---
_id: '900'
abstract:
- lang: eng
text: 'The main forces directing long-term molecular evolution remain obscure. A
sizable fraction of amino-acid substitutions seem to be fixed by positive selection,
but it is unclear to what degree long-term protein evolution is constrained by
epistasis, that is, instances when substitutions that are accepted in one genotype
are deleterious in another. Here we obtain a quantitative estimate of the prevalence
of epistasis in long-term protein evolution by relating data on amino-acid usage
in 14 organelle proteins and 2 nuclear-encoded proteins to their rates of short-term
evolution. We studied multiple alignments of at least 1,000 orthologues for each
of these 16 proteins from species from a diverse phylogenetic background and found
that an average site contained approximately eight different amino acids. Thus,
without epistasis an average site should accept two-fifths of all possible amino
acids, and the average rate of amino-acid substitutions should therefore be about
three-fifths lower than the rate of neutral evolution. However, we found that
the measured rate of amino-acid substitution in recent evolution is 20 times lower
than the rate of neutral evolution and an order of magnitude lower than that expected
in the absence of epistasis. These data indicate that epistasis is pervasive throughout
protein evolution: about 90 per cent of all amino-acid substitutions have a neutral
or beneficial impact only in the genetic backgrounds in which they occur, and
must therefore be deleterious in a different background of other species. Our
findings show that most amino-acid substitutions have different fitness effects
in different species and that epistasis provides the primary conceptual framework
to describe the tempo and mode of long-term protein evolution.'
acknowledgement: |
The work was supported by Plan Nacional grants from the Spanish Ministry of Science and Innovation, to F.A.K. and C.N. C.K. was supported by the European Union FP7 project Quantomics (KBBE2A222664). F.A.K. is a European Molecular Biology Organization Young Investigator and Howard Hughes Medical Institute International Early Career Scientist. We thank B. Lehner and T. Warnecke for input and a critical reading of the manuscript.
author:
- first_name: Michael
full_name: Breen, Michael S
last_name: Breen
- first_name: Carsten
full_name: Kemena, Carsten
last_name: Kemena
- first_name: Peter
full_name: Vlasov, Peter K
last_name: Vlasov
- first_name: Cédric
full_name: Notredame, Cédric
last_name: Notredame
- first_name: Fyodor
full_name: Fyodor Kondrashov
id: 44FDEF62-F248-11E8-B48F-1D18A9856A87
last_name: Kondrashov
orcid: 0000-0001-8243-4694
citation:
ama: Breen M, Kemena C, Vlasov P, Notredame C, Kondrashov F. Epistasis as the primary
factor in molecular evolution. Nature. 2012;490(7421):535-538. doi:10.1038/nature11510
apa: Breen, M., Kemena, C., Vlasov, P., Notredame, C., & Kondrashov, F. (2012).
Epistasis as the primary factor in molecular evolution. Nature. Nature
Publishing Group. https://doi.org/10.1038/nature11510
chicago: Breen, Michael, Carsten Kemena, Peter Vlasov, Cédric Notredame, and Fyodor
Kondrashov. “Epistasis as the Primary Factor in Molecular Evolution.” Nature.
Nature Publishing Group, 2012. https://doi.org/10.1038/nature11510.
ieee: M. Breen, C. Kemena, P. Vlasov, C. Notredame, and F. Kondrashov, “Epistasis
as the primary factor in molecular evolution,” Nature, vol. 490, no. 7421.
Nature Publishing Group, pp. 535–538, 2012.
ista: Breen M, Kemena C, Vlasov P, Notredame C, Kondrashov F. 2012. Epistasis as
the primary factor in molecular evolution. Nature. 490(7421), 535–538.
mla: Breen, Michael, et al. “Epistasis as the Primary Factor in Molecular Evolution.”
Nature, vol. 490, no. 7421, Nature Publishing Group, 2012, pp. 535–38,
doi:10.1038/nature11510.
short: M. Breen, C. Kemena, P. Vlasov, C. Notredame, F. Kondrashov, Nature 490 (2012)
535–538.
date_created: 2018-12-11T11:49:06Z
date_published: 2012-10-25T00:00:00Z
date_updated: 2021-01-12T08:21:45Z
day: '25'
doi: 10.1038/nature11510
extern: 1
intvolume: ' 490'
issue: '7421'
month: '10'
page: 535 - 538
publication: Nature
publication_status: published
publisher: Nature Publishing Group
publist_id: '6748'
quality_controlled: 0
status: public
title: Epistasis as the primary factor in molecular evolution
type: journal_article
volume: 490
year: '2012'
...