effect. Recently, newly emerging experimental techniques have allowed researchers to carry out concomitant multi-perturbations and to uncover the causal functional contributions of system elements. This study presents a rigorous and quantitative multi-perturbation analysis of gene knockout and neuronal ablation experiments. In both cases, a quantification of the elements' contributions, and new insights and predictions, are provided. Multi-perturbation analysis has a potentially wide range of applications and is gradually becoming an essential tool in biology. Which are the important elements of a system? What are their relative contributions to the performance of the various tasks the system is involved in? These simple and basic questions typically arise when analyzing the workings of any system, and of biological systems in particular. In the latter, the elements may be genes, proteins, cells, or tissues, depending on the level and scope of the analysis. To address these questions in a causal manner, perturbations are required, where the elements are perturbed and the resulting performance function is recorded. This approach has been one of the cornerstones of biological research. However, it has usually been confined to the perturbation of a single element at a time, which may lead to misleading results if the elements of the system functionally interact with each other. This paper addresses these questions by providing a quantitative and rigorous method for the analysis of multi-perturbation experiments, where more than one element may be concomitantly perturbed. The workings of the new method are demonstrated in the analysis of genetic multi-knockout experiments of DNA repair in the yeast Saccharomyces cerevisiae and a neural circuit in the nematode Caenorhabditis elegans accounting for chemotaxis. However, the method is general and can be applied to study many other systems in numerous pertinent biological domains.