Fitness landscape of the fission yeast genome

Grech, L. et al. (2019) Fitness landscape of the fission yeast genome. Molecular Biology and Evolution, 36(8), pp. 1612-1623. (doi: 10.1093/molbev/msz113) (PMID:31077324) (PMCID:PMC6657727)

Abstract

The relationship between DNA sequence, biochemical function, and molecular evolution is relatively well-described for protein-coding regions of genomes, but far less clear in noncoding regions, particularly, in eukaryote genomes. In part, this is because we lack a complete description of the essential noncoding elements in a eukaryote genome. To contribute to this challenge, we used saturating transposon mutagenesis to interrogate the Schizosaccharomyces pombe genome. We generated 31 million transposon insertions, a theoretical coverage of 2.4 insertions per genomic site. We applied a five-state hidden Markov model (HMM) to distinguish insertion-depleted regions from insertion biases. Both raw insertion-density and HMM-defined fitness estimates showed significant quantitative relationships to gene knockout fitness, genetic diversity, divergence, and expected functional regions based on transcription and gene annotations. Through several analyses, we conclude that transposon insertions produced fitness effects in 66–90% of the genome, including substantial portions of the noncoding regions. Based on the HMM, we estimate that 10% of the insertion depleted sites in the genome showed no signal of conservation between species and were weakly transcribed, demonstrating limitations of comparative genomics and transcriptomics to detect functional units. In this species, 3′- and 5′-untranslated regions were the most prominent insertion-depleted regions that were not represented in measures of constraint from comparative genomics. We conclude that the combination of transposon mutagenesis, evolutionary, and biochemical data can provide new insights into the relationship between genome function and molecular evolution.

• Item Type: Articles
• Additional Information: L.G. was supported by a UCL Grand Challenges Award to J.B. C.J.R.I. was supported by a Sir Henry Dale Fellowship, jointly funded by the Wellcome Trust and the Royal Society (Grant No. 101239/Z/13/Z). This work was supported by a Wellcome Trust Senior Investigator Award to J.B. (Grant No. 095598/Z/ 11/Z).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Illingworth, Dr Chris
• Authors: Grech, L., Jeffares, D. C., Sadée, C. Y., Rodríguez-López, M., Bitton, D. A., Hoti, M., Biagosch, C., Aravani, D., Speekenbrink, M., Illingworth, C. J.R., Schiffer, P. H., Pidoux, A. L., Tong, P., Tallada, V. A., Allshire, R., Levin, H. L., Bähler, J., and Wilke, C.
• College/School: College of Medical Veterinary and Life Sciences > School of Infection & Immunity; College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Virus Research
• Journal Name: Molecular Biology and Evolution
• Publisher: Oxford University Press
• ISSN: 0737-4038
• ISSN (Online): 1537-1719
• Published Online: 11 May 2019
• Copyright Holders: Copyright © 2019 The Authors
• First Published: First published in Molecular Biology and Evolution 36(8):1612-1623
• Publisher Policy: Reproduced under a Creative Commons License