Splendor and misery of adaptation, or the importance of neutral null for
understanding evolution
Eugene V. Koonin
BMC Biology 2016 14:114
DOI: 10.1186/s12915-016-0338-2 ©
The Author(s). 2016
Published: 23 December 2016
Abstract
The
study of any biological features, including genomic sequences, typically
revolves around the question: what is this for? However, population genetic
theory, combined with the data of comparative genomics, clearly indicates that
such a “pan-adaptationist” approach is a fallacy. The proper question is: how
has this sequence evolved? And the proper null hypothesis posits that it is a
result of neutral evolution: that is, it survives by sheer chance provided that
it is not deleterious enough to be efficiently purged by purifying selection.
To claim adaptation, the neutral null has to be falsified. The adaptationist
fallacy can be costly, inducing biologists to relentlessly seek function where
there is none.
The Panglossian paradigm and adaptationist just-so stories
Darwin’s concept of
evolution is centered on natural selection, or survival of the fittest[1].
Although Darwin did realize that organisms possess structures and even entire
organs that might not have an extant function, as is the case of rudiments[2],
on the whole, selectionist thinking has heavily dominated the biological
literature ever since. In its extreme but not uncommon form, the selectionist,
or adaptationist, paradigm perceives every trait as an adaptation. Under this
view of biology, the first and most important question a researcher asks about
any structure (including any genomic sequence) is: what is it for? Often, this
question is followed up with experiments aimed at elucidating the perceived
function.
Is the pan-adaptationist paradigm valid, especially at the
genomic level? In a classic 1979 article[3],
unforgettably entitled “The spandrels of San Marco”, Stephen Jay Gould and
Richard Lewontin mounted the first all out, frontal attack on
pan-adaptationism, which they branded the Panglossian Paradigm after the
inimitable Dr. Pangloss of Voltaire’s Candide ou L’Optimisme[4],
with his “best of all possible worlds”. The argument of Gould and Lewontin is
purely qualitative and centers on the metaphorical notion of spandrels, as they
denoted biological structures that do not appear to be adaptations per se but
rather are necessary structural elements of an organism[5].
The analogy comes from architectural elements that are necessitated by the
presence of gaps between arches and rectangular walls, and that can be
exploited decoratively to host images, as with the images of archangels and
evangelists in the Venetian San Marco basilica (Fig. 1): the spandrels have an
essential structural function and by no means have been designed for this
decorative purpose. Analogously, biological spandrels can be exapted
(recruited) for various functions, although their origin is non-adaptive
(exaptation is a new term introduced by Gould and Vrba to denote gain or switch
of function during evolution). Rather than hastily concocting adaptationist
“just-so stories” (in reference to Rudyard Kipling’s book of lovely tales[6] on
how the elephant got his trunk (Fig. 2) and the jaguar his spots—did
Kipling actually sense the inadequacy of naïve adaptationism?), submitted Gould
and Lewontin, a biologist should attempt to carefully and objectively
reconstruct the evolutionary histories of various traits of which many will
emerge as spandrels.
Fig. 1
The spandrels of
San Marco. The structures that support the arches of the San Marco basilica in
Venice are notable for the pictures that decorate them; however, the original
role of these structures (spandrels) has nothing to do with the images they
carry
Fig. 2
How the elephant
got his trunk. An illustration from Rudyard Kipling’s Just So Stories, in which
he imagines how striking features of various animals came into being. Here the
elephant’s nose is seen being stretched into a trunk as the elephant strains to
escape when it is seized by a crocodile. (The actual title of the story is “The
elephant’s child”)
Spandrels
and exaptation are elegant and biologically relevant concepts but do they
actually refute pan-adaptationism? Seemingly not—in particular because
clear-cut examples of spandrels are notoriously difficult to come up with.
Nevertheless, the essential message of Gould and Lewontin, that telling just-so
stories is not the way to explain biology, stands as true and pertinent as ever
in the post-genomic era. Let us explore the reasons for this, which could
actually be simpler and more fundamental than those envisaged by Gould and
Lewontin.
The fortunes of adaptationism in the (post)genomic era
The adaptationism debate
took a new dimension and became far more acute with the realization and
subsequent compelling demonstration by genomic sequencing that, at least in the
genomes of complex multicellular organisms, the substantial majority of the DNA
did not comprise protein-coding sequences. Hence the notion of junk DNA which
flew in the face of adaptationist thinking like no other concept before[7],[8],[9].
Junk DNA seems to cause a visceral reaction of denial in many if not most
biologists, indeed, those that consider themselves “good Darwinists”: how could
it be that the majority of the DNA in the most complex, advanced organisms is
non-functional garbage? Taken at face value, this possibility seems to defy
evolution by natural selection because one would think that selection should
eliminate all useless DNA.
The most typical
“refutation” of the junk DNA concept involves “cryptic functions” and
essentially implies that (almost) every nucleotide in any genome has some
functional role—we simply do not (yet) know most of these functions. Recent
discoveries of functional genomics and systems biology do add some grist to the
adaptationist mill. Although protein-coding sequences comprise only about 1.5%
of mammalian genomic DNA, the genome is subject to pervasive transcription—that
is, (nearly) every nucleotide is transcribed at some level, in some cells and
tissues[10],[11],[12].
Moreover, it has been shown that numerous non-coding transcripts are functional
RNA molecules, in particular long non-coding RNAs (lncRNAs), that are involved
in a variety of regulatory processes[13],[14],[15].
All these findings led to “genomic pan-adaptationism”—the view that cryptic
functions rule, so that (nearly) all of those transcripts covering the entire
genome actually perform specific, elaborate roles that remain to be uncovered
by focused experimentation[16],[17],[18],[19].
This view has reached its pinnacle in the (in)famous announcement by the ENCODE
project of the “functionality of 80% of our genome”[20],[21],[22],[23].
In the elegant phrase of Elizabeth Pennisi, the ENCODE project has “written a
eulogy for junk DNA”[24].
Genomic
pan-adaptationism may be attractive to many biologists, but it faces a
formidable problem that was emphasized by several evolutionary biologists
immediately after the publication of the striking claims by ENCODE[25],[26],[27],[28].
Careful estimates of the fraction of nucleotides in mammalian genomes that are
subject to selection, as assessed by evolutionary conservation, produce values
of 6 to 9% [29],[30],[31].
Allowing some extra for very weakly selected sites, no more than 10% of the
genome qualifies as functional, under the key assumption that selection equals
functionality25, 31. This assumption hardly needs much
justification: the alternative is functionality that is not reflected in
evolutionary conservation over appreciable time intervals, a contradiction in
terms. So the evolutionary estimates of the role of adaptation in shaping
complex genomes are a far cry from genomic pan-adaptationism that is deemed
compatible with or even a consequence of pervasive transcription. Where do we
go from here?
In the light of population genetics
“Nothing in biology
makes sense except in the light of evolution”—arguably, this famous
pronouncement of Theodosius Dobzhansky[32],[33]
is by now embraced by all biologists (at least at the level of lip service).
However, an essential extension to this statement is not nearly as widely recognized.
It was formulated by Michael Lynch and goes thus: “Nothing in evolution makes
sense except in the light of population genetics”[34].
Yet, without this addition, Dobzhansky’s statement, even if manifestly valid in
principle, makes rather little sense in practice. Indeed, population genetic
theory serves to determine the conditions under which selection can or cannot
be effective. As first shown by Sewall Wright, the evolutionary process is an
interplay of selection and random drift, or simply put, fixation of mutations
by chance[35],[36].
For adaptive evolution to occur, selection has to be powerful enough to clear
the drift barrier[37],[38]
(Fig. 2). Without going in detail into the theory, the height of the
barrier is determined by the product Ne s
where Ne is the effective population size and s
is the selection coefficient associated with the given mutation. If |Ne
s| > > 1, the mutation will be deterministically
eliminated or fixed by selection, depending on the sign of s. In
contrast, if |N e s| < 1,
the mutation is “invisible” to selection and its fate is determined by random
drift. In other words, in small populations, selection is weak and only
strongly deleterious mutations are weeded out by purifying selection; and
conversely, only strongly advantageous mutations are fixed by positive
selection. Considering the empirically determined characteristic values of N
e and s, these simple relations
translate into dramatically different evolutionary regimes depending on the
characteristic effective population sizes of different organisms34, 36, [39].
Simple estimates show
that in prokaryotes, with Ne values on the order
of 109, the cost of even a few non-functional nucleotides is high
enough to make such useless sequences subject to efficient purifying selection
that “streamlines” the genome[40].
Hence virtually no junk DNA in prokaryotes, which have “wall-to-wall” genomes
composed mostly of protein-coding genes, with short non-coding, intergenic
regions. Exceptions are observed only in the genomes of some parasitic bacteria
that most likely go through population bottlenecks and thus cannot efficiently
purge accumulating pseudogenes due to enhanced drift[41],[42].
The situation is dramatically different in the genomes of
multicellular eukaryotes, especially animals, that form small populations, with
N e of about 104 to 105.
In these organisms, only strongly deleterious or strongly beneficial mutations,
with |s| > 10−4, clear the drift barrier and accordingly
are either eliminated or fixed by selection (Fig. 3). These parameters of the
evolutionary regime seem to account for the major genomic features of different
organisms, in particular, the baroque genomes of multicellular organisms36.
Consider one of the most striking aspects of eukaryotic genome organization,
the exon–intron gene architecture. Virtually all eukaryotes possess at least
some introns, and the positions of many of these have been conserved through
hundreds of millions of years[43],[44].
Counterintuitive as this might seem, evolutionary reconstructions in my
laboratory clearly indicate that the ancestral state in most major groups of
eukaryotes and, apparently, the last common eukaryotic ancestor had an intron
density close to that in extant animals[45].
Why have eukaryotes not lost their introns? The adaptationist perspective has a
ready “just-so story”: introns perform important biological functions. And
indeed, this is the case for quite a few introns that harbor genes for small
non-coding RNAs and, less frequently, proteins and are involved in various
regulatory roles[46].
Nevertheless, the inconvenient (for adaptationism) fact is that a substantial
majority of introns harbor no detectable genes, show no appreciable sequence
conservation even in closely related organisms, and, overall, look much like
junk44. The population-genetic perspective provides concrete
indications that this is what they are. Simple estimates taking into account
the characteristic values of Ne, mutation rate, and the
target size for deleterious mutations in splicing signals (only about 25 base
pairs per intron) show that purifying selection in typical populations of
multicellular eukaryotes is too weak to weed out individual introns[47],[48].
Therefore, the introns persist in eukaryotic genomes simply because, at an
early stage of eukaryotic evolution, they invaded the genomes as mobile
elements, and subsequently, in many (but by no means all) lineages of
eukaryotes, selection was not strong enough to get rid of them. To cope with
this inescapable burden, eukaryotes have evolved a global solution, the highly
efficient splicing machinery (see next section).
Fig. 3
The drift
threshold and evolutionary regimes. The Ne
s = 1 (s = 1/Ne
) line is the drift threshold that separates the domains of the N e~
s phase space
corresponding to the selection-dominated and drift-dominated evolutionary
regimes
Introns
are by no means the only genomic feature that is apparently there just because
it can be. Along the same lines, it is easy to show that even duplications of
individual genes have limited deleterious effect and fall below the drift
threshold in organisms with small Ne. The notorious pervasive
transcription seems to belong in the same category. The minimal sequence
requirements (that is, the selection target) for spurious transcription are
less thoroughly characterized than those for splicing but are most likely to be
of the same order if not lower, in which case, transcriptional noise simply
cannot be eliminated by selection, resulting in pervasive transcription.
Global vs local selection: adapting to the ineffectiveness of adaptation
A
major corollary of the population-genetic perspective on evolution is a
dramatic change in the very nature of prevailing evolutionary solutions
depending on the power of selection, which is primarily determined by the
effective population size. The local solutions that are readily accessible in
the strong selection regime, in particular in large populations of
prokaryotes—because even features associated with very small s values
are subject to selection—are impossible in the weak selection regime, that is,
in small, drift-dominated populations. This ineffectiveness of local solutions
dictates a completely different evolutionary strategy: that is, global
solutions that do not eliminate deleterious mutations as they arise, but
instead minimize the damage from genomic features and mutations whose
deleterious effects are not sufficient to clear the draft barrier in small
populations[49],[50].
Introns once again present a perfect example. Because introns cannot be
efficiently eliminated by selection, eukaryotes have evolved, first, the highly
efficient and precise splicing machinery, and second, multiple lines of damage
control such as nonsense-mediated decay, which destroys aberrant transcripts
containing premature stop codons36, [51].
In a more speculative vein, the nucleus itself may have evolved as a
damage-control device that prevents the exit of unprocessed transcript to the
cytoplasm[52],[53].
The elaborate global solutions for damage control are by no means limited to
introns. For example, the germline expression of transposons, a class of
genomic parasites that under weak selection cannot be efficiently eliminated,
is suppressed by the piRNA systems, a distinct branch of eukaryotic RNA
interference[54].
The switch from local to global solutions necessitated by the ineffectiveness
of selection in small populations signifies a major shift in the character of
adaptation: under this evolutionary regime, much of adaptation involves
overcoming such ineffectiveness.
Subfunctionalization, constructive neutral evolution, and pervasive exaptation
Paradoxical as this may
seem, the weak evolutionary regime promotes evolution of phenotypic complexity.
Precisely because many genomic changes cannot be efficiently eliminated, routes
of evolution that are blocked under strong selection open up. Consider
evolution by gene duplication, the mainstream route of evolution in complex
eukaryotes[55].
In prokaryotes, duplications are rarely fixed because the deleterious effect of
a useless gene-size sequence is sufficient to make them a ready target for
purifying selection, since being identical, gene duplicates are useless
immediately after duplication except in rare cases of beneficial gene dosage
effects. By contrast, in eukaryotes, duplicates of individual genes cannot be
efficiently eliminated by selection and thus often persist and diverge[56],[57],[58],[59].
The typical result is subfunctionalization, whereby the gene duplicates undergo
differential mutational deterioration, losing subsets of ancestral functions[60],[61],[62].
As a result, the evolving organisms become locked into maintaining the pair of
paralogs. Subfunctionalization underlies a more general phenomenon, denoted
constructive neutral evolution (CNE)[63],[64],[65],[66].
CNE involves fixation of inter-dependence between different components of a
complex system through partial mutational impairment of each of them.
Subfunctionalization of paralogs is a specific manifestation of this
evolutionary modality. The CNE seems to underlie the emergence of much of the
eukaryotic cellular complexity, including hetero-oligomeric macromolecular
complexes such as the proteasome, the exosome, the spliceosome, the
transcription apparatus, and more. The prokaryotic ancestors of each of these
complexes consist of identical subunits that are transformed into
hetero-oligomers in eukaryotes as illustrated by comparative genomic analysis
from my laboratory, among others[67],
conceivably because of relaxation of selection that enables CNE.
Another major phenomenon
that shapes the evolution of complexity is pervasive recruitment of “junk”
genetic material for diverse functions. There are, of course, different kinds
of junk in genomes28. Exaptation of parts of mobile genetic elements
(MGE) is one common theme. Sequences originating from MGE are routinely
recruited for regulatory functions in eukaryotic promoters and enhancers[68],[69],[70].
In addition, MGE genes have been recruited for essential functions at key
stages of eukaryotic evolution. Striking examples include telomerase and the
essential spliceosomal subunit Prp8, both of which originate from the reverse
transcriptase of group II self-splicing introns[71],
the major animal developmental regulator Hedgehog that derives from an intein[72],
and the central enzyme of vertebrate adaptive immunity, the RAG1-RAG2
recombinase that evolved from the transposase of a Transib family transposon[73],[74].
Apart from MGE, the numerous “junk” RNA molecules produced
by pervasive transcription represent a rich source for exaptation from which
diverse small and large non-coding RNAs and genes encoding small proteins are
recruited (Fig. 4)[75],[76].
Actually, the two sources for the recruitment of new functional molecules
strongly overlap given the conservative estimates of at least half of the
mammalian genome and up to 90% of plant genomes deriving from MGE[77].
Fig. 4
The routes of
exaptation. The cartoon schematically shows two types of evolutionary events:
exaptation of a function-less transcript that becomes, for example, a lncRNA
and exaptation of a MGE that becomes, after transposition, a regulatory region
of a pre-existing gene. The thickness of the arrows
denotes the increase in expression level that is assumed to occur after
exaptation
These routes of
exaptation that appear to be central to eukaryotic evolution notably deviate
from Gould’s and Lewontin’s original spandrel concept3, 5
(Fig. 4). The spandrels of San Marco and their biological counterparts are
necessary structural elements that are additionally used (exapted) for other
roles, such as depicting archangels and evangelists. The material that is
actually massively recruited for diverse functions is different in that it is
not essential for genome construction but rather is there simply because it can
be, that is, because selection is too weak to get rid of it. Using another
famous metaphor, this one from Francois Jacob[78],[79],
evolution tinkers with all this junk, and a small fraction of it is recruited,
becoming functional and hence subject to selection76. The term
exaptation may not be the best description of this evolutionary process but
could perhaps be retained with an expanded meaning.
The extensive
recruitment of “junk” sequences for various roles calls for a modification to
the very concept of biological function76. Are the “junk” RNA
sequences resulting from pervasive transcription non-functional? In the strict
sense, yes, but they are endowed with potential, “fuzzy” functional meaning and
represent the reservoir for exaptation (Fig.4). The recruitment of genes from
MGE represents another conundrum: these genes encoding active enzymes certainly
are functional as far as the MGE is concerned but not in the context of the
host organism; upon recruitment, the functional agency switches.
The pervasive exaptation
in complex organisms evolving in the weak selection regime appears as a
striking paradox: the overall non-adaptive character of evolution in these
organisms enables numerous adaptations which ultimately lead to the dramatic
rise in organismal complexity39. In a higher abstraction plane,
though, this is a phenomenon familiar to physicists: entropy increase begets
complexity by creating multiple opportunities for the evolution of the system[80],[81].
Changing the null model of evolution
The population genetic
perspective calls for a change of the null model of evolution, from an
unqualified adaptive one to one informed by population genetic theory, as I
have argued elsewhere[82],[83].
When we observe any evolutionary process, we should make assumptions on its
character based on the evolutionary regime of the organisms in question34.
A simplified and arguably the most realistic approach is to assume a neutral
null model and then seek evidence of selection that could falsify it. Null
models are standard in physics but apparently not in biology. However, if
biology is to evolve into a “hard” science, with a solid theoretical core, it
must be based on null models, no other path is known. It is important to
realize that this changed paradigm by no means denies the importance of
adaptation, only requires that it is not taken for granted. As discussed above,
adaptation is common even in the weak selection regime where non-adaptive
processes dominate. But the adaptive processes change their character as
manifested in the switch from local to global evolutionary solutions, CNE, and pervasive
(broadly understood) exaptation.
The time for naïve
adaptationist “just so stories” has passed. Not only are such stories
conceptually flawed but they can be damaging by directing intensive research
toward intensive search for molecular functions where there is none. However,
science cannot progress without narratives, and we will continue telling
stories, whether we like it or not83. The goal is to carefully
constrain these stories with sound theory and, certainly, to revise them as new
evidence emerges. To illustrate falsification of predictions coming out of the
population genetic perspective, it is interesting to consider the evolution of
prokaryotic genomes. A straightforward interpretation of the theory implies
that under strong selection, genomes will evolve by streamlining, shedding
every bit of dispensable genetic material47. However, observations
on the connection between the strength of purifying selection on protein-coding
genes and genome size flatly contradict this prediction: the strength of
selection (measured as the ratio of non-synonymous to synonymous substitution
rates, dN/dS) and the total number of genes in a genome are
significantly, positively correlated, as opposed to the negative correlation
implied by streamlining[84].
The results of mathematical modeling of genome evolution compared with genome
size distributions indicate that, in the evolution of prokaryotes, selection
actually drives genome growth because genes acquired via horizontal transfer
are, on average, beneficial to the recipients[85].
This growth of genomes is limited by diminishing returns along with the
deletion bias that seems to be intrinsic to genome evolution in all walks of
life[86].
Thus, a major prediction of the population genetic approach is refuted by a new
theoretical development pitted against observations. This result does not imply
that the core theory is wrong, rather that specific assumptions on genome
evolution, in particular those on characteristic selection coefficient values
of captured genes, are unwarranted. Streamlining is still likely to efficiently
purge true function-less sequences from prokaryotic genomes.
The above example may
carry a general message: the population genetic theory replaces adaptationist
just-so stories with testable predictions, and research aimed at falsification
of these can improve our understanding of evolution. We cannot get away from
stories but making them much less arbitrary is realistic. Furthermore, although
most biologists do not pay much attention to population genetic theory, the time
seems to have come for this to change because, with advances in functional
genomics, such theory becomes directly relevant for many directions of
experimental research.
Abbreviations
CNE: Constructive neutral evolution MGE: Mobile
genetic element
Declarations
Acknowledgements
Not applicable.
Funding
The author’s research is supported by
intramural funds of the US Department of Health and Human Services (to the
National Library of Medicine).
Availability of data and materials
Not applicable.
Author’s contributions
EVK wrote the manuscript.
Author’s information
Eugene V. Koonin is at the National Center
for Biotechnology Information, National Library of Medicine, National
Institutes of Health, Bethesda, MD 20894, USA.
Competing interests
The author declares that he has no competing
interests.
Consent for publication
Not
applicable.
Open Access
This
article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/),
which permits unrestricted use, distribution, and reproduction in any medium,
provided you give appropriate credit to the original author(s) and the source,
provide a link to the Creative Commons license, and indicate if changes were
made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/)
applies to the data made available in this article, unless otherwise stated.
References
[3] Gould SJ, Lewontin RC. The spandrels of San Marco
and the Panglossian paradigm: a critique of the adaptationist programme. Proc R
Soc Lond B Biol Sci. 1979;205(1161):581–98.
[4] Voltaire. Candide, ou L'Optimisme, traduit de
L.Allemand Mr. Le Docteur Ralph. Paris: Sirene; 1759.
[5] Gould SJ. The exaptive excellence of spandrels as a
term and prototype. Proc Natl Acad Sci U S A. 1997;94(20):10750–5.
[8] Doolittle WF, Sapienza C. Selfish genes, the
phenotype paradigm and genome evolution. Nature. 1980;284(5757):601–3.
[10] Jacquier A. The complex eukaryotic transcriptome:
unexpected pervasive transcription and novel small RNAs. Nat Rev Genet.
2009;10(12):833–44.
[11] Dinger ME, Amaral PP, Mercer TR, Mattick JS.
Pervasive transcription of the eukaryotic genome: functional indices and
conceptual implications. Brief Funct Genomic Proteomic. 2009;8(6):407–23.
[12] Hangauer MJ, Vaughn IW, McManus MT. Pervasive
transcription of the human genome produces thousands of previously unidentified
long intergenic noncoding RNAs. PLoS Genet. 2013;9(6):e1003569.
[13] Mercer TR, Dinger ME, Mattick JS. Long non-coding
RNAs: insights into functions. Nat Rev Genet. 2009;10(3):155–9.
[15] Deniz E, Erman B. Long noncoding RNA (lincRNA), a
new paradigm in gene expression control. Funct Integr Genomics 2016. Epub ahead
of print.
[16] Amaral PP, Dinger ME, Mercer TR, Mattick JS. The
eukaryotic genome as an RNA machine. Science. 2008;319(5871):1787–9.
[17] Berretta J, Morillon A. Pervasive transcription
constitutes a new level of eukaryotic genome regulation. EMBO Rep.
2009;10(9):973–82.
[22] Ecker JR, Bickmore WA, Barroso I, Pritchard JK,
Gilad Y, Segal E. Genomics: ENCODE explained. Nature. 2012;489(7414):52–5.
[24] Pennisi E. Genomics. ENCODE project writes eulogy
for junk DNA. Science. 2012;337(6099):1159. 1161.
[25] Graur D, Zheng Y, Price N, Azevedo RB, Zufall RA,
Elhaik E. On the immortality of television sets: “function” in the human genome
according to the evolution-free gospel of ENCODE. Genome Biol Evol.
2013;5(3):578–90.
[26] Niu DK, Jiang L. Can ENCODE tell us how much junk
DNA we carry in our genome? Biochem Biophys Res Commun. 2013;430(4):1340–3.
[27] Doolittle WF. Is junk DNA bunk? A critique of
ENCODE. Proc Natl Acad Sci U S A. 2013;110(14):5294–300.
[28] Graur D, Zheng Y, Azevedo RB. An evolutionary
classification of genomic function. Genome Biol Evol. 2015;7(3):642–5.
[29] Smith NG, Brandstrom M, Ellegren H. Evidence for
turnover of functional noncoding DNA in mammalian genome evolution. Genomics.
2004;84(5):806–13.
[30] Ponjavic J, Ponting CP, Lunter G. Functionality or
transcriptional noise? Evidence for selection within long noncoding RNAs. Genome
Res. 2007;17(5):556–65.
[31] Ponting CP, Hardison RC. What fraction of the human
genome is functional? Genome Res. 2011;21(11):1769–76.
[32] Dobzhansky T. Nothing in biology makes sense except
in the light of evolution. Am Biol Teacher. 1973;35:125–9.
[33] Ayala FJ. Nothing in biology makes sense except in
the light of evolution: Theodosius Dobzhansky: 1900–1975. J Hered.
1977;68(1):3–10.
[34] Lynch M. The frailty of adaptive hypotheses for the
origins of organismal complexity. Proc Natl Acad Sci U S A. 2007;104 Suppl
1:8597–604.
[35] Wright S. Adaptation and selection. Genetics,
paleontology and evolution. Princeton: Princeton University Press; 1949.
[37] Sung W, Ackerman MS, Miller SF, Doak TG, Lynch M.
Drift-barrier hypothesis and mutation-rate evolution. Proc Natl Acad Sci U S A.
2012;109(45):18488–92.
[38] Lynch M, Ackerman MS, Gout JF, Long H, Sung W,
Thomas WK, Foster PL. Genetic drift, selection and the evolution of the
mutation rate. Nat Rev Genet. 2016;17(11):704–14.
[40] Lynch M, Marinov GK. The bioenergetic costs of a
gene. Proc Natl Acad Sci U S A. 2015;112(51):15690–5.
[41] Kuo CH, Ochman H. The extinction dynamics of
bacterial pseudogenes. PLoS Genet. 2010;6(8):e1001050.
[42] Goodhead I, Darby AC. Taking the pseudo out of
pseudogenes. Curr Opin Microbiol. 2015;23:102–9.
[43] Roy SW, Gilbert W. The evolution of spliceosomal
introns: patterns, puzzles and progress. Nat Rev Genet. 2006;7(3):211–21.
[44] Rogozin IB, Carmel L, Csuros M, Koonin EV. Origin
and evolution of spliceosomal introns. Biol Direct. 2012;7:11
[45] Csuros M, Rogozin IB, Koonin EV. Resonstructed
human-like intron density in the last common ancestor of eukaryotes. PLoS
Comput Biol. 2011:in press.
[48] Koonin EV. Intron-dominated genomes of early
ancestors of eukaryotes. J Hered. 2009;100(5):618–23.
[49] Rajon E, Masel J. Evolution of molecular error
rates and the consequences for evolvability. Proc Natl Acad Sci U S A.
2011;108(3):1082–7.
[50] Xiong K, McEntee JP, Porfirio D, Masel J. Drift
barriers to quality control when genes are expressed at different levels.
Genetics. 2016.
[51] Koonin EV. The origin of introns and their role in
eukaryogenesis: a compromise solution to the introns-early versus introns-late
debate? Biol Direct. 2006;1:22.
[52] Martin W, Koonin EV. Introns and the origin of
nucleus-cytosol compartmentalization. Nature. 2006;440(7080):41–5.
[53] Martin W, Koonin EV. Introns and the origin of
nucleus-cytosol compartmentalization. Nature. 2006;440(7080):41–5
[54] Czech B, Hannon GJ. One loop to rule them all: the
ping-pong cycle and piRNA-guided silencing. Trends Biochem Sci.
2016;41(4):324–37.
[56] Lynch M, Conery JS. The evolutionary fate and
consequences of duplicate genes. Science. 2000;290(5494):1151–5.
[57] Kondrashov FA, Rogozin IB, Wolf YI, Koonin EV.
Selection in the evolution of gene duplications. Genome Biol.
2002;3(2):RESEARCH0008
[58] Innan H, Kondrashov F. The evolution of gene
duplications: classifying and distinguishing between models. Nat Rev Genet.
2010;11(2):97–108.
[59] Kondrashov FA. Gene duplication as a mechanism of
genomic adaptation to a changing environment. Proc Biol Sci.
2012;279(1749):5048–57.
[60] Lynch M, Force A. The probability of duplicate gene
preservation by subfunctionalization. Genetics. 2000;154(1):459–73.
[61] Lynch M, O’Hely M, Walsh B, Force A. The
probability of preservation of a newly arisen gene duplicate. Genetics.
2001;159(4):1789–804.
[62] Gout JF, Lynch M. Maintenance and loss of
duplicated genes by dosage subfunctionalization. Mol Biol Evol.
2015;32(8):2141–8.
[63] Stoltzfus A. On the possibility of constructive
neutral evolution. J Mol Evol. 1999;49(2):169–81.
[64] Gray MW, Lukes J, Archibald JM, Keeling PJ,
Doolittle WF. Cell biology. Irremediable complexity? Science.
2010;330(6006):920–1
[65] Stoltzfus A. Constructive neutral evolution:
exploring evolutionary theory’s curious disconnect. Biol Direct. 2012;7:35.
[66] Lukes J, Archibald JM, Keeling PJ, Doolittle WF,
Gray MW. How a neutral evolutionary ratchet can build cellular complexity.
IUBMB Life. 2011;63(7):528–37.
[67] Makarova KS, Wolf YI, Mekhedov SL, Mirkin BG,
Koonin EV. Ancestral paralogs and pseudoparalogs and their role in the
emergence of the eukaryotic cell. Nucleic Acids Res. 2005;33(14):4626–38.
[68] Jordan IK, Rogozin IB, Glazko GV, Koonin EV. Origin
of a substantial fraction of human regulatory sequences from transposable
elements. Trends Genet. 2003;19(2):68–72.
[69] Thornburg BG, Gotea V, Makalowski W. Transposable
elements as a significant source of transcription regulating signals. Gene.
2006;365:104–10.
[70] Bourque G. Transposable elements in gene regulation
and in the evolution of vertebrate genomes. Curr Opin Genet Dev. 2009;19(6):607–12.
[71] Dlakic M, Mushegian A. Prp8, the pivotal protein of
the spliceosomal catalytic center, evolved from a retroelement-encoded reverse
transcriptase. RNA. 2011;17(5):799–808.
[73] Kapitonov VV, Jurka J. RAG1 core and V(D)J
recombination signal sequences were derived from Transib transposons. PLoS
Biol. 2005;3(6):e181.
[74] Kapitonov VV, Koonin EV. Evolution of the RAG1-RAG2
locus: both proteins came from the same transposon. Biol Direct. 2015;10:20.
[76] Koonin EV. The meaning of biological information.
Philos Trans A Math Phys Eng Sci. 2016;374(2063):20150065.
[77] Kannan S, Chernikova D, Rogozin IB, Poliakov E,
Managadze D, Koonin EV, Milanesi L. Transposable element insertions in long
intergenic non-coding RNA genes. Front Bioeng Biotechnol. 2015;3:71.
[80] Volk T, Pauluis O. It is not the entropy you
produce, rather, how you produce it. Philos Trans R Soc Lond B Biol Sci.
2010;365(1545):1317–22.
[81] Kleidon A. Life, hierarchy, and the thermodynamic
machinery of planet Earth. Phys Life Rev. 2010;7(4):424–60.
[82] Koonin EV. A non-adaptationist perspective on
evolution of genomic complexity or the continued dethroning of man. Cell Cycle.
2004;3(3):280–5.
[83] Koonin EV. The logic of chance: the nature and
origin of biological evolution. Upper Saddle River: FT Press; 2011
[84] Novichkov PS, Wolf YI, Dubchak I, Koonin EV. Trends
in prokaryotic evolution revealed by comparison of closely related bacterial
and archaeal genomes. J Bacteriol. 2009;191(1):65–73.
[85] Sela I, Wolf YI, Koonin EV. Theory of prokaryotic
genome evolution. Proc Natl Acad Sci U S A. 2016;113(41):11399–407
[86] Kuo CH, Ochman H. Deletional bias across the three
domains of life. Genome Biol Evol. 2009;1:145–52.
