Toward More Accurate Ancestral Protein Genotype–Phenotype Reconstructions with the Use of Species Tree-Aware Gene Trees

The resurrection of ancestral proteins provides direct insight into how natural selection has shaped proteins found in nature. By tracing substitutions along a gene phylogeny, ancestral proteins can be reconstructed in silico and subsequently synthesized in vitro. This elegant strategy reveals the c...

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Main Authors:	Groussin, Mathieu, Hobbs, Joanne K., Szöllősi, Gergely J., Gribaldo, Simonetta, Arcus, Vickery L., Gouy, Manolo
Format:	Online
Language:	English
Published:	Oxford University Press 2015
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4271536/

id	pubmed-4271536
recordtype	oai_dc
spelling	pubmed-42715362015-01-13 Toward More Accurate Ancestral Protein Genotype–Phenotype Reconstructions with the Use of Species Tree-Aware Gene Trees Groussin, Mathieu Hobbs, Joanne K. Szöllősi, Gergely J. Gribaldo, Simonetta Arcus, Vickery L. Gouy, Manolo Fast Track The resurrection of ancestral proteins provides direct insight into how natural selection has shaped proteins found in nature. By tracing substitutions along a gene phylogeny, ancestral proteins can be reconstructed in silico and subsequently synthesized in vitro. This elegant strategy reveals the complex mechanisms responsible for the evolution of protein functions and structures. However, to date, all protein resurrection studies have used simplistic approaches for ancestral sequence reconstruction (ASR), including the assumption that a single sequence alignment alone is sufficient to accurately reconstruct the history of the gene family. The impact of such shortcuts on conclusions about ancestral functions has not been investigated. Here, we show with simulations that utilizing information on species history using a model that accounts for the duplication, horizontal transfer, and loss (DTL) of genes statistically increases ASR accuracy. This underscores the importance of the tree topology in the inference of putative ancestors. We validate our in silico predictions using in vitro resurrection of the LeuB enzyme for the ancestor of the Firmicutes, a major and ancient bacterial phylum. With this particular protein, our experimental results demonstrate that information on the species phylogeny results in a biochemically more realistic and kinetically more stable ancestral protein. Additional resurrection experiments with different proteins are necessary to statistically quantify the impact of using species tree-aware gene trees on ancestral protein phenotypes. Nonetheless, our results suggest the need for incorporating both sequence and DTL information in future studies of protein resurrections to accurately define the genotype–phenotype space in which proteins diversify. Oxford University Press 2015-01 2014-11-04 /pmc/articles/PMC4271536/ /pubmed/25371435 http://dx.doi.org/10.1093/molbev/msu305 Text en © The Author 2014. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. http://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Groussin, Mathieu Hobbs, Joanne K. Szöllősi, Gergely J. Gribaldo, Simonetta Arcus, Vickery L. Gouy, Manolo
spellingShingle	Groussin, Mathieu Hobbs, Joanne K. Szöllősi, Gergely J. Gribaldo, Simonetta Arcus, Vickery L. Gouy, Manolo Toward More Accurate Ancestral Protein Genotype–Phenotype Reconstructions with the Use of Species Tree-Aware Gene Trees
author_facet	Groussin, Mathieu Hobbs, Joanne K. Szöllősi, Gergely J. Gribaldo, Simonetta Arcus, Vickery L. Gouy, Manolo
author_sort	Groussin, Mathieu
title	Toward More Accurate Ancestral Protein Genotype–Phenotype Reconstructions with the Use of Species Tree-Aware Gene Trees
title_short	Toward More Accurate Ancestral Protein Genotype–Phenotype Reconstructions with the Use of Species Tree-Aware Gene Trees
title_full	Toward More Accurate Ancestral Protein Genotype–Phenotype Reconstructions with the Use of Species Tree-Aware Gene Trees
title_fullStr	Toward More Accurate Ancestral Protein Genotype–Phenotype Reconstructions with the Use of Species Tree-Aware Gene Trees
title_full_unstemmed	Toward More Accurate Ancestral Protein Genotype–Phenotype Reconstructions with the Use of Species Tree-Aware Gene Trees
title_sort	toward more accurate ancestral protein genotype–phenotype reconstructions with the use of species tree-aware gene trees
description	The resurrection of ancestral proteins provides direct insight into how natural selection has shaped proteins found in nature. By tracing substitutions along a gene phylogeny, ancestral proteins can be reconstructed in silico and subsequently synthesized in vitro. This elegant strategy reveals the complex mechanisms responsible for the evolution of protein functions and structures. However, to date, all protein resurrection studies have used simplistic approaches for ancestral sequence reconstruction (ASR), including the assumption that a single sequence alignment alone is sufficient to accurately reconstruct the history of the gene family. The impact of such shortcuts on conclusions about ancestral functions has not been investigated. Here, we show with simulations that utilizing information on species history using a model that accounts for the duplication, horizontal transfer, and loss (DTL) of genes statistically increases ASR accuracy. This underscores the importance of the tree topology in the inference of putative ancestors. We validate our in silico predictions using in vitro resurrection of the LeuB enzyme for the ancestor of the Firmicutes, a major and ancient bacterial phylum. With this particular protein, our experimental results demonstrate that information on the species phylogeny results in a biochemically more realistic and kinetically more stable ancestral protein. Additional resurrection experiments with different proteins are necessary to statistically quantify the impact of using species tree-aware gene trees on ancestral protein phenotypes. Nonetheless, our results suggest the need for incorporating both sequence and DTL information in future studies of protein resurrections to accurately define the genotype–phenotype space in which proteins diversify.
publisher	Oxford University Press
publishDate	2015
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4271536/
_version_	1613169100609028096

Toward More Accurate Ancestral Protein Genotype–Phenotype Reconstructions with the Use of Species Tree-Aware Gene Trees

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