Charlotte Miton

Position:

Post-Doctoral Fellow (2014-present)

cmiton[at]msl.ubc.ca

Link: Google Scholar, Research Gate , Twitter

Education:

Ph.D. in Biochemistry (2009-2014) University of Cambridge, UK.

M.Sc. Genetics and Physiology (2008-2009) Université Blaise Pascal, France.

M.Sc. Biochemical Engineering (2006-2009) Polytech’ Clermont-Ferrand, France.

Classe préparatoire BCPST (2004-2006) Lycée Le Fresne Angers, France.

Background

I originally studied Biochemical Engineering at Polytech’Clermont-Fd in France, where I undertook my first research projects on distinct aspects of protein function and evolution. In 2008, I worked with Dr. Gutierrez-Rojas (UAM Iztapalapa, Mexico) on the characterization of an evolving bacterial consortium for bioremediation. In 2009, I worked with Dr. V. Tiranti (IRCCS Foundation Carlo Besta Institute, Milan) on the effects of SNPs in a protein involved in a neurodegenerative disorder. Since then, I have been interested in chasing the molecular mechanisms behind the evolution of protein functions. This led me to join Dr. F. Hollfelder and Dr. M. Hyvönen at Cambridge for my PhD work. There, I investigated the impact of mutations on enzyme chemistry and structure through an in depth mechanistic, kinetic and structural analysis of every intermediate genotype along the evolutionary trajectory of a promiscuous arylsulfatase.

Research interests:

I am interested in the exploration of the molecular mechanisms underlying organismal adaptation through functional innovation. I aim at providing detailed molecular analyses that use in depth biochemical and structural studies to illuminate the evolutionary history of proteins, with a fondness for promiscuous enzymes. My research focuses on the genetic, phenotypic, structural or mechanistic constraints that shape enzyme evolutionary pathways and often originate from mutational epistasis. I am currently exploring a long-standing question in evolutionary biology, which asks whether adaptation relies on stochastic events due to historical contingency, or rather follows a deterministic path, repeatedly imposed by specific molecular or environmental constraints. Numerous studies report striking examples of evolutionary convergence or parallelism at the organismal, molecular or genetic levels: how closely related should orthologous proteins be to trigger a repeated evolutionary outcome? We ‘replayed’ the evolution of an enzyme, PTE phosphotriesterase, which had been previously evolved toward an arylester substrate. Starting from an immediate neutral neighbor that only differs at the genotype level by a single amino acid mutation and is phenotypically similar, we repeated the laboratory evolution under identical experimental conditions. An analysis of mutational tolerance in the evolved variants is disclosing the emergence of genetic incompatibility and contingency during adaptation. Our findings emphasize the difficulty of predicting evolutionary outcomes, even when evolution originates from virtually identical starting points.

Publications:

Baier F, Hong N, Yang G, Pabis A, Miton CM, Barrozo A, Carr PD, Lamerlin SCL, Jackosn CJ, Tokuriki N*, “Cryptic genetic variation shapes the adaptive evolutionary potential of enzymes” eLife, 2019, 8, e40789

Miton CM, Jonas S, Fischer G, Duarte F, Mohamed MF, van Loo B, Kintses B, Kamerlin SCL, Tokuriki N, Hyvönen M, Hollfelder F. “Evolutionary repurposing of a sulfatase: A new Michaelis complex leads to efficient transition state charge offset” Proc Natl Acad Sci USA. 2018 Jul 31;115(31) 

 Miton, C. M., & Tokuriki, N. (2016). How mutational epistasis impairs predictability in protein evolution and design. Protein Science. 25 (7), 1260–1272.

Colin, P-Y., Kintses, B., Gielen, F., Miton, C. M., Fischer, G., Mohamed, M. F., et al. (2015). Ultrahigh-throughput discovery of promiscuous enzymes by picodroplet functional metagenomics. Nature Communications, 6, 10008.