PT  - JOURNAL ARTICLE
AU  - Nicholas C. Jacobs
AU  - Ji Woong Park
AU  - Timothy R. Peterson
TI  - Cell Fitness is an Omniphenotype
AID  - 10.1101/487157
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 487157
4099  - http://biorxiv.org/content/early/2019/07/20/487157.short
4100  - http://biorxiv.org/content/early/2019/07/20/487157.full
AB  - Genotype-phenotype relationships are at the heart of biology and medicine. Numerous advances in genotyping and phenotyping have accelerated the pace of disease gene and drug discovery. Though now that there are so many genes and drugs to study, it makes prioritizing them difficult. Also, disease model assays are getting more complex and this is reflected in the growing complexity of research papers and the cost of drug development. Herein we propose a way out of this arms race. We argue for synthetic interaction testing in mammalian cells using cell fitness – which reflect changes in cell number that could be due to a number of factors – as a readout to judge the potential of a genetic or environmental variable of interest (e.g., a gene or drug). That is, if a mammalian gene or drug of interest is combined with a known perturbation and causes a strong cell fitness phenotype relative to that caused by the known perturbation alone, this justifies proceeding with the gene/drug in more complex models like mouse models where the known perturbation is already validated. This recommendation is backed by the following: 1) human protein-coding genes important to cell fitness under normal growth conditions involve nearly all classifications of cellular and molecular processes; 2) Nearly all human genes important in cancer – a disease defined by altered cell number – are also important in other complex diseases; 3) Many drugs affect a patient’s condition and the fitness of their cells comparably. Taken together, these findings suggest cell fitness could be a broadly applicable phenotype for understanding gene and drug function. Measuring cell fitness is robust and requires little time and money. These are features that have long been capitalized on by pioneers using model organisms that we hope more mammalian biologists will recognize.