Fun collaborative work with Michael Palladino and Georg Petschenka http://www.pind.pitt.edu/labs/palladino-laboratory/ …https://www.uni-giessen.de/fbz/fb09/institute/iib/ento/ag/ag-petschenka …
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Update: This is now published in eLife and online here: https://doi.org/10.7554/eLife.48224 …. A key addition is that we add a validation experiment for inferring mixture proportions, and relative activities, in inhibition assays using biphasic fits to mixtures of sensitive/insensitive enzymes
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For those that won’t read the paper, or find it a bit too jargon laden (like my brother the economist), I offer the following Twitter digest: 1/10
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The effects of key amino-acid substitutions underlying cardiac-glycoside (CG) insensitivity, despite occurring repeatedly in insect evolution, strongly depend on the genetic background on which they occur. In fact, many of these are lethal when engineered into Drosophila 2/10
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We show this lethality can be rescued by changing Alanine 119 -> Serine (A119S) a site not previously implicated in CG-insensitivity. The phylogenetic distribution of substitutions at this site suggests it may have played a key role in multiple CG-insensitive insect lineages 3/10
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Despite rescuing lethality of multiple CG-insensitivity substitutions, flies engineered with A119S are neurologically impaired, implying that other sites would need to be modified to compensate for the dysfunction associated with this permissive substitution 4/10
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Engineering whole animals interestingly revealed aspects of these substitutions that would be missed in biochemical assays. 5/10
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For eg, Asparagine->Histidine at position 122 results in a CG-insensitive enzyme but lethal when inherited from both parents (aka “homozygous”) & neurological defects when not homozygous. Adding A119S rescues lethality, but animals still exhibit residual neurological defects 6/10
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Neurological defects are also apparent in animals with A119S on its own. Despite these detrimental effects, A119S confers a survival advantage to adults upon CG-exposure 7/10
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These findings raise interesting questions about how and “simple” adaptation like this evolves in the first place. Are the permissive/detrimental effects of A119S general or specific to the Drosophila melanogaster version of the protein? 8/10
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Future work is aimed at answering these and related questions with the aim of understanding what limits the rate of adaptation in this system, and more generally adaptive protein evolution. 9/10
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I hope that helps! Let me know if I can clarify anything in this thread. 10/10
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