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Year:2019
Thecausesofevolvabilityandtheirevolution
Payne,JoshuaL;Wagner,Andreas
Abstract: Evolvabilityistheabilityofabiologicalsystemtoproducephenotypicvariationthatisboth
heritableandadaptive. Ithaslongbeenthesubjectofanecdotalobservationsandtheoreticalwork. In
recentyears,however,themolecularcausesofevolvabilityhavebeenanincreasingfocusofexperimental
work.Here,wereviewrecentexperimentalprogressinareasasdierentastheevolutionofdrugresis-
tanceincancercellsandtherewiringoftranscriptionalregulationcircuitsinvertebrates. Thisresearch
revealstheimportanceofthreemajorthemes:multiplegeneticandnon-geneticmechanismstogenerate
phenotypicdiversity,robustnessingeneticsystems,andadaptivelandscapetopography.Wealsodiscuss
themountingevidencethatevolvabilitycanevolveandthequestionofwhetheritevolvesadaptively.
DOI:https://doi.org/10.1038/s41576-018-0069-z
PostedattheZurichOpenRepositoryandArchive,UniversityofZurich
ZORAURL:https://doi.org/10.5167/uzh-166216
JournalArticle
AcceptedVersion
Originallypublishedat:
Payne, Joshua L;Wagner, Andreas (2019).The causesof evolvabilityand theirevolution.Nature
Reviews.Genetics,20(1):24-38.
DOI:https://doi.org/10.1038/s41576-018-0069-z
1
The causes of evolvability and their evolution 1
Joshua L. Payne
1
and Andreas Wagner
2
2
1. Institute of Integrative Biology, ETH Zurich, Zurich, 8092, Switzerland 3
2. Department of Evolutionary Biology and Environmental Studies, University of Zurich, 8092, Switzerland 4
Correspondence to A.W. 5
e-mail: andreas.wagner@ieu.uzh.ch 6
7
Abstract | Evolvability is the ability of a biological system to produce phenotypic variation that is both 8
heritable and adaptive. It has long been the subject of anecdotal observations and theoretical work. In recent 9
years, however, the molecular causes of evolvability have been an increasing focus of experimental work. 10
Here we review recent experimental progress in areas as different as the evolution of drug resistance in 11
cancer cells and the rewiring of transcriptional regulation circuits in vertebrates. This research reveals three 12
major themes: the importance of multiple, genetic and non-genetic mechanisms to generate phenotypic 13
diversity, of robustness in genetic systems, and of adaptive landscape topography. We also discuss the 14
mounting evidence that evolvability can evolve, and the question of whether it evolves adaptively. 15
16
[H1] Introduction 17
Evolvability research is now entering its fourth decade. Although the term was first used as early as 1932, 18
evolvability as a scientific subdiscipline of evolutionary biology is often associated with a 1989 article by 19
Richard Dawkins
1
describing what are now called digital organisms
2
. Today, research on evolvability is 20
integral to multiple fields, including population genetics, quantitative genetics, molecular biology, and 21
developmental biology. Not surprisingly then, this diversity of research has led to various definitions of 22
evolvability
3
. We here focus on one of them, because we consider it the most fundamental: Evolvability is the 23
ability of a biological system to produce phenotypic variation that is both heritable and adaptive. The 24
definition is fundamental because, first, heritable phenotypic variation is the essential raw material of 25
evolution. Second, unless a biological system has the potential to produce variation that is adaptive 26
2
(beneficial) in some environments, adaptation by natural selection is impossible. Third, the definition is broad 27
enough to apply to fields as different as population genetics and molecular biology, which study evolvability 28
in different ways
3
. 29
30
Most early evolvability research was theoretical or guided by few experimental studies
1,3-11
. This has changed. 31
Research on evolvability is becoming increasingly experimental and driven by advances in high-throughput 32
technologies (Box 1). The observations from such experiments are providing a mechanistic understanding of 33
how living systems generate heritable adaptive variation
12
. We focus this Review on such experimental 34
studies, which come from a diversity of fields, ranging from developmental to cancer biology. Many make no 35
explicit mention of evolvability, yet they all shed light on the causes of evolvability, and some also on its 36
evolution. They are relevant for phenomena as different as the evolution of antibiotic resistance in bacteria, 37
and the evolutionary rescue of populations threatened by climate and other environmental change. Their 38
insights fall into three major categories, which provide a scaffold for this Review. 39
40
The first major category encompasses molecular mechanisms that create phenotypic heterogeneity, and do so 41
not just through DNA mutations, but even in the absence of such mutations. These mechanisms have become 42
central to evolvability research, because they allow
isogenic populations [G] to create phenotypic variation, 43
some of which may facilitate survival in new or rapidly changing environments, and may thus provide time 44
for an advantageous phenotype to be reinforced or stabilized via DNA mutation, gene duplication, 45
recombination, or epigenetic modification. The second category of evidence revolves around robustness, 46
which is central to evolvability, because it allows an evolving population to explore new genotypes without 47
detrimentally affecting essential phenotypes. The resulting genotypic diversity may serve as a springboard for 48
subsequent mutations to generate novel phenotypes, or it may bring forth new phenotypic variation when the 49
environment changes. The third category of evidence regards the topographical features of an adaptive 50
landscape, such as its smoothness, and a population’s location within such a landscape. These factors 51
determine the amount of adaptive phenotypic variation that mutation can bring forth. Adaptive landscapes 52
3
provide a useful geometric framework to encapsulate genotype-phenotype (or fitness) relationships that affect 53
evolvability. 54
55
Unfortunately, space constraints prevent us from reviewing other important aspects of evolvability research, 56
including the roles of
phenotypic plasticity [G] , organismal development, modularity [G] , and pleiotropy 57
[G] , as well as theoretical advances. Additionally, we frame our Review primarily around mechanisms of 58
pre-mutation evolvability [G] and mechanisms that do not require genetic change, although we briefly 59
discuss some mechanisms of post-mutation evolvability [G] , where recombination plays an especially 60
important role
13
. 61
62
[H1] Phenotypic heterogeneity 63
Heritable phenotypic variation is the raw material of natural selection, and the best-known mechanisms to 64
create such variation are DNA mutation and recombination. However, because the role these mechanisms 65
play in generating phenotypic variation is well established and has been extensively reviewed
13,14
, we here 66
focus on another class of mechanisms whose astonishing diversity is only beginning to come to light through 67
recent experimental work
15
. These mechanisms create phenotypic heterogeneity without creating genetic 68
variation. 69
70
Non-genetic mechanisms to create phenotypic heterogeneity can be found in many processes affecting the 71
expression of genetic information. We review four such mechanisms: stochastic gene expression, errors in 72
protein synthesis, epigenetic modifications, and protein promiscuity. Each mechanism can create phenotypic 73
variation in a population of genetically identical individuals
16
. Such variation can for example provide a 74
competitive advantage to subpopulations with adaptive phenotypes in fluctuating environments
17,18
. These 75
phenotypes may themselves be heritable, eventually made permanent by mutation or epigenetic modification, 76
or they may simply ‘buy time’ for a population to adapt in other ways to an environmental challenge (Fig. 77
1a). 78
4
79
[H2] Stochastic gene expression. Stochastic gene expression, or
gene expression noise [G] has multiple 80
causes, including the efficiency of transcription and translation
19,20
, as well as the regulation of gene 81
expression by low-abundance molecules whose numbers fluctuate randomly in a cell
21
(Fig. 1b). It can create 82
non-genetic, adaptive diversity in phenotypes as diverse as viral latency [G] , bacterial competence [G] and 83
antibiotic resistance, as well as drug resistance in cancer
22-24
. 84
85
One example where stochastic gene expression causes adaptive phenotypic variation is persistence, where 86
some cells in an isogenic population exhibit a physiologically dormant phenotype called a persister 87
phenotype
25
. This phenotype is adaptive, because a dormant subpopulation has the potential to survive drugs 88
that require active growth for killing, affording the persistent subpopulation time to acquire resistance-89
conferring DNA mutations. This was recently demonstrated in a laboratory evolution experiment of 90
Escherichia coli populations subjected to intermittent exposures of ampicillin
26
, in which persistence served 91
as a stopgap until some individuals acquired resistance-causing mutations. 92
93
Persistence arises in only a small fraction of a population, so one might think that the resulting
population 94
bottleneck [G] would hinder evolvability by reducing the supply of beneficial mutations. However, a recent 95
study of non-small-cell lung cancer indicates that this need not be the case
27
. These cells stochastically 96
express a persistent phenotype, mediated by an altered chromatin state
28
. A population derived from one of 97
these cells was exposed to the drug erlotinib, which resulted in the formation of multiple persistent 98
subpopulations. Seventeen of these subpopulations were later expanded in isolation from each other until 99
drug resistance emerged through DNA mutations. Genetic analysis of the resistant clones uncovered several 100
distinct resistance mechanisms, indicating that several evolutionary paths to resistance remained despite the 101
population bottleneck. In sum, persistence can facilitate evolvability, because it allows some individuals 102
(individual cells in this example) to survive long enough to experience adaptive genetic change. 103