Huneman - Persp Sci 2018

The Multifaceted Legacy of
the Human Genome Program

for Evolutionary Biology: An
Epistemological Perspective
Philippe Huneman
Institut d’Histoire et de Philosophie des
Sciences et des Techniques (CNRS/
Université Paris i Pantheon Sorbonne
This paper discusses the claim that alternative views to evolutionary biology
based on novel advances in understanding the molecular and developmental
bases of variation and inheritance should be captured as a shift from “statis-
tical” to “mechanistic” explanatory schemes (Pigliucci and Müller 2011).
Granted, statistical approaches characterized the Modern Synthesis, but by
examining the epistemic features of postgenomic science I claim that this is
not a proper characterization of the current epistemic shift. I will first char-
acterize the dual nature of the gene in development and inheritance, accounting
for it in terms of difference between two sorts of causal ascriptions. Following
the shift in postgenomic science regarding the concepts of genes, variation and
inheritance, I will first argue that, in contrast to mechanistic explanations,
the shift provides us with novel topological explanatory frameworks to
approach genomic networks of many sorts, and novel and nucleotide-focused
statistical tools unlikely to translate directly into the mechanistic modeling
The author is extremely grateful to Chris Donohue, Antonine Nicoglou, and Arnaud
Pocheville, whose comments and suggestions have been indispensable for the arguments
of this paper. A first version of those arguments has been presented as an invited lecture
at the History and philosophy of biology seminar of the National Human Genome Research
Institute (Bethesda) in December 2016, and then at the Montréal-Duke-Toronto-Paris-
Cambridge Consortium for History and Philosophy of Biology in May 2017 in Montreal.
I thank both audiences; insightful comments have been given by Thomas Heams, Annick
Lesne, and Joseph McInnerney on the first version and they are also warmly acknowledged.
Hugh Desmond and Chris Donahue should be thanked for a thorough language check.
Finally, sharp and detailed comments by two anonymous reviewers have substantially im-
proved the paper. This work is supported by the LIA CNRS Paris-Montréal ‘Epistemic and
Conceptual Issues in Evolutionary Biology. The author thanks the Institut de France and
the Fondation Desmaret for the support to the work that led to this publication.
Perspectives on Science 2019, vol. 27, no. 1
© 2019 by The Massachusetts Institute of Technology doi:10.1162/posc_a_00302
117
118 Epistemological Perspective on Genome Project Legacy
of causal roles. I claim that instead of addressing epistemic changes on the

basis of the classical statistics vs. mechanisms difference one should rather
acknowledge the diversification of explanatory modes proper to postgenomic
science, and to the consequences of this for evolutionary biology.
1. Introduction
Evolutionary biology, in the sense of the Modern Synthesis, which in the
1930s and 1940s articulated Darwinian natural selection and Mendelian
genetics around population and quantitative genetics, is currently under-
going a set of theoretical challenges based on various empirical and
conceptual advances (Pigliucci and Müller 2011; Laland et al. 2014;
Huneman and Walsh 2017; Müller 2017). Some authors propose an “Ex-
tended Synthesis,” which should integrate novel processes and modeling
styles within our approach to evolution and adaptation; other authors ar-
gue that the new empirical advances in evolutionary biology, such as the
acknowledgment of the role of phenotypic plasticity in evolution ( West-
Eberhard 2003; Nicoglou 2015), the impact of epigenetic phenomena on
inheritance (Bonduriansky and Day 2009; Danchin et al. 2011), or cases
of directed variation through developmental constraints such as genetic
channeling (Brakefield 2006; Maynard Smith et al. 1985), are likely to
be accounted for within the conceptual framework set forth by the Mod-
ern Synthesis ( Wray et al. 2014; Welch 2017). Granted, the Extended
Synthesis encompasses several claims, both about new problems that evo-
lutionary biologists should address, and new approaches, concepts, or
methods that should be considered. Recently, Müller (2017), one of its
major proponents, summarized the Extended Synthesis idea in these
terms:
Besides the expanded range of selection to multiple levels of
organization, the generative properties of developmental systems are
viewed as responsible for producing phenotypic specificity, whereas
natural selection serves to release that developmental potential.
Particular forms of phenotypic change are taken as the result of
internal generative conditions rather than external pruning. Thus,
a significant amount of explanatory weight is shifted from external
condition to the internal properties of evolving populations.
(…) Instead of chance variation in DNA composition, evolving
developmental interactions account for the specificities of phenotypic
construction.
As indicated here, Müller emphasizes the major role of development as a
“constructive” process within evolution. In this paper, I consider the claim
that development should be reintegrated within evolution and wonder
Perspectives on Science 119
about an interpretation of the possible shift in explanatory modes that this

requires. More precisely, I will focus on the role of genes in development
and evolution; indeed, a reason for some of the calls for a revision of the
Modern Synthesis in evolutionary biology comes from our new knowledge
of gene and genomes. Müller (2017) specified in this sense that the shift of
our understanding of genes in development and evolution is crucial in jus-
tifying an appeal to an Extended Synthesis:
This interpretation is also based on a fundamentally different account
of the role of genes in development and evolution. In the EES, genes
are not causally privileged as programs or blueprints that control and
dictate phenotypic outcomes, but are rather parts of the systemic
dynamics of interactions that mobilize self-organizing processes in
the evolution of development and entire life cycles.
My perspective here is epistemological: I will ask in this paper if in the
exploration of genes in development and evolution some new explanatory
regimes arise, which would warrant the sort of explanatory shift vindicated
by some proponents of the Extended Synthesis. The paper does not assess
either the Extended Synthesis as a project, or the need and possibility of
integrating development within evolution. It simply explores some ex-
planatory changes occurring within the sciences that deal with evolution
and development, hence with genes, after what is called the post-genomic
turn. And it confronts them with epistemological reflections advanced by
some supporters of the Extended Synthesis.
I will concentrate on the situation in evolutionary biology as it is affected
by the post-genomic turn, namely the change in our understanding of gene
and gene functions subsequent to the completion of the Human Genome
Project in 2003,1 through which genomics extends to many aspects cor-
relative to DNA beyond mere DNA sequencing. Granted, many avenues
of critique concur on the call for an Extended Synthesis, the oldest of
which come from evolutionary developmental theory and predate the post-
genomic turn. Yet, it is still interesting to consider the post-genomic turn
here, since many of the new advances about development and inheritance
come from post-genomic science.
I will start by focusing on the dual causal nature of genes in develop-
ment and inheritance (§2). Then I will consider several shifts that occurred
in our understanding of molecular mechanisms proper to genomic systems
after the achievement of the Human Genome Project (2003), in which the
complete sequencing of human genomes and some key model-organism ge-
nomes constituted an acknowledged milestone (§3). In order to understand
1. See Richardson and Stevens (2015) on the phrase “postgenomic turn.”

the epistemological changes that are brought about by this new approach to
genes and genomics, and their consequences for evolutionary theorizing, I
will consider a proposition made by Pigliucci and Müller (2011) about
the substitution of a mechanistic explanatory mode for the statistical explan-
atory mode of the Modern Synthesis (§4). To this end, I will evaluate the
extent to which our mechanistic understanding of genes in development
and inheritance is enriched after the postgenomic turn. I will finally assess
Müller and Pigliucci’s claim about an epistemic turn supporting the Ex-
tended Synthesis project. In a word, I will argue that the epistemological
landscape of explanatory types we nowadays witness in this field is much
more complex and richer than what is claimed by some supporters of an
Extended Synthesis, and possibly, in general, by many participants in those
debates when they use philosophical arguments about explanatory types.
2. The Double Role of Genes and the Uses of Causation

Notwithstanding the many disagreements between the “architects” of the
Synthesis (here left wholly aside since this is not a history paper),2 the
Modern Synthesis mostly considered that natural selection is the main
agency of evolution and that it acts upon Mendelian populations within
which variation is constituted by mutation and recombination. Julian
Huxley in a 1951 letter to Mayr wrote: “Natural selection, acting on the
heritable variation provided by the mutations and recombination of a
Mendelian genetic constitution, is the main agency of biological evolu-
tion.” Population and quantitative genetics are therefore the sciences that
model this evolutionary change, and hence play a key epistemic role in the
MS understanding of evolution: “The core of the synthetic theory is pretty
much just the theory of population genetics,” argues Beatty (1986). And
epistemologically, the kind of explanations provided by models in those
disciplines are in essence couched in terms of statistics and probabilities.
According to the Modern Synthesis indeed, each step in the modeling of
evolution and the explaining of organismal changes and diversity relied
on statistical knowledge. First, the genotype-phenotype relations were
inferred from statistical correlations. Second, fitness is a probabilistic
magnitude describing the reproductive chances of genotypes. The overall
theorizing about evolution— the population genetic models and the quan-
titative genetic models, as the heart of the Modern Synthesis— built on such
statistical descriptions and probabilistic modeling. Phenotypic variation,
the fuel of natural selection, is understood as a trait distribution and is
2. On the lack of unity in the Modern Synthesis from the viewpoint of a historian of
science, see Cain (2009).
statistically assessed; it is not the production of novel traits whose mecha-

nisms should be uncovered (Müller 2017).
For many supporters of a revision of the Modern Synthesis, this epis-
temological standard is indeed supposed to change with new advances
that encompass the knowledge produced in post-genomic fields, among
others— fields where the epigenetics and genomics of development are
explored— since we now have access to fine-grained molecular mechanisms
of variation and inheritance to which the architects of the Synthesis had no
access. Before turning to the epistemology of such postgenomic advances I
will first focus on the concept of the gene, since genes are crucial in pop-
ulation genetics and therefore in the Modern Synthesis approach to evolu-
tion, as well as in genetics and the genomics of development.
2.1. Developmental Genes and Evolutionary Genes: Two Uses

of Causation
One must first distinguish two aspects of the gene concept: the gene as a
substrate of inheritance, which plays a key role in evolution; and the gene
as a driving unit in development, sometimes characterized under the label
“genetic program.” The distinction between development and inheritance—
which would have seemed strange to 19th century biologists for whom the
two processes were not independent and not even separate (Amundson
2005)— is a hallmark of the Modern Synthesis. Development is an indi-
vidual process about the trajectory leading the zygote to a reproducing
adult, while inheritance is about traits in populations and their pattern
of re-occurrence across generations. This separation is a key conceptual
turn that allows for modern Darwinian biology, and makes it possible to
neglect development in evolution (Pocheville 2018a), a move to which the
Extended Synthesis objects, as Müller’s words quoted above can attest.
But, as we know, genes are essentially involved in those two processes.
Yet, even if genes are in each case ascribed a causal role, they entail caus-
ally distinct commitments. While genes are an important causal factor in
development, along with other factors sometimes lumped under the term
“environment,” genes in evolution correspond to a specific part of the par-
tition of phenotypic variance in population— a part often reduced to “ge-
netic additive variance,” called “narrow heritability”— and account for the
response to selection, often written R. A common way to formulate R is
the “breeder’s equation,” which states that R=hS, where h is the narrow
heritability and S is the selection coefficient (the fitness difference between
the fitter homozygote and a heterozygote).3
3. More sophisticated formulations of the equation replace h by the G matrix (Arnold
et al. 2008), the variance-covariance matrix of genes, but this doesn’t concern us here.
Starting with Fisher, the phenotypic variation in a population at a given

generation has indeed been partitioned into environmental variance, ge-
netic additive variance, covariance between environment and genotypes,
and genetic variance due to epistatic interactions and to dominance. Thus,
according to Fisher, only genetic additive variance accumulates generation
after generation, while the others may be unstable— for instance because of
recombination— and do not allow for cumulative selection. This variance is
therefore the key to adaptive evolution, since adaptive evolution requires
evolved traits or stages of the same trait to accumulate, and constitutes what
is of interest for biologists such as Fisher and the tradition of population
geneticists and behavioral ecologists influenced by him4— e.g., Anthony
Edwards, Warren Ewens, Alan Grafen, and other Oxford biologists.
Thus, while the developmental aspect of genes concerns the decompo-
sition of causal factors acting in a system in which genes seem to play a key
role— often leading authors like Crick to appeal to the notion of “informa-
tion” (see Pocheville 2018b for a reconceiving of this “Crick information”
in more general terms)— the evolutionary aspect concerns the decomposi-
tion of variance in a population. Importantly, a knowledge of the genes in
this latter sense, namely partitioning variance, cannot directly or generally
translate into knowledge of the relative weight of the causal role of genes in
a given individual in the population under scrutiny. Lewontin (1974) made
a detailed and influential study of the analysis of variance, which emphasized
the lack of any straightforward bridge between such analysis and any causal
conclusions of interest about individual organisms— especially when the
nature of the genetic background of the trait under focus is unknown,
as is often the case.5 Knowing which genes are responsible for most of
the variation of a given phenotype in a given environment thus does not
exclude that the maximum causal weight for the process building of this
trait in a given individual should mostly be ascribed to environmental fac-
tors. Inversely, to extrapolate from heritability measures a causal role for
genes regarding given traits independently of environments is hazardous,
because one should then assume the comparability of environments; other-
wise, it’s plausible that narrow heritability indeed varies according to the
environment (Visscher et al. 2008), while the “causal force” of genes should
in principle be measured and remain constant across environments.
4. See Tabery (2014) for an examination of Fisher’s claim that non-additive terms are
less important, and for the consequences of this claim.
5. Lewontin doesn’t say that inferring from heritability measures to causal factors in
individual traits is impossible, but that there is no general and principled way to do it. This
operation presupposes strict conditions on environmental homogeneity, kinds of popula-
tions considered, etc.
In evolutionary biology, an allele is therefore a difference-maker, mean-

ing that having or not having it makes a difference to the trait value and
then to the phenotypic variance for this trait, independently of the pro-
cesses underpinning genetic expression; and this difference is reliably
transmitted to the next generation (Dawkins 1982). Notice that such dif-
ference can be very small, but it is precisely (narrow) heritability in which
evolutionists are interested, no matter its intensity. A narrow heritability
does not preclude evolution, since according to the breeder’s equation that
governs response to selection (as a product of selection coefficient and
heritability), a strong selection coefficient in this case will still ensure evo-
lutionary change (or an infinite time) (Pocheville 2018a). One way (though
not the only one) to formulate this difference-making is in terms of con-
ditional probability: having the allele increases the probability of express-
ing the phenotype under focus. This difference made by the allele
impinges within the population onto the frequencies of various trait
values. The part of the population’s phenotypic variance (regarding the
trait under focus) on which the allele makes a difference belongs therefore
to the genetic variance (itself decomposed for further reasons into non-
additive and additive genetic variance, the latter being the most relevant
for evolution and selection, as mentioned above).
In development, on the other hand, genes define a kind of causal factor,
which is a component of a process; such a factor, within an individual,
combines with other factors in order to produce at each stage a specific state
of the developing organism. To be a cause here, is to be a moment within a
process, and cannot be abstracted from the intertwining of all the causes that
make up the whole process. It’s not just about making a difference, possibly
assessed by statistics; it’s about playing a specific role within a process.
Philosophers such as Salmon (1984) or Dowe (1995) showed that a cause
in this sense is a particular state of affairs in the physical world, satisfying
some physical conditions (e.g., conserving key quantities such as energy).6
Thus, early molecular biology committed to a sequential view of devel-
opment in which genes are the main causal factor, since they were under-
stood as a program that drives the building of a normal adult from the
zygotic stage, assuming the proper environmental cues. This sequential
view, often understood cybernetically with the notion of “program” (first
coined by Mayr [1961], and simultaneously by Jacob and Monod in their
operon paper [Jacob and Monod 1961]), provided a causal reading of the
statistical genotype-phenotype correlations used by evolutionary biologists.
However, our recent understanding of development rejects this sequential
6. There are other views on this issue of process causation, for instance those of Bailly
and Longo (2011), but this is not the place to consider such controversies.
and program-based view; as Müller (2017) stated, “development is not a

linear reading out of a code or program but a systemic process of feedback
interactions between genetic and non-genetic templates, cells and tissues
that mobilizes physical and autonomous properties at different scales and
depends on local as well as global environments.” Of course, once this is
acknowledged, the question relevant to evolutionary biology still remains:
to what extent is this complex causal structure of development compelling
us to change our understanding of evolution, while the causal role of genes
in development (namely, causal component of a process) is heterogeneous to
the causal role of genes in evolution (namely difference making regarding
heritability)? I will now explain the main epistemological issue faced in this
context by the project of integrating development within evolution.
2.2. A Synthesis between Developmental Gene and Evolutionary

Gene? Issues about Explanatory Monism
There is a certain natural appeal in the claim made by the Modern
Synthesis— and challenged by Extended Synthesis proponents and more gen-
erally by Evo-Devo scientists— that development doesn’t really pertain to
evolution. If development and evolution instantiate different kinds of causal
explanation or inference, they cannot therefore be simply synthesized,
pace the wish expressed by Evo-Devo supporters such as Gilbert et al.
(1996), especially because one causal ascription pertains to difference-making
in the context of populations while the other pertains to composing causal
processes at the individual level.7
Conversely, in order to substantiate such a call for synthesis between de-
velopment and evolution, one should show that this division of causal re-
gimes described in the previous paragraph within the gene concept is
outdated within current genomic science. That is the reason why a claim
for an extended synthesis that would rely on integrating development within
evolution must overcome the epistemic objection to the fact that partitioning
variance (namely, genes in heritability) and ascribing the weight of causal
factors (namely, genes in development) as two distinct epistemic operations
properly characterize the developmental and evolutionary approaches.
Thus, if development actually plays a principled key role in evolution,
as Evo-Devo scientists forcefully argued, one has to look at the new ex-
planatory strategies regarding the causal role of genes in development
and inheritance according to postgenomic biology. We will now turn to
7. Because of this double difference, a single mathematical framework that could

unify both causal ascriptions is very difficult to establish, even though in general a differ-
ence in causal inferences may authorize a single mathematical framing.
a characterization of this move and assess more generally the epistemology

of postgenomic understanding and explanations.
3. The Postgenomic Turn: Three Major Changes

Much, though not everything, of what we now know about development
relates to our fine-grain understanding of genes, epigenetics and environ-
mental relations and interactions, a field of study that falls under the
scope of postgenomic science. So, what does theoretically happen with
the post-genomic turn with respect to this distinction between partition-
ing total variance and assessing causal weights in a multifactorial process?
To answer this question, one should first summarize the reconceptualiza-
tion of variation, inheritance, and the roles of genes that took place after
the postgenomic turn, since, as Müller (2017) put it, any Extended Syn-
thesis assumes a “fundamentally different account of the role of genes in
development and evolution.”
Here I will first consider three correlated features of the post-genomic
turn relevant to the double causal nature of the genes emphasized above,
and the way it is now understood. Both of these advances complexify the
notion of the gene, as is well known (e.g., Neumann-Held 2001; Moss
2003; Griffiths and Stotz 2013). Genes used to be simple units of coding,
units of variation, and units of inheritance, but each of these simplifica-
tions has been challenged by our current understanding of genomics. More
precisely, given that the Modern Synthesis uses the key concepts of genes,
variation, and inheritance as the building bricks of its theories, those new
advances challenge three monolithic ideas corresponding to those key
notions: (a) a simple link between gene and protein or trait; (b) a simple
view of variation as mutation and recombination; and (c) a simple equation
between unit of inheritance and gene.
a) First there is the well-known fact that genes do not simply produce a
specific protein on the basis of an environmental input, but mostly operate
within genomic networks through which their effects are upregulated and
downregulated in a complex system, making gene expression possible and
responsive to environmental states at any stage of the lifecycle of the
organism. This conceptual shift had already started with Jacob and Monod’s
operon concept (which introduced the phrase “genetic program”), but ma-
tured with Davidson’s Gene regulatory network concept (Davidson 1986).8
A gene regulatory network can, with few exceptions, be represented as a
mixed graph in which the nodes represent levels of gene expression or
8. Much work has been done since the 1980s on gene networks in general; a pio-
neering theoretical work is that of Stuart Kauffman on Boolean networks of genes— see
Kauffman 1993.
RNA concentrations, the edges correspond to a direct influence between

nodes, and the undirected edges correspond to other associations between
levels of gene expression levels or RNA concentration. The expression of a
target gene is here regulated and modulated by thousands of interconnected
genes and gene products, regulating alternatively the expressions of each in
accordance with the environment of the cell and then of the organism (de la
Fuente 2010). Even though some argue that they cannot constitute by
themselves an explanation of anything, GRNs and other genetic networks
are crucially involved in the explanation of development and have been
shown to underlie basic developmental theory concepts such as morphoge-
netic fields or morphogen gradients (Levine and Davidson 2005).
Developmental biology had for decades identified a mechanism through
which pattern formation is ensured: it relies on the various concentrations
of a substrate emitted by the cells, and to which cells are sensitive (Wolpert
1969). More precisely, this substance, called the morphogen, is released by
the cells, and at a specific location its concentration varies in a specific way;
this defines a gradient, and cells react in a particular way to their position
along the gradient, adopting the behavior that constitutes the target pat-
tern. Lewis Wolpert described the model here under the name the “French
flag model,” in that it turns a continuous distribution of morphogens (a
gradient) into a discontinuous pattern. However, explaining how the cell
responds differentially to something is not clear-cut; that’s what the genetic
networks framework contributes to explain, by showing how distinct values
of the concentration gradient trigger distinct regulatory responses by a tran-
scriptional network (Balaskas et al. 2012).
In this context, it is not enough to say that a one-to-one idea of protein-
gene relation, as suggested by the idea of genetic code, should be replaced by
a many-to-one mapping, as early critiques of the most simplistic models of
population genetics had it.9 The many-to-one view was indeed inbuilt in
early genetics, with the notions of epistasis and pleiotropy. In fact, in consid-
ering dominance after Fisher, Huxley had already indicated in 1936 that genes
are not effective outside a “gene-complex”: dominance and recessiveness
are to be regarded as modifiable characters, not as unalterable inherent
properties. Mutations become dominant or recessive through the action of
other genes in the gene-complex. (…) mutations which are initially
deleterious may become advantageous either in the altered environment
or in an altered genetic background. (Huxley 1936)
But what is new now is our understanding of how pleiotropy and
epistasis are realized: each allele functions as a member of a network, and
9. Think, for example, of Mayr’s well known attack on “bean bag genetics” (Mayr 1959).
its relations with other genes modulate its role in the expression of a
target gene, which involves both pleiotropy (one-to-many gene-protein
relations) and epistasis (many-to-one gene-protein relation). Moreover,
each gene is part of many networks, and each network involves many of
the genes in a different way, all of which gives an idea of the complexity
of the gene-protein-trait relations. This shift could be conceived in terms
of a shift from the gene to the genome as the key agent involved in
evolution and development (in contrast for example to the focus on gene
inherent in the “gene’s eye view” (Dawkins 1982) and the discussions this
triggered). Any revision of the epistemological role of genes in develop-
ment and in inheritance should start from this overwhelming fact of the
use of gene networks in our understanding of genes.
b) A novel notion of variation arises from the sequencing of the human
genome (along with the genomes of fruit flies, mice, nematodes, yeast, the
sequencing of which was also part of the HGP), and challenges the idea
that variation is a question of recombination and mutation. Granted, those
may condition variation, but they are not sufficient conditions, as I will
now explain. Our progressive understanding of genomics indeed yielded
two so-called paradoxes regarding genes as DNA sequences: the C-value
paradox, and the G-value paradox (Elliott and Gregory 2015). The C-value
paradox is about the fact that the number of nucleotides in organisms’
DNA does not correlate with the size of the organisms: some plants and
yeast have as many nucleotides in their genomes as humans have; nor does
it match in complexity either (assuming there is some correlation between
complexity and size). As formulated later on, the G-value paradox is about
the fact that the amount of coding in DNA sequences does not seem to
correspond to the complexity of organisms (however complexity is de-
fined): humans as well as some plants or insects have tens of thousands
of genes, while some species have much more.10 Our intuition would be
that whatever the meaning of “complexity” is, more complex organisms
need more instructions to be built and to fulfill their functions, hence more
genes in the sense of coding sequences. But this is not the case at all. Thus,
basically, what explains the G-value and the C-value paradoxes is that few
genes can produce many variant transcripts (e.g., due to alternative splicing
or other processes) and then many proteins, and that they produce more of
them in some genomic and cellular contexts than in other genomic contexts.
Thus, a plausible hypothesis is that the uses of these genes within the genomic
system integrated in the cell machinery accounts for the distinct complexities
of organisms, not the mere amount of (coding) genes. Genome is the primitive
10. Complexity and size may not evolve independently; the relation between their evo-
lutions has been intensively studied; for a recent overview see McCarthy and Enquist (2005).
system, and genes are now defined in genomics as units within those systems,
though there may be several ways to define them. This leads to the need for
several concepts of genes (e.g., Neumann-Held 2001; Moss 2003; Griffiths and
Stotz 2013), since DNA sequence as a coding sequence is not enough to denote
the content involved in the functioning and development of the cell.
However, inversely many genomic networks are likely to yield the same
gene products or genomic expression profile (see Ciliberti et al. 2007 for an
exploration of the network of GRNs). This overall fact challenges a key
tenet of the Modern Synthesis, namely the fact that, as in the earlier cita-
tion from Huxley, variation is due to mutation and recombination. We
now know that mutations may just not produce variation, and that large
variation can be achieved with almost no mutations, but rather through
the reconfiguration of the network either by a change in the global net-
work output after environmental shift or a small change in a regulatory
gene that triggers major changes in the overall functioning of the network.
David et al. (2013) provided an experimental evolution model based on
the synthetic yeast genome in which adaptations to glucose deprivation
take place in various ways “with or without these significant mutations,
indicating that additional factors participated in this regulation and that
the regulatory network could reorganize in multiple ways to accommodate
different mutations.” In the context of gene networks, variation as a fuel to
adaptive evolution is not in principle to be equated with mutations.
For this reason, the major debate about the relative roles of mutation
and selection in evolution, which pervaded the whole history of evolution-
ary theories, is to be resettled here. At the time of the Modern Synthesis,
Fisher proposed the very strong argument that mutations cannot be the
source of the adaptive evolution of traits, since beneficial mutations should
be necessarily small. In effect, for him, the larger the mutation, the greater
the chance that it would largely impact many traits within an organism,
since organisms are always tightly integrated wholes; however, this would
mean that it would surely harm some of those traits. Because of this argu-
ment, couched in a model now called Fisher’s geometric model (see Martin
and Lenormand 2008) macromutations cannot lead to evolution. Large mu-
tations a priori negatively affect the functional integration of organisms, so
beneficial mutations must be small. However, if mutation can affect not only
coding but also non-coding regulatory genes (something we have known for
several decades), and since these non-coding genes play a role in regulating
the expression of various genes within a gene regulatory network, a mutation
may be large and still poorly affect traits directly. Carroll (2005) claimed in
this sense that most of the mutations involved in the emergence of novelties
in evolution are mutations on regulatory genes rather than coding genes.
David and colleagues go further and indicate that a major adaptive change
may not be initiated by mutations and may require a dynamic rearrange-

ment of the whole network:
in several fundamental aspects our results demonstrate that
regulatory adaptation is a more complex and dynamic process that is
unlikely to be explained by a single static change like a mutation in
the DNA sequence. We have shown that a genetic change in the
form of a single mutation, while maintaining a full correlation with
the adaptive growth phenotype on the level of the population, was
certainly not sufficient to ensure growth on Glu–his [amino-acids] in
a considerable number of individual cells. (David et al. 2013)
The whole debate about small and large mutations and their role in the
question as to whether mutation or selection drives evolution is, therefore,
reset. In any case, the idea that variation is provided by mutation and
recombination should be updated, to the extent that “mutations” mean
many distinct things and not just “point mutations” on nucleotides, which
would make variation available indefinitely as the architects of the Modern
Synthesis used to think (Beatty 2016).
Variation has been the target of two leading programs developed after the
completion of the HGP, namely the HapMap11 and the 1000 Genomes pro-
grams.12 After 2002, both were intended to map the variations of the human
genome, targeting haplotypes blocks common in several populations, in order
to provide insights on genetic diversity and tools to study the genetic bases of
common diseases. Later research on variation revealed that not only “single nu-
cleotide polymorphisms” (SNPs), but “submicroscopic variants, which include
deletions, duplications and large-scale copy-number variants— collectively
termed copy-number variants or copy-number polymorphisms— as well
as insertions, inversions and translocations” constitute genomic variation,
making the notion of variation even more complex.13
c) Moreover, networks include many elements that are not by them-
selves genetic (even given the controversies over what “gene” could mean),
or at least not made up of DNA— histones, methyl groups, and more gen-
erally all that are included in “epigenetic elements,” proteins, etc. Some
argue that the very notion of inheritance must take this into account
and that this would solve the problem of “missing heritability” (Maher
2008),14 which arose by applying SNP-based methods to the explanation
11. International HapMap Consortium (2003).

12. The 1000 Genomes Project Consortium (2010).
13. Feuk et al. (2006).
14. One can define missing heritability as the difference between the heritability observed
in family and pedigree studies and heritability as explained through SNPs or another type of
of human phenotypic variation (e.g., Danchin et al. 2011). More generally,

the functioning of genomes is now inseparable from other sources of
agency within the cell, such as proteins, transcripts, epigenetic marks, etc.— a
set of factors that is studied in sub-disciplines whose names end in
“-omics” (metabolomics, proteomics, transcriptomics, etc.) and whose un-
derstanding relies on new techniques of high-throughput sequencing and
mapping. Thus, the key idea that genes constitute heritability, as proposed
by the Modern Synthesis, is challenged here, too (Danchin and Pocheville
2014). In this context, many other epistemological novelties arise, above
all the field of “systems biology,” and the emphasis on physical forces
(Forgacs and Newman 2005), organization of the cell and cytoplasm,15
etc. Nevertheless, I will not consider these since my focus here is on the
new understanding of gene/genomics in development and evolution.
However, one should not infer that the formal apparatus of population
genetics is falsified; for instance, extending inheritance can still be inter-
preted in classical terms to the extent that one extends the Price equation,
which is a statistical descriptor of heritable change between generations, to
include non-genetic terms responsible for some heritable phenotypic var-
iance (Helantera and Uller 2010). Thus, any verdict about a key change in
explanatory modes based on such a shift in the notion of inheritance should
be cautiously assessed.
Those three changes (a, b, c) thereby impinge on the epistemology of
variation and inheritance, which is foundational to the notion of evolution
by natural selection and to selectionist explanations. In the next section, I
will consider this epistemology by assessing the proposal of Pigliucci and
Müller (2011) for an epistemological rationale for the Extended Synthesis.
4. Explanation in Post-Genomic Contexts: An Embarrassment of Riches
4.1. An Epistemological Justification for an Extended Synthesis

It is not certain whether those changes concerning the understanding of
genes justify the kind of explanatory switch needed to yield any coales-
cence of the two explanatory aspects of genes— in development and in in-
heritance. Assuming that the advances in our understanding of genome
variant (aka effect size, where most variants are of small effect). Actually, missing heritability may
be partly explained by the serious undercounting of structural variation in the genome, that then
leads to problems in how the reference sequence was initially assembled, because the entire hu-
man genome is still not sequenced. However, one of the issues that has come up recently is that
family studies may, due to poor design, have overestimated heritability. Thus, the solutions for
the missing heritability problem are probably multiple. (I thank Chris Donohue for having
brought this to my attention.)
15. See Montévil (2018) on the case of molecular motors.
structure and functioning indeed warrant such changes and therefore jus-
tify the sort of explanatory move pushed by the defenders of an Extended
Synthesis, we may first want to see such a justification formulated. For that
reason I will focus here on a philosophical rationale for the Extended Syn-
thesis formulated by Pigliucci and Müller (2011). In their attempt to for-
mulate a rationale for the move they are calling for in their book, these
authors suggest that whereas the Modern Synthesis biologists used statis-
tical models of gene frequency change to capture evolution because they
did not yet have access to fine-grained mechanisms, the Extended Synthe-
sis can rely on a much deeper knowledge of molecular and developmental
processes, and therefore is in a position to capture the mechanisms under-
lying evolution and adaptation. Thus, they contend that “the shift of em-
phasis from statistical correlation to mechanistic causation arguably
represents the most critical change in evolutionary theory today.”
As we have seen, Modern Synthesis is indeed intrinsically based on sta-
tistical models and probabilistic knowledge. Müller and Pigliucci argue
that the insufficiency of statistical explanations in evolutionary biology
was made manifest in the recent advances of molecular and developmental
biology, including the postgenomic turn that I discussed in section 3. Such
a rationale appeals to a philosophical distinction between statistical and
mechanistic concepts, and therefore engages the current literature about
causal explanations and mechanisms in science (e.g., Craver and Darden
2013; Glennan 2017).16
In this section, I will therefore consider the explanatory regimes in-
volved in the exploration of genomes and their role in inheritance— hence
in evolution— as well as in development, in order to assess the validity of
Müller and Pigliucci’s interpretation. It will appear that while explanatory
innovations do occur in the postgenomic science of heredity and develop-
ment, those changes cannot be captured by the move from statistics to
mechanisms hypothesized by these authors. Therefore, their epistemolog-
ical argument cannot be the proper rationale for the move to an Extended
Synthesis, at least if one considers the legacy of the HGP for evolutionary
biology. However, a more general consequence will be that post-genomic
science, to the extent that it involves our knowledge of inheritance and
development, displays several epistemological regimes, so that an argu-
ment pinpointing a single explanatory change cannot justify the move
towards a new Synthesis in evolution.
16. There is a strong relation between this claim by Müller and Pigliucci and the so-
called “statisticalist interpretation” of natural selection, advanced initially by Walsh, Ariew,
Lewens and Matthen (Walsh et al. (2002); Matthen and Ariew (2002); Walsh (2010)). This
important debate about the nature of selection is wholly left aside here.
The first part of the section (4.2) addresses the way our postgenomic
science understands the role of genes in the development and functioning
of cells and organisms. I will consider whether the thinking emerging here
is a form of mechanistic thinking that could indeed be likely to supersede
the statistical thinking proper to the Modern Synthesis and mostly used to
handle genes as inheritance units. The second part (4.3) will look at geno-
mics’ attempts to identify markers of heritable traits, and see whether they
could translate into an ascription of causal roles which, in turn, would allow
a general mechanistic framework to address inheritance and evolution
together— in contrast with my discussion in section 2 of the explanatory
heterogeneity of the two roles of the gene.
4.2. Network and Topological Explanations

Müller and Pigliucci contrast the fine-grained knowledge of mechanisms
with the statistical understanding proper to population genetics and then
the Modern Synthesis. Mechanism has recently been the subject of several
extended philosophical elaborations. The very notion of a mechanistic ex-
planation, as it has been elaborated in recent neo-mechanist philosophy of
science, often involves granting some entities in the models a causal role as
that which, through their activity, yields the explanandum as the outcome
of a mechanism. Various statements of mechanistic philosophy do coexist
and differ— e.g., Craver and Darden 2013; Glennan 2017— but they concur
in ascribing a crucial role to detecting key entities and their key activities in
order to establish mechanisms, even though each of them is context-
dependent, defined at a given scale and level and within an explanatory
strategy (see e.g., Craver 2013). Modeling in such a framework means iden-
tifying the relevant entities, ascribing them the proper causal role, and
sketching the relevant organization in which such causal roles can be ful-
filled. Is it the case then that we meet such a kind of explanation in the
context of the postgenomic science of the role of genes in the development
and functioning of organisms?
First of all, with regard to the development and functioning of organ-
isms and cells, the complexity of the genomic network is such that focus-
ing upon the specific causal action of a given allele is often not practically
possible. This constrains the explanatory strategy in a way I will now de-
scribe. Consider first the fact of the robustness of gene networks, namely
the fact that shutting down some genes or many of them in a GRN does
not ipso facto change the outcome of the network; on the contrary, many
networks indeed support the deletion of many genes (Wagner 2005a). If
each gene were performing a specific function, detectable in the phenotype,
such robustness would not be possible— except if there were many func-
tionally similar copies of each gene. However, Wagner clearly distinguishes
such redundancy-based robustness from the many cases where the focal gene
does not have a redundant copy somewhere else (Wagner 2005b). In this
case, labeled “distributed robustness,” one should acknowledge that the gene
network keeps doing the same thing in the absence of the gene under focus.
This points to the following fact: genes have a context-sensitive, network-
defined effect rather than a specific causal role.17 Granted, one could always
say that each gene has a repertoire of several possible causal roles, disposi-
tionally triggered each time a gene is altered in the network; but given the
size of the network and the number of possible gene combinations, de-
scribing such a repertoire would be extremely difficult.
Thus, finding out the causal role of an allele in a given network (and not
just its influence on its neighbors) is not straightforward because this role
will depend upon thousands of interactions with other genes and may
change depending on a change in other genes or gene products in the net-
work. What is explanatory therefore is often not the gene qua having a
causal role in the system but the whole network made up by the various
effects of the genes in various contexts defined by various arrangements of
the network. Thus, the explanation of genomic expression (e.g., skeletoge-
netic micromere structure in sea urchins (Oliveri et al. 2008)) may partly
rely on network properties rather than on some allele’s specific causal role.
I am not arguing that this is the only way to infer behavior from our
knowledge of gene networks; in some cases, one can list the frequency at
which a given gene impacts each phenotype and construe an expression profile
for this gene.18 However, this strategy misses the originality of network un-
derstanding as may be allowed by GRN modeling. When, as we have seen,
Huxley in 1936 summarized the ideas of population geneticists that genes
are not simply proxies for traits but that their phenotypes depend upon the
genetic background in which they are embedded, he possibly justified
exactly the same strategy. However, what’s new in the GRN and other
gene networks is that this multiple context-dependent expression of genes
is fine-grained into a hierarchical pattern: genes are downregulated and/or
upregulated. Thus, a mere summary expression profile for genes would
miss such an interesting insight into the reasons why genes have distinct
expression profiles.
Exploring a gene network may however provide the idea of dividing the
genes, as nodes, into several categories defined internally to the network.
For instance, in a paper about the GRN regulating the development of the
heart in zebra fish, the authors, after having reconstructed the network,
17. This holds however they are defined, and whether they are DNA sequences, tran-
scripts, or sets of possible DNA sequences does not make much of a difference here.
18. My thanks to an anonymous reviewer for raising this objection.
draw inferences regarding the role of individual genes as targets of regu-

lators based on the properties of the network: the graph “appears to show a
large number of interactions, with a few highly connected nodes and many
nodes with a few connections, which are likely to represent regulators and
their targets, respectively” (Hill et al. 2017).
Moreover, the global topology could instead be very informative.19
Thus, it may happen that the topology constrains the network in such a
way that some outcomes of the dynamics are prescribed by its very topol-
ogy. This is the case with properties such as stability with respect to the
failure of individual genes, when it is entailed by the scale-free structure of
a network (example analyzed in Huneman 2010; see more complex exam-
ples in Huneman 2018b). I do not claim that this explanatory strategy is
the only one possible, or even that it is the most used one, but that there is
something novel here due to the appeal to gene networks.
Instead of exactly capturing the causal mechanisms of development at
the level of alleles, one thus sometimes infers interesting dynamics or dy-
namical properties— such as limit cycles, equilibria, robustness, etc.—
from global topological constraints, in a way that is labeled “topological
explanation” (Huneman 2010, 2018a; Woodward 2013). As an example,
according to Klemm and Bornholdt (2005), the explanation of the prop-
erty of cell signaling robustness is sometimes given not by an examination
of the genes involved in the signaling network and their causal role but
mostly by the specific topology of the network under focus. In this paper
they consider networks in a very abstract way, with clear applications to
GRNs. They question whether the network may reliably or not transmit a
sequence of signals, even if each element fluctuates in timing. The network
oscillates and produces sequences of outputs: some networks are more re-
liable than others in reproducing the sequence while the timing of inputs
and each element’s response fluctuate. The behavior of the network tends
to oscillation cycles, which can be considered as attractors of the network’s
dynamics. Some are reliable, some are unreliable; the latter ultimately
amplify fluctuations and desynchronize the signal, whereas the former
dampen fluctuations and reliably produce the expected output. The chal-
lenge then is to find out the reason why. Each node in this network— genes,
transcripts, etc.— may undergo some delay in reacting to the incoming sig-
nal, and therefore it’s important that the whole system still proves reliable in
giving an overall response to an initial environmental signal; otherwise the
19. Someone could object that specifying the topology is about the organization of the
mechanism, and that therefore the explanation that targets networks topology is a kind of
mechanistic explanation. This is not the place to answer such an objection, which has been
dealt with by Felline (2015) and Huneman (2017, 2018a).
cell and the organism will malfunction in their environment. Klemm and
Bornholdt found that reliable attractors cycles are those constituted by per-
vasive triangular elements (minimal subgraphs) that deliver the signal
through the triangle and then to the next node. The fluxes along the edges
as well as their orientation is not so relevant to the reliability of the perfor-
mance. The topology of the network proves therefore to be the main differ-
ence between reliable and unreliable attractors. Hence reliability can be
attested by examining the mere topological properties of the subgraphs.
As they stress: “The likelihood of reliable dynamical attractors strongly
depends on the underlying topology of a network.”
The same kind of reasoning applies to other networks such as the protein-
protein interaction networks (PPI). A recent study by Alvarez-Ponce
et al. (2017) for instance has shown that, even though the different rates of
evolution of different proteins in a lineage may be affected by many factors
(e.g., their level of gene expression, etc.), the most important factor is a topo-
logical one, namely the centrality of the protein in the PPI network, this cen-
trality being understood on the basis of three topological parameters: degree,
betweenness (number of shortest paths between all pairs of other proteins that
pass throughout a certain protein), or closeness (one divided by the average
distance between a protein and all other proteins in the network).
A more general indication of the fruitfulness of topological consider-
ations in explanations about networks, as opposed to the focus on the ac-
tivities of genes as entities within a mechanism to be reconstructed, is the
notion put forth by Uri Alon of network “motives.” In metabolic net-
works, transcription-regulation gene networks or PPI ( Yeger-Lotem
et al. 2004), there are topological patterns (small subnetworks) that recur
much more frequently than randomly expected. Those “motives,” because
of their topology, may do something in the transmission within the overall
network— they are like “logical gates” in a network (Figure 1). For
instance, one of the motives may function as a feed-forward loop because
of its topology (see C in figure 1). As the authors write, “The topology of
this motif enables composite regulation schemes.” The point, here, is that
the shift towards genomic networks in the postgenomic turn does seem to
offer topological explanations rather than mechanistic explanations, at least
in the view of neomechanicists.
To sum up, it is not the case in our explanations of development and
development-related network functioning in the postgenomic context that
a gene as a DNA sequence20 will itself be a unit of expression and develop-
mental action, and a causal-role bearer in an explanatory mechanism. Thus,
even though our understanding of variation involved in developmental
20. Actually, what “the gene” is here depends on the network.

Figure 1. Some network motives in transcriptional networks, according to Yeger-

Lotem et al. (2004).
molecular mechanisms exceeds by far that of the MS, the kinds of expla-
nations we gather in this context are not stricto sensu, or not always, mech-
anistic explanations. This is not to deny that mechanistic explanations
occur in this field, nor even that they may be the most frequent case of
explanations— but it surely counters the claim that what happens here
is an intensification of mechanistic regimes of explanation at fine-grain
levels of biological reality. In this perspective, one is not justified to think
of the lessons of the postgenomic turn in terms of the replacement of a
statistical explanatory scheme by a mechanistic understanding.
In addition, one could also consider that our understanding of topolog-
ical constraints allows us to understand something about evolution itself.
That is why, the case I make here for the rise of topological explanations
within postgenomic contexts— even though mechanistic explanations are
still more frequent— is relevant to a discussion of the epistemological
features of any evolutionary paradigm change. Erwin (2017) reminds us
of this in reviewing the various topological and metric spaces considered
by evolutionary biologists to make sense of novelty in evolution. Following
work by Wagner, Fontana, Schuster, Stadler, and others on RNA net-
works, he considers the space of RNA sequences and the way its topology
may constrain evolution and especially the possibility of evolutionary “nov-

elties.” In this space, RNA sequences are separated by a change in base
pairs; many random sequences are not realized, and those that are realized
are more or less distant, and more or less accessible from one another.
Erwin adds: “If different two-dimensional structures are taken as novelties
the critical point is that some random networks will have many adjacencies
to other random networks, leading to the expectation that shifting be-
tween the two folded structures represented by different networks should
be relatively easy (think of the boundary between France and Germany— a
step out of France is likely to land in Germany). By contrast, other
networks will be relatively isolated, with few adjacencies to other neutral
networks (Monaco is surrounded by France, but few steps out of France
would land in Monaco; the converse is not true, as any step out of Monaco
necessarily lands in France). The novel structures represented by the iso-
lated networks will be relatively inaccessible, but for this example it is the
topology of the sequence space that determines the accessibility of the
phenotypic novelties” (Erwin 2017, p. 4) Hence topological accessibility
provides an explanation that swamps any mechanistic investigation of
RNA-based processes.
Thus, even though we may have many reasons to include development
within evolution, and that our knowledge of development and its evolu-
tion involves mechanistic schemes of explanation, it is not the case that
this integration should inevitably lead to a mechanistic explanation of evo-
lution, as we saw in this examination of the deployment of topological ex-
planations in the postgenomic era. Now, I turn to the other aspect of
genes, namely their role in inheritance, and the possibility that a causal
understanding of the role of genes regarding traits can be sustained
through novel methods of detecting genes involved in heritable traits.
4.3. Statistics, Inheritance and Phenotypes

Notwithstanding the above development, there is doubt that our detailed
postgenomic knowledge of the implication of mutations in many diseases,
e.g., in diabetes or obesity (Locke et al. 2015; Shunghin et al 2015), points
towards knowledge of what some genes do. The heterogeneity of partition-
ing variance and identifying a role in a process, related to the two faces of the
gene— inheritance (hence evolution) and development— precluded that, in
the classical framework, one could easily unify evolution and development.
Except under very strict conditions, it prevented inferences being drawn
from heredity measures to developmental factors. In the postgenomic con-
text, is there a sense that such obstacles have been overturned? In this sec-
tion I will consider how postgenomic studies in postgenomic contexts can
identify genes for traits and possibly change the explanatory landscape of
evolution and development.
4.3.1. ENCODE, Functions and the Genome. We saw that the dream of
mapping particular genes onto phenotypes vanished, as the amount of cod-
ing genes proved to be far smaller than the amount of traits, especially with
the HGP. One gave up the idea that a gene could be mapped onto a trait in
a cell of an organism for which it’s responsible. However, a recent develop-
ment could be seen as the continuation of this idea, namely the ENCODE
project, which aims at listing in a conveniently tractable way the functional
effects of genes within gene networks (rather than within cell or organismal
phenotype) (ENCODE Project 2012). ENCODE has strong ties with the
above-mentioned HapMap program, which was intended to explore varia-
tion in the human genome. Through ENCODE, many genes are now ascribed
some functions internal to their embedding within networks. Annotations are
also intended to capture variation. This led to criticism of the old idea that
most DNA is junk DNA, and of the very notion of junk DNA, since even
though many sequences are not exons, i.e., they are not expressed in traits,
they do something in the networks of gene regulation and gene expression,
and that something has been quantified (ENCODE Project Consortium
2012). The results of such enquiries have been labeled “functions” of the
genes. Yet, as highlighted by Doolittle (2013), the sense of “function” accord-
ing to which all sequences are ascribed functions— contrary to the previous
belief that many of them were junk DNA— is controversial, especially with
regard to the concept of function in evolutionary theory, namely functions as
“selected effects” (Neander 1991).
However, it’s not even clear that those “functions” are causal-role functions—
the main alternative philosophical account of biological functions (e.g.,
Cummins 1975)— because what they do is so context-dependent that one
cannot say that two given genes have two causal roles allowing them to be
part of the same mechanism, since they perform a multiplicity of context-
dependent things. Hence, nothing ensures that the two “functions” will be
referred to the same context, which is a requisite for saying those are two
causal-role functions of a given item (since “being a function” is here as-
cribed in reference to a specific context, i.e., a system under study).21 Using
21. An analogous and sharper critique has been made by Graur and colleagues: “EN-
CODE adopted a strong version of the causal role definition of function, according to which
a functional element is a discrete genome segment that produces a protein or an RNA or
displays a reproducible biochemical signature (e.g., protein binding). Oddly, ENCODE not
only uses the wrong concept of functionality, it uses it wrongly and inconsistently. (…)
According to ENCODE, for a DNA segment to be ascribed functionality it needs to 1)
be transcribed, 2) be associated with a modified histone, 3) be located in an open-chromatin
area, 4) bind a transcription factor, or 5) contain a methylated CpG dinucleotide. (…) This
another understanding of function, such as the organizational conception

(Montévil and Mossio 2015), would here face the same difficulty in ac-
counting for “functions” in the ENCODE context, since the whole argu-
ment according to which all these genes are constraints for the metabolic
system22 is lacking, and would require a prior general understanding of
the dynamics of the gene network, while in turn those functional ascrip-
tions are supposed to help model this dynamics.
Thus, the ENCODE project does not exactly model the genomic net-
works as mechanisms in the sense that philosophers of science mean
(e.g., Glennan or Craver). It provides interesting tools to enquire about
some dysfunctions and the role of mutations in them, but it’s not clear
that it allows us to identify the functions as the causal roles of genes.
Yet, this should be the case according to the classical idea that genes have
functions, which are the traits to which they contribute in the organisms,
notwithstanding the concept of function one uses— be it systemic or
etiological.
The controversy about the real meaning of the ENCODE program is
still on going. In any case, it’s hard to see it as a straightforward applica-
tion of a mechanistic modeling program. Without following the negative
assessments by Graur et al. (2013) and Doolittle (2013), it should rather
be seen as the elaboration of a heuristic tool for exploring our genomic data
than as a genuine explanatory framework.
4.3.2. Inferring Causal Roles from a Statistical Detection of Genetic Markers
in the Postgenomic Era: The Paradox of Resolution. The ENCODE project does
not directly touch upon the organism phenotype. However, a very impor-
tant endeavor of genomics consists in considering a given trait value and
identifying which nucleotidic variants increase the frequency with which
individuals will display this trait value. As indicated above, it is an
approach that uses the difference-making scheme of causation to capture
some effect of gene differences upon phenotypic variation. The genes on
which a mutation makes a difference for the trait are the genes that to-
gether constitute the heritability of the trait.
Medical applications are crucial here, and a major target for genomic
studies, for instance those carried out at the National Human Genome
Research Institute, concerns obesity, diabetes, depression, and other wide-
spread illnesses that strongly affect health systems. Genomic techniques
kind of argument is false because a DNA segment may display a property without neces-
sarily manifesting the putative function. For example, a random sequence may bind a tran-
scription factor, but that may not result in transcription” (Graur et al. 2013, p. 580).
22. Being a constraint on the system’s thermodynamic processing maintained by the very
activity of the system itself is the basic conception supporting the “organizational account” of
functions.
allow us to do Genome Wide Association Studies (GWAS), namely, studies

that compare a group that has a trait and a group that doesn’t at millions
of target nucleotides, so that the single nucleotidic polymorphisms (SNP)
relevant in this between-group difference can be identified (Visscher et al.
2008).
We are here concerned then with genes as they are involved in the he-
reditary transmission of trait— the heritability aspect, as specified above.
Those studies are epistemologically novel compared to the Modern Synthe-
sis and classical population genetics, because the detection of the genetic
bases of traits starts at the level of nucleotides— once SNPs were used to
calibrate tests— and not with family groupings, as classical linkage studies
classically used to find out genes involved in traits heritability.
Now, as I mentioned earlier, classically there was a heterogeneity be-
tween the cause of traits in development and the partition of variance in
heredity studies, which implies that no principled inference between he-
redity and causal roles in development can be warranted (§1). For this rea-
son, bridging the gap between development and evolution, as the
Extended Synthesis requires, involves showing that this heterogeneity
can be overcome. Through their new methodological approach, post-
genomic analyses identify many new genes involved in various traits (IQ,
Obesity, Type B Diabetes, etc.). What does this involvement mean? Even
though inheritance and development are different, could the attribution of
SNPs for traits now directly lead to an assessment of the role of genes in
trait building, thus avoiding the difficulties of the classical approach as
Lewontin (1974) theorized them? With postgenomics, analyses do not
start with pedigree, but seem to capture the mechanistic bases of traits
(i.e., nucleotides)— hence the hope that they would translate more directly
into a knowledge of the mechanisms of trait-building by pinpointing genes
with a relevant causal activity regarding those traits. Thus, while post-
genomic analyses such as GWAS studies are of a statistical nature, is it the
case that they could provide a way to direct inferences to causal role, and
then help to sketch causal mechanisms about traits and their evolution, a
result that would validate Pigliucci and Müller’s appreciation?
A key aspect of the research programs in the genomics of obesity or
depression, for instance, is the quest for variants that are likely to account
for some of the variance in phenotypes. Many of them have indeed been
identified in depression (Major Depressive Disorders Working Group 2013;
Mullins and Lewis 2017), schizophrenia (Schizophrenia Working Group
2014), obesity (Locke et al. 2015; Shungin et al. 2015), diabetes (Saxena
et al. 2007; Morris et al. 2012; Voight et al. 2010), etc. (See Figure 2,
for example, of a map of SNPs involved in metabolic diseases). Between
2005 and 2009 hundreds of associations of common genetic variants
Figure 2. SNPs involved in metabolic human diseases. Excerpt retrieved from the
GWAS Catalog: https://www.ebi.ac.uk/gwas/. Excerpt from the EBI-NHGRI
catalogue of identified SNPs. 2A is a magnified version of 2B, inorder to make
colour representation of SNPs and colour code more visible.
correlated with over 80 diseases and traits have been found. The method-
ology always consists in finding a correlation between variance on the trait
and variation on a given locus, possibly on the whole genome (GWAS). No
knowledge of the causal architecture of gene expression is required here
(even though knowing the dominance, recessivity, and epistasis relation
would be helpful to fine-grain the results), but what matters is the fact
that those variants make a difference in the probability of the trait under
focus for the subpopulations that have those variants. Moreover, as Laber
and Cox (2017) notice about SNPs involved in diabetes type II and obesity,
“the vast majority of these SNPs are in non-coding regions of the genome
and distal to promoters, suggesting they act through gene regulation which
makes their functional interpretation challenging.”23
These studies rely on the resolution power of our detection tools, which,
here, rests upon the size of the sample. The Major Depressive Disorder GWAS
(Genome-Wide Association Studies) consortium indeed noted in 2013: “Her-
itability alone reveals little about genetic architecture. In the absence of a de-
tailed understanding of genetic architecture, sample size and phenotypic
homogeneity are the critical determinants of discovering robust and replicable
genetic associations” (MDD 2013; my emphasis). This is straightforward:
the larger the size, the greater the chance one will find a variant that is slightly
more represented in the subpopulation with the trait under study than in the
other subpopulation. This explains for example why, by switching to cohorts
that are about 180,000 people (Okbay et al. 2016) instead of 9,000 (MDD
GWAS 2013), researchers found many mutations involved in depression. As
Mullins and Lewis (2017) indicate, “this number [of genetic associations] is
now expected to increase linearly with sample size, as seen in other polygenic
disorders.” Considering the study of genetic loci involved in depression, they
measured the effect of shifting sample size in the following way: “The
CHARGE study of 51,258 participants would have 50% power to detect
a variant accounting for 0.0058% of trait variance. A study of 180,000
participants, similar to SSGAC, could detect a variant accounting for
0.017% of trait variance (with 50% power).”24
Undoubtedly the same trend will affect the research of genetic variants
in schizophrenia, in many diseases, and possibly in behavioral traits.25 As a
study of depression indicates, “it has become clear that the effects of com-
mon genetic variants for most complex human diseases are considerably
smaller than many had anticipated. This implies that sample sizes necessary
for identification of common genetic main effects were far larger than could be
attained by single-research groups or existing consortia” (MDD 2013).
The consequence of this trend towards larger sample sizes, however, is
that all those mutations detected by enlarging the cohort size will con-
tribute only very slightly to explaining phenotypic variance on a given trait.
Moreover, if one assumes that a difference-making effect on heritability can
translate into a causal role in individuals, the mutations will have a vanishingly
23. See also Ziegler and Sun (2012): “Unexpectedly, many of the identified associa-
tions did not map to genes but to gene deserts, and the biology underlying these discoveries
is rarely immediately apparent.”
24. CHARGE and SSACG are two consortium studies on the genetics of depression.
25. See Longino (2013) and Schaffner (2016) on assessing the genetics of human behavior.
small causal effect on the trait in a given individual. I call this the “paradox
of resolution.”
The reason for this paradox is the following. Given the random choice of
an individual in the whole population affected by the focal trait, the
chances that she will have this mutation (detected only in a very-large-
sample GWAS study) will in fact be very low. Since one needs a very large
sample to manifest the statistical relevance of this mutation to the vari-
ance, such statistical relevance is not salient in small samples. In other
words, here the chances that an individual has trait T given she has allele
X are extremely weakly higher than for an individual not having X
(everything else being equal); and this vanishingly small increase in prob-
ability is correlated to the resolution power: it is smaller if the resolution
needs to be higher. Therefore, in a randomly chosen individual with allele
X, chances are high that this allele makes no significant difference to her
having trait T. Considering this reasoning from another perspective, the
putative mechanism explaining why she has T will not likely accept the
focal mutation (or SNP allele) X as a causal entity, because the chances
are small that indeed the individual will have allele X. The paradox of
resolution therefore entails that the greater our capacity to find out alleles
involved in heritability of a given focal trait, the less likely will those alleles
have a robust causal role in developing the trait, if we intend to derive
causal roles from our knowledge of alleles involved in heritability. Thus,
what the new methods with their dependence upon resolution power teach
us about genes involved in heritable traits, is precisely something that will
appear quite causally irrelevant if inferences are warranted from detected
trait-related SNPs to the causes of trait development.
GWAS analyses are indeed providing us with much more detailed de-
tection of the genetic bases of heritability of the traits under study than the
classical genetic linkage analysis based on family groupings, since they
address traits at the level of nucleotides, not genes themselves (however
they are defined). However, as Juran and Lazaridis (2011) put it in a paper
about the “genomics in post-GWAS era,” “the main lesson learned from
the early GWAS efforts is that though many disease-associated variants
are often discovered, most have only a minor effect on disease, and in total
explain only a small amount of the apparent heritability,” which directly
stems from the paradox of resolution. What comes next, the so-called
post-GWAS methods, overcomes indeed some of the limitations of the
GWAS methods, especially the focus on common variants (since the target
nucleotides―SNPs―on which GWAS studies focus are common variants
and hence the studies ignore all the rare variants)26 but may not surmount
26. See e.g. Lin et al. (2018).

the paradox of resolution I just sketched here, if they still use a resolution
power based on increased sample size.
Thus, when Lewontin criticized in principle the derivation of causal
weight from analysis in phenotypic variance, he was pointing to a limit
that is not overcome by current genomics, since the paradox of resolution
now prevents such direct inferences, and in turn, prevents elaborating
mechanisms that would show genes robustly involved in the production
of traits.
This paradox does not hamper the GWAS and post-GWAS projects
themselves, since the intent of those studies is not to explain the causes
of the traits under scrutiny, but precisely to identify mutations likely to
increase a risk when it comes to diseases. However, from the viewpoint
of the causal analysis of those traits, it affects the project of drawing major
mechanistic consequences from this extended knowledge of the bases of
the heritability of some focal traits.
GWAS methods and their successors allow genomes to be broadly con-
sidered, without making any assumptions regarding the relation between
genes and traits or a direct correlation between genotype and phenotype
levels— in sum, they allow genes to be considered as elements of genomic
networks rather than as instructions for traits. However, the very idea of a
polygenic score for a trait, namely the addition of the detected SNPs that
make a difference for the trait as derived from GWAS studies, does not fit
into a mechanistic paradigm of an explanation of the trait and its
development since those scores say nothing about the possible activities
of the alleles involved.
The Modern Synthesis relied on sophisticated statistical tools to capture
evolutionary change. However, my cursory investigation of the study of the
genetic bases of traits in the postgenomic framework does not support the
view that this statistical approach has been replaced by a mechanistic un-
derstanding of heritability and then evolution. On the contrary, while the
knowledge here is relying on new methods, in principle it does not allow
us to get a grip on the causal levers involved in the traits.
In fact, current epistemic use of GWAS data is limited by the purely
SNP-oriented character of the method, which tells us precisely nothing
about the varying context-dependent effects of the genes. Thus, polygenic
scores are very poorly informative about the biological reality of the genetic
architecture of traits and its dynamics. Geneticists increasingly acknowl-
edge this fact: “Given the complex genetic architecture and synergistic ef-
fects among these genes, the holistic effect of a gene network or a pathway
is expected to have a larger effect than the sum of individual effects from
each gene. In addition, it is usually challenging to interpret the genetic
associations for their functional connection with the trait only based on
the annotation of a single gene” (Sun 2012). The future of GWAS methods
lies precisely in the coupling of their articulation in terms of reconstructed
genomic networks with the topological explanations to which they give
rise, as seen in section 4.2. Sun (2012) summarizes such prospects in these
words: “Biological networks and pathways are built to represent the func-
tional or physical connectivity among genes. Integrated with GWAS data,
the network- and pathway-based methods complement the approach of
single genetic variant analysis, and may improve the power to identify
trait-associated genes.”
Thus, more than the embedding of developmental and evolutionary
knowledge within a single systematic mechanist framework, the new epis-
temological perspectives offered to evolutionary theory by a postgenomic
take on the role of genes in inheritance and development should be under-
stood as a plurality of explanatory modes, including topological explana-
tion and powerful nucleotide-focused statistical tests.
5. Conclusions
To sum up, besides some mechanical fine-grained understanding of the in-
volvement of genes as signals in cascades, we found in postgenomic contexts
several novel epistemic features relevant to evolutionary theory: a set of topo-
logical explanations for network properties proper to gene or protein networks
(4.2); a novel statistical understanding of genomic patterns as responsible
for traits, that goes beyond the one-or-two-loci-genotype/phenotype
statistical correlations on which the Modern Synthesis relied, and that uses
novel detection and statistical tools (4.3). More precisely, pace Pigliucci
and Müller (2011), what we do in the postgenomic era, at least regarding
genomes, does not really foster a mechanistic explanation instead of the
classical use of genotype-phenotype correlation and statistical fitness-based
modeling of evolutionary dynamics. Rather, it involves several explanatory
practices intended to make sense of the high-throughput output of geno-
mic data, while discovering mechanisms appears difficult because of the
problems of applying some functional talk to the whole genome (4.3.1)
and because of the paradox of resolution (4.3.2).
An epistemological consequence of these shifts brought about by the
HGP thereby consists in a diversification of explanatory modes when it
comes to capturing the status of genomes and the production of phenotypic
traits through development as well as through inheritance. Even if, for some
reason not explored in this paper, we have to integrate development within
evolution, and if, by undertaking this, new advances in molecular and
developmental processes, as well as epigenetic inheritance, plasticity, or
cultural inheritance compel us to shift from the statistical kind of expla-
nations proper to the MS to a mechanistic kind of explanation, still the
novel epistemological features of the contributions of the postgenomic

science of development and inheritance do not warrant such a shift. How-
ever, those features are interestingly novel, and whatever the status of the
integration of various new advances in biology, they will partly charac-
terize the epistemological framework proper to the evolutionary biology
to come.
In conclusion, we may be compelled to change our understanding of
evolution and evolutionary processes in the wake of the postgenomic turn,
but not because we know more about mechanisms; rather, we may have to
do so because systems are so complicated that we have developed very
powerful statistical and topological tools, that may percolate into the
knowledge and modeling of difference-making proper to the causality of
genes in evolutionary contexts, that often stand at the basis of evolutionary
modeling.
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The Multifaceted Legacy of

the Human Genome Program

of causal roles. I claim that instead of addressing epistemic changes on the

about an interpretation of the possible shift in explanatory modes that this

1. See Richardson and Stevens (2015) on the phrase “postgenomic turn.”

2. The Double Role of Genes and the Uses of Causation

statistically assessed; it is not the production of novel traits whose mecha-

2.1. Developmental Genes and Evolutionary Genes: Two Uses

Starting with Fisher, the phenotypic variation in a population at a given

In evolutionary biology, an allele is therefore a difference-maker, mean-

and program-based view; as Müller (2017) stated, “development is not a

2.2. A Synthesis between Developmental Gene and Evolutionary

7. Because of this double difference, a single mathematical framework that could

a characterization of this move and assess more generally the epistemology

3. The Postgenomic Turn: Three Major Changes

RNA concentrations, the edges correspond to a direct inﬂuence between

may not be initiated by mutations and may require a dynamic rearrange-

11. International HapMap Consortium (2003).

of human phenotypic variation (e.g., Danchin et al. 2011). More generally,

4. Explanation in Post-Genomic Contexts: An Embarrassment of Riches

4.1. An Epistemological Justiﬁcation for an Extended Synthesis

4.2. Network and Topological Explanations

draw inferences regarding the role of individual genes as targets of regu-

20. Actually, what “the gene” is here depends on the network.

Figure 1. Some network motives in transcriptional networks, according to Yeger-

may constrain evolution and especially the possibility of evolutionary “nov-

4.3. Statistics, Inheritance and Phenotypes

another understanding of function, such as the organizational conception

allow us to do Genome Wide Association Studies (GWAS), namely, studies

26. See e.g. Lin et al. (2018).

novel epistemological features of the contributions of the postgenomic

Cain, Joe. 2009. “Rethinking the Synthesis Period in Evolutionary

Felline, Laura. 2015. “Mechanisms Meet Structural Explanation.” Synthese.

Juran, B. D., and Karl N. Lazaridis. 2011. “Genomics in the Post-GWAS

McCarthy, M. C., and Brian Enquist. 2005. “Organismal Size, Metabolism

Pocheville, Arnaud. 2018b. “Biological Information as Choice and Con-

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