Studies of protein evolution in the Harms lab
IMB Retreat
September 2016
Proteins are amazing molecular machines...
...that were put together by a blind evolutionary process.
Lab approaches:
Trace historical changes in protein function
Studies of sequence space
Model system: calcium-sensing S100 proteins
The S100 protein family has expanded radically across the vertebrates
Family expanded across the vertebrates
Wheeler et al. In review.
Different S100 proteins have evolved a huge variety of functions:
- Regulation of cell motility and proliferation (A6)
- Metal transport/sequestration (A11, B)
- Direct antimicrobial activity (A8, A9, A12)
- Pro-inflammatory signaling (A4,A7,A8,A9,A12)
- Substrate transport (A9,A10)
Experimental studies in the lab. Evolution of:
- ...protein binding specificity (S100A5 and S100A6)
- ...transition metal binding (Wheeler In review)
- It is ubiqutious in the family
- It was acquired multiple times at different sites
- ...multifunctionality (S100A8, S100A9)
TLR4 activation by S100A9
- Evolved concomitant with S100A9
- Activation is by a different mechanism than the exogenous TLR4 ligand
Andrea Loes
Lab approaches:
Trace historical changes in protein function
Studies of sequence space
Epistasis is important for evolution:
- Stochastically opens evolutionary trajectories
Harms & Thornton (2014) Nature 512:203
- Limits evolutionary trajectories
Weinreich et al (2006) Science 312(7):111
- Makes evolution irreversible
Shah et al. (2015) PNAS 112(25):E3226
Evolutionary memory: the effect of a mutation depends on a past substitution
But what about high-order epistasis
Long-term memory? The effect of a mutation depends on a whole collection of previous substitutions
Sailer & Harms (in review)
Genotype-phenotype maps exhibit extensive high-order epistasis
Hall et al. (2010). J. Hered 101(1):S75-S84
Sailer & Harms (in review)
High-order epistasis alters evolutionary trajectories.
Sailer & Harms (in prep)
High-order epistasis is "baked in" to proteins?
Simple physical models of proteins exhibit high-order epistasis
Sailer, Wheeler & Harms (in prep)
Where we're going:
- How high does it go? Experimental measurement of 10th-order epistasis
- Predicting missing portions of genotype-phenotype maps
Studies of protein evolution in the Harms lab