## 1. Setting the Scene: Different Kinds of Meanings of Genotype and Phenotype



The meaning of the terms given at the start of the introduction may at
first seem clear, but conceptual questions have accompanied or been
implied by the use of the terms since their introduction to
English-language readers by Johannsen's (1911) "The
Genotype Conception of Heredity" and up until the present. How
does an individual organism's DNA influence the processes of
development of its traits over its lifetime--processes that also
involve other influences? How can an individual organism's
traits be used to identify its DNA sequence? Why are the terms
genotype and phenotype still used if they simply refer to the
individual's DNA and traits? One answer to this last question is
that what counts is less the meaning of the terms than what their use
has come to *signify*, in particular, that certain issues have
been resolved: the barrier between the organism's life course
and DNA transmitted to the next generation; evolution is change in
frequencies of genes or DNA sequences in populations over time;
development of traits will eventually be understood in terms of a
composite of the effects of DNA on the organism; what counts is what
is underneath or inside the observable surface; and findings about
heredity derived using one meaning of terms affirm findings derived
using a different meaning. How firmly resolved are these issues? If
one wants to open them up for further scrutiny, it could be helpful to
question the meaning of genotype, phenotype, and the distinction
between them.



Another response to why the terms continue to be used is that the
predominant meanings are not the only ones. Type connotes a
*class*. This sense of the terms leads to further questions:
What makes organisms similar enough to be grouped in a genotype as a
class? ...or in a phenotype as a class? How is the membership of
organisms in a genotype manifest in their membership in a
phenotype--or phenotypes? How can the membership of organisms in
a phenotype be used to identify their membership in a genotype? Type
also connotes an *abstraction* away from the full set of
observed characteristics. What then is to be accentuated and what
de-emphasized about a genotype and phenotype, as DNA and traits or as
classes--especially when asking any of the previous questions?
And how--by what concepts, methods, and models--is what has
been de-emphasized to be brought back and *re-integrated* into
the scientific account? 



To make sense of the original meanings of the terms and the
distinction between them as well as the coexistence of different kinds
of meanings since then, a specific kind of abstraction (see entry on
 abstract objects)
 is pertinent, namely, the *material* practices of
*control* over biological materials and conditions advanced in
modern experimental biology and agricultural breeding or entailed in
the allied use of *models in analysis of data*. Reliable
methods more than endorsable theories are the touchstone of this kind
of abstraction. It is within a framing of control--and the
consequent challenge of reintegration--that this entry discusses
the other senses already mentioned of the terms genotype and
phenotype: in the context of the relationship between an
individual's DNA and traits; what the use of the terms
signifies; and grouping into classes. (Given the continuing
coexistence of the different kinds of meaning of the terms, qualifiers
are used when there might be ambiguity.)



Although there may be grounds to revise various positions and
inquiries about the genotype-phenotype *relationship* in light
of assumptions made about control and eventual reintegration, such
discussion lies beyond the scope of this entry. (If the
genotype-phenotype relationship were the entry's focus, more
attention would need to be given to philosophical arguments about
causality and about abstraction as it relates to causal claims; see
Winther 2014 for an entry point and
 section 7.)
 The entry also cannot do justice to the rich social and economic
history of heredity, where concrete cases abound concerning the
control of biological materials for production and
breeding--dating from well before the genotype-phenotype
distinction through to present-day biotechnology. (Readers wanting to
reintegrate the history and context might usefully start with the
essays collected in Muller-Wille et al. 2008b, Deichmann et al.
2014, and Muller-Wille & Brandt 2016, and references cited
therein. Muller-Wille 2008 and Bonneuil 2016, in particular,
describe Johannsen's professional and modernizing aspirations
and place them in their economic context. Rolls-Hansen 2014 places
Johannsen's 1911 contribution in the context of shifts in his
views over his career.) 


## 2. The Goals and Open Questions of Johannsen (1911)



Marcel Weber (2014) notes that, because many areas of modern biology
"are profoundly experimental disciplines, an increased attention
[in philosophy of biology] to the experiment in biology was
inevitable" (see also entry on
 gene).
 Yet, how an area of biology becomes experimental in the first place
as well as the implications of that shift also warrant attention. A
recounting of Johannsen (1911) in this vein serves not only to
introduce his original genotype-phenotype distinction, but also to
point to various conceptual and methodological complexities that are
associated with redefining heredity on the basis of breeding
experiments. The detail in this section and the next is important not
as a matter of doing history, but to insert distance from the
predominant current-day meanings and establish a space in which modern
users of his terms can consider issues that had been left behind.


### 2.1 Goals: Establish Repeatable Outcomes and Expose Hidden Processes



The overarching project for Johannsen (1911) was to promote a shift
from "morphological-descriptive" natural history (1911:
134), in which appearances could mislead or be spun into speculative
theories, to an "exact science" (1911: 131) using the
experimental control of biological materials and conditions needed to
establish repeatable outcomes and expose hidden processes. 


#### 2.1.1 Alternative to "Transmission-Conception" of Heredity



A specific variant of Johannsen's overarching project was to
articulate an alternative to traditional accounts of heredity, which,
in his words, 



> 
> 
> tried to conceive or "explain" the presumed transmission
> of general or peculiar characters and qualities
> "inherited" from parents or more remote ancestors. (1911:
> 129) 
> 
> 
> 



In rejecting such a "transmission-conception" of heredity
(his term), Johannsen sought specifically to depart from two
approaches: a) the analysis by biometricians of continuous variation
(such as the spread of heights in a given population), which showed
traits of offspring to be numerically correlated with those of their
parents, grandparents, and so on--such analysis preserved the
possibility of "ancestral influences" (1911: 138); and b)
particulate theories, such as those of August Weismann and Darwinians
that could be seen as consistent with transmission of parental traits
to the zygote (the initial cell resulting from a fusion of gametes or
*germ cells*, i.e., egg and sperm). Johannsen saw no evidence
for the idea that the "elements responsible for
inheritance... involve the different organs or tissue-groups of
the individual developing from the zygote" (1911: 131).



Johannsen's alternative involved four steps of concept and
method:


1. "[T]he objects for scientific research" are
"'types' of organisms distinguishable by direct
inspection or... by finer methods of measuring or description,
[which] may be characterized as '*phenotypes.*'
Certainly phenotypes are real things" (1911: 134);
2. There are germ cells that form a basis for development of an
organism of the next generation;
3. Denote as a *genotype* the *class of organisms*
that share the same basis for development in the germ cells;
4. Use experimentally manufactured subsets of possible phenotypes,
namely, inbred lines of beans, to demonstrate the significance of the
preceding items. (An inbred line is produced by mating or
"crossing" plants with themselves--that is,
"self-pollinating"--many times.)



In Johannsen's experiments, the plants in any line showed
variation in a given trait under differing conditions, but selection
among the plants for that trait did *not* result in improvement
from one generation to the next. Whatever the nature of the germ cells
that seeds from a line shared, and in whatever ways it
"reacted" during the plant's development thus
"interfering with the totality of all incident factors, may it
be external or internal" (1911: 133), seeds of the next
generation did not result in plants that matched their parent any more
than plants from any other seed from the same line (a theory
summarized in
 Figure 1).
 Plants from the inbred line were instances of a genotype; variation
in the traits grown from the seeds was, borrowing from Richard
Woltereck, the *norm of reaction (Reaktionsnorm)* of that
genotype; a plant's relative position in the norm of reaction
was not transmitted to its offspring; and (with the emphasis
Johannsen's) "*selection is not able to shift the
nature of genotypes*" (1911: 137). Because the nature or
constituents of a genotype were *stable*, the
"genotype-conception" of heredity was
"ahistoric" (1911: 139). (Note: Johannsen did not adopt
Weismann's term *germplasm* to denote the material basis
for animal development sequestered from the *somatoplasm* early
each generation [Churchill 1974: 19]. Yet, whatever the material basis
of development was for plant genotypes, it was similarly shielded from
most of the interactions that occur during the organism's
lifetime within the organism and with the environment.)



![[a diagram. in the upper left is a cluster (1) of 6 interlaced circles labeled 'generation 1' and 'range of cells'. An arrow (1) labeled 'reproduction (by those that survive) to another cluster (2) of 4 interlaced circles labeled 'generation 2'. From cluster 1 an arrow (2) points to a third cluster (3) in the upper right of a copy of cluster 1's circles except 2 circles have dashed lines. This cluster is labeled 'range of adult, parent organisms with observable traits (not all survive to reproduce)'. Arrow 2 crosses a large oval (1) labeled 'environmental concerns'; below the arrow and within the oval is the text 'development of traits, as reactions of germ cells with environmental conditions'. From cluster 2 an arrow (3) goes to the right labeled at the end with 'etc'. This third arrow also crosses an oval (2) and below the arrow and within the oval is the text 'development'. From cluster 3, three dashed arrows point in the general direction of arrow 3. Over these dashed arrows is a shaded box with italic text stating 'No transmission of _peculiar_ traits from parents to next generation']](fig1.svg)

Figure 1: Johannsen's view of
heredity: Germ cells that form a basis for development of an organism
get reproduced for the next generation unaffected by the development
of the traits over the life course. 



#### 2.1.2 Unambiguous Use of Phenotypes to Distinguish Genotypes



Phenotypes might, Johannsen noted, be a mix of several genotypes (as
illustrated by the sole figure in the 1911 article; Churchill 1974).
To remove the ambiguity of appearance--to be able to use
phenotypes to distinguish genotypes--he relied on research that
was flourishing after the rediscovery in 1900 of Gregor Mendel's
experiments on peas. Those experiments can be summarized as
follows:


1. Conditions in which the peas were grown were kept as uniform as
possible from one plant to the next.
2. Inbred lines were established that differed one from the other in
ways that Mendel dichotomized, e.g., round or wrinkly peas; tall or
dwarf plants.
3. By preventing self-pollination, different inbred lines could be
crossed to produce what are called *hybrids* (F1) and then
self-pollinated to produce the next generation (F2).
4. The F1 hybrids all showed one of any pair of dichotomous traits.
Around 3/4 of the F2 generation showed that trait; 1/4
showed the other trait. (For example, when a pure breeding
purple-flowered variety was crossed to a pure breeding white-flowered
form, all the F1 offspring were purple-flowered. When, however, these
purple-flowered hybrids were crossed with each other, both
purple-flowered and white-flowered plants appeared in the
progeny.)
5. From the F1 and F2 ratios Mendel concluded that two
"factors" influenced each trait of the pea plant, one from
the pollen and one from the ovary of the parent plants. In turn, only
one of the two factors went to each pollen and ovary (Law of
Segregation), each unaffected by the nature of the other factor it had
previously been paired with.
6. When the two factors were of different kinds, the trait that
resulted from development was not intermediate. Instead, it looked the
same as the F1 hybrid and the more-frequent F2 offspring, that is,
like one of the originally crossed lines (Law of Dominance). In other
words, although the F1 hybrids appeared the same as one of the inbred
parents, the hybrids could be shown, through the ratios of the two
traits in the F2 generation, to belong, using Johannsen's terms,
to a different genotype--a *heterozygote* (i.e., paired
factors different from each other), not a *homozygote* (i.e.,
paired factors the same).


### 2.2 Advances, Ambiguities and Open Questions



The experiments of Johannsen and Mendel (summarized in
 Figure 2)
 can be seen as having achieved the goals given above
 (section 2.1).
 



![[a diagram. Two clusters each of three non-intersecting circles arranged in a triangle. The cluster to the left is labeled ' reproducible & stable genotypes as whole germ cells'; the cluster to the left is labeled 'controlled & reproducible phenotypes'. An arrow goes from the right cluster to the left cluster and is labeled 'identification'. The arrow also crosses an oval labeled 'controlled conditions'.]](fig2.svg)

Figure 2: Mendel-Johannsen method:
Inbreeding, controlled crosses, and control of experimental conditions
allows unambiguous use of phenotypes to distinguish genotypes.




Johannsen's experiments on inbred lines produced repeatable
outcomes and illuminated hidden processes: traits acquired during
development in certain conditions were not transmitted to offspring,
that is, the nature or constituents of the genotype were shielded from
most of the interactions within the organism and with the environment
that occur during the organism's lifetime. Even if the reactions
of different genotypes under various conditions resulted in
"differences between the phenotype-curves [that] may vary
considerably or may even vanish entirely" (Johannsen 1911: 145),
a specific "genotypical constitution always reacts in the same
manner under identical conditions" (1911: 146). Mendelian
experiments crossing inbred lines extended this genotype-conception of
heredity. Hidden processes were exposed in the sense that sexual
reproduction involves joining together of pairs of factors--for
which Johannsen coined the term *genes.*  That meant the
reappearance in F2 of traits not visible in F1 could be explained
without any ancestral influence. The rest of his goals were also
fulfilled: The dichotomous nature of Mendel's traits afforded
Johannsen the distance he desired from the analysts of continuous
variation who had entertained ancestral influences. Mendelian
researchers had a method to remove the ambiguity of appearance so
genotypes could be distinguished from each other (and their
constituents shown to be stable). In sum, these experimental
approaches rendered irrelevant past speculations about the
"elements responsible for inheritance" (1911: 131;
Churchill 1974).



At the same time, Johannsen (1911) introduced many ambiguities and
questions about the import of his new terms. At first sight, the sense
of classes is predominant. The phenotype, consisting of organisms
"distinguishable by direct inspection or... by finer
methods of measuring or description" (1911: 134), is used to
identify the genotype as a class of organisms that shares constituents
stable from generation to generation. Yet, no method is discussed to
divide a natural varying population into phenotypes, let alone
identify a genotype-as-class in such populations. It is in the
restricted realm of inbred lines that identifying genotypes from
phenotypes is possible, albeit not reliably if a phenotype includes a
mix of inbred lines. Notice, however, if an inbred line is bred true
(i.e., not crossed with any other lines), it is a genotype-as-class.
There is no need to divide up the lines into phenotypes in order to
identify genotypes, and it matters not that the traits of individuals
in an inbred line vary with the conditions in which the individuals
are raised. Indeed, the norm of reaction of the inbred line is one way
to think of the genotype as an abstracted type.



Moreover, there is no need to identify the material basis of the
genotypic constituents shared by the inbred line. Nevertheless,
Mendel's experiments had begun to expose the constituents'
nature. When inbred lines were crossed then self-pollinated, the
traits of individuals raised under uniform conditions could be
analyzed statistically by employing--and thereby
demonstrating--a model of genotypic constituents as pairs of
segregating factors. In these experiments, phenotypes and genotypes as
classes still play a role, with the F2 phenotypes being used to
identify whether apparently identical F1 phenotypes are heterozygote
or homozygote genotypes. It might be asked whether Johannsen's
reference to the "finer methods of measuring or
description" could be construed to include the disambiguating
analysis of ratios after inbreeding, crossing, and self-pollination?
If the answer is yes, the inbred parent could be classified as a
different phenotype from the F1 hybrid. In that case, the Johannsenian
study of heredity would amount to generating phenotypes--classes
of organisms distinguished by "finer methods of measuring or
description" of traits--that are isomorphic with
genotypes--classes of organisms that share identical stable
constituents. 



Yet, the experimental control of biological material and conditions
that make such a mapping possible also provided the Mendelian
researchers of the early twentieth century a means to investigate the
genotype-as-material-constituents (see
 section 3).
 Indeed, Johannsen's conception of the genotype as a class of
organisms *sharing stable genotypic constituents* already
pointed that way. However, in taking up that direction of research
what was left unaddressed was the relevance for understanding heredity
*in naturally varying populations* of phenotype-to-genotype
mapping and investigations of the constituents of genotype using
Mendelian methods. Johannsen (1911) does not address those issues
(which are returned to in
 section 5),
 but he does point to several other concerns about the concepts,
methods, and implications of the genotype conception of heredity.
These follow.


#### 2.2.1 Continuous Variation



The continuous variation common in regular populations did not, for
Johannsen, contradict the discontinuity of genotypes: 



> 
> 
> The well-known displacement... of a population... proceeding
> from generation to generation in the direction indicated by the
> selection--is due to the existence a priori of genotypical
> differences in such populations. (1911: 137) 
> 
> 
> 



Such selection changed the relative proportion of genotypes in the
population, not any genotype itself. There could have been room here
for reconciliation with the biometrical view of variation in
non-experimental populations, but that avenue was not pursued by
Johannsen. Instead, like many other exponents of Mendel's
rediscovered work, he chose to dispute the idea that different types
of organism could be "evolved from each other by extremely small
steps in genotypical change". Instead, "the mutations
really observed in nature have all shown themselves as considerable,
discontinuous saltations" (1911: 158; i.e., jumps).


#### 2.2.2 Particulate Factors



Mendelian experiments fostered a particulate view of heredity in the
way that two factors influence a given trait. (In that sense, the old
transmission conception had not been fully banished.) Yet Johannsen
wanted the genotype to be seen *as a whole*:
"[C]haracters may be determined by several different genes,
and... one sort of gene may have influence upon several different
reactions" (1911: 153). He advised that "the talk of
'genes for any particular character' ought to be
omitted..." (1911: 147). If this view was to be made into
exact science, some method for analyzing the genotypical constitution
or genotype as a whole was needed. Johannsen did not provide one.



Johannsen raised another concern about genes as particulate factors
when he asserted that the traits "of the *organism in
toto* are the results of the reactions of the genotypical
constitution" (1911: 147; his emphasis); there was no
"suggestive value" in the idea that "discrete
particles of the chromosomes are 'bearers' of special
parts of the whole inheritance in question" (1911: 131-2).
Yet Mendel's original experiments could be seen to support that
very idea: the traits of the peas were not only dichotomous, but there
was no pattern of co-occurrence of variants of the different traits,
as would be the case if, say, crinkly peas occurred more often on
dwarf plants. Given such *independent assortment* of traits, it
would make sense, *contra* Johannsen, to talk of a pair of
factors or genes *for* crinkly peas. A new transmission
conception of heredity was plausible.


#### 2.2.3 Species-Shared Organization



Johannsen also noted that 



> 
> 
> there may be... very narrow limits for [Mendelian] analysis: the
> entire organization may never be "segregated" into genes.
> (1911: 153) 
> 
> 
> 



To put that in another way, the influence of factors that are
*identical* for all members of a species cannot be studied
through Mendelian crosses. The genotype-conception of heredity, by
centering on genotypic *differences* associated with phenotypic
differences, shifted attention away from the species-typical aspects
of the germ cells and subsequent development. Mendelian analysis
focused on differences over *similarity*, even though both
aspects were included in then prevailing conceptions of heredity (Sapp
1987). (Similarity was part of heredity in the sense that, for the eye
color of some flies to differ from the rest of the population, the
initial cell or zygote of the fly has to be able to develop into an
organism that has eyes with color.) 


#### 2.2.4 Mechanics of Development



Morphological-descriptive natural history is, as Johannsen (1911)
desired, downplayed in the pursuit of experimentally generated and
repeatable outcomes, yet his writing did not acknowledge that the same
pursuit characterized a well-established field of zoological research,
"developmental mechanics" (*Entwicklungsmechanik*).
This experimental field had a morphological focus on how cells become
arranged into tissues, organs, and the organism's overall form,
and how such organization is regenerated after disturbance or through
the formation of germ cells (see entry on
 developmental biology).
 Important contemporaries of Johannsen grappled with the tensions
between Mendelism and development (Deichmann 2014), but he merely
evoked development in broad strokes--as the genotypes reacting or
"interfering with the totality of all incident factors"
(1911: 133)--and left the mechanics or dynamics as a secondary
concern. For the new genotype-conception of heredity, stability of the
genotype across generations was the primary fact. In putting mechanics
to the side, the descriptive side of studies of heredity that
Johannsen decried can be seen persisting, to some degree, in his
original definitions of phenotype and genotype as *classes* of
organisms. 


#### 2.2.5 Shared Nature of the Germ Cells



Johannsen placed not only the developmental processes, but also the
material make-up of the germ cells or the genes outside the scope of
his genotype-conception of heredity: "[T]he nature of the
'genes'... is as yet of no value to propose any
hypothesis" (1911: 133). Yet, the shift (mentioned earlier),
where the focus in studies of heredity moved on to the material
make-up, was prefigured by his referring to the *genotypical
constitution* and noting that "a 'genotype' is
the sum total of all the 'genes' in a gamete or in a
zygote" (1911: 132-3). A further shift towards exposing
the dynamics of development that build on those constituents was
prefigured when Johannsen referred to "phenotypes... i.e.,
the reactions of the genotypical constituents" (1911: 145). 



![[a diagram. Two clusters each of three non-intersecting circles arranged in a triangle; each circle has a dashed outer circle and an inner solid line circle. The cluster to the left is labeled ' reproducible & stable genotypes'; the cluster to the left is labeled 'controlled & reproducible phenotypes against background of organism's other traits'. An arrow goes from one of the circles on the right cluster to one of the circles in the left cluster and is labeled 'identification'. The arrow also crosses an oval labeled 'controlled conditions'. An arrow goes from the inner solid circle of one for the left cluster's circles down to the text 'generation 2'; the arrow is labeled 'transmission of genes']](fig3.svg)

Figure 3: Extensions of Mendel-Johannsen
method: Identification of genotypes as *parts* of germ cells
corresponding to *differences* in phenotypes as specific traits
- Location of genotypes on chromosomes - Further control and
reproducibility of genotypes and phenotypes - Heredity as
transmission of genes (pairs of which make up genotypes) - DNA as
material basis of genes.



## 3. From Mendelian Research and Models to the Present: Advances, Ambiguities and Persisting Questions



The conservatism expressed in Johannsen (1911) about identifying the
material basis of genes, as the nature of the germ cells shared by a
genotype, was not so evident among the Mendelian researchers who
quickly came to adopt the new terms gene, genotype, and phenotype
during that decade. The focus moved beyond refuting what Johannsen
called the "transmission-conception" of heredity and
towards heredity as transmission in the new sense of genes going from
parents to the germ cells of offspring
 (Figure 3).
 Research in laboratory genetics and agricultural breeding extended
Mendelian methods productively, but it also allowed some of the
conceptual and methodological problems of Johannsen introduced in
 section 2
 to persist and ramify.


### 3.1 Particulate Factors--Mapping Genes Along Chromosomes



Mendelian research soon showed the independent assortment of factors
in Mendel's experiments to be a special case, not a law.
Departures from independent assortment of traits allowed the
identification of linkage groups, in which variants of two or more
traits co-occur, which eventually were shown to correspond to the
proximity of their place or *locus* on distinct chromosomes.
(Indeed, Mendelian research helped expose properties of the
chromosomes, such as their role in sex determination, and investigate
many other biological issues. Waters [2004] criticizes philosophers
who interpret Mendelism solely in terms of establishing a theory of
inheritance: "Posing and solving carefully orchestrated pedigree
problems was the means, not the ends, of classical genetics".)
Johannsen's resistance to the idea that "discrete
particles of the chromosomes are 'bearers' of special
parts of the whole inheritance" (1911: 131-2) was shared
by others (Deichmann 2014), but such reservations did not hold back
the rise of Mendelianism to a dominant position in research into
heredity well before the material make-up and functioning of those
particles--the genes--was revealed in the 1950s. The
particulate view was affirmed by producing heritable alterations in
phenotypes after bombarding organisms with high-energy ionizing
radiation. 



It remained central to experiments involving crosses between lines
that, as much as possible, those lines were inbred and identical and
homozygous for genes influencing all traits apart from for the traits
under study. While the identical homozygous genes might have an
influence on the *development* of any focal trait,
*differences* in that trait could be attributed to
*differences* in the genes that were not identical among the
crossed lines. (Indeed, by the 1930s heredity had come to refer to the
transmission of and cross-generational patterns in these differences,
not to the development of the similarities from which differences
depart [Sapp 1987].) Genotype could be applied to *classes of
organisms with a specific pair of genes* (or small set of pairs)
or to *the specific pairs of genes* themselves (matching the
connotation of type as an abstraction away from the full set of
observed characteristics). In Mendelian experiments
phenotypes-as-classes demarcated by a small set of traits could be
used to identify genotypes-as-classes. Then, once the genotype as
pair(s) of genes was mapped to a locus on the chromosome, the
direction could be reversed: the phenotype would then be the subset of
an organism's traits associated with the genotype under given
conditions (a forerunner here of the predominant current-day
meaning).


### 3.2 Identification of Phenotypes and Genotypes--Complications



Mendelian methods of inference based on a small set of traits and
pairs of genes were complicated by phenomena that came to be called
epistasis, expressivity, penetrance, and incomplete dominance and, to
a lesser extent, by a background level of mutation for any gene being
studied. Muriel Wheldale's genetic analysis of the color of
snapdragon flowers, for example, showed that plants with one or more
dominant alleles (i.e., variants of the gene) at a certain locus would
show color patterns that she was able to associate with the genotype
at three other loci, but plants with two recessive alleles at the
first locus would be white no matter what--the homozygote
recessive genotype had an *epistatic* effect over the other
genotypes. A range of phenotypes may be shown to correspond to the
same genotype--*expressivity*. A phenotype that is
associated with a certain genotype may be observed for only a fraction
of individuals in or with that genotype--*penetrance*.
With respect to expressivity and penetrance, researchers try to link
the observed variation to conditions occurring during development,
stochastic developmental noise, or differences remaining at loci not
under study, and to decide where in the range of the trait, say,
melanin pigmentation, to demarcate one phenotype from another.
*Incomplete dominance* means the occurrence of an intermediate
phenotype (e.g., pink snapdragon flowers resulting from crosses of
white and red inbred lines). 



Incomplete dominance removed some of the ambiguities in using
phenotypes to distinguish genotypes, but the combination of the four
phenomena and linkage for multiple loci meant that Mendelian
researchers had to distinguish among multiple hypotheses about the
genotypes consistent with observed patterns of traits in the offspring
of crosses. Background levels of mutation, including mutations in
non-germ cells during the lifetime, ensure that even
genotypes-as-classes consisting of clones or of identical or
*monozygotic* twins are not made up of strictly identical
members. Nevertheless, with suitable organisms and for certain traits,
and under the inbreeding and control of conditions typical of
Mendelian experiments, the painstaking work of inferring genotypes (as
pairs of genes) from phenotypes could bear fruit.


### 3.3 Continuous Variation



Not all aspects of the study of heredity could be made an experimental
endeavor through Mendelian methods. There were many traits for which
the continuous variation could not be subdivided into discrete
phenotypes, let alone linked to genotypes, especially for traits in
agriculture of economic interest such as yield of plant and animal
varieties or breeds. By the end of the 1910s Ronald Fisher and Sewall
Wright had begun to address the need to reconcile the discreteness of
genotypes with continuous variation in many observable traits. In the
mathematical models of a field that came to be known as
*quantitative genetics*, differences between unobserved
theoretical genotypes (in the sense of pairs of genes) at each of a
large number of loci contribute to differences in the trait, modulated
by degrees of correspondingly theoretical dominance and epistasis.
Under the reasonable assumption that more of the genes are shared
among relatives than in the population as a whole, data on a given
trait as it varies across genealogically defined lines or groups of
specified relatedness could be analyzed so as to provide predictions
of changes in the average value of the trait in the population under
selective breeding. Of course, the trait values and thus the
predictions depended on the conditions in which the organisms
developed, but in the laboratory and, to varying degrees, in
agricultural breeding, conditions could be replicated. For the
breeder, the focus of the quantitative genetic data analysis on
differences in the trait makes practical sense; it is not necessary to
know the mechanisms through which the traits developed as organisms
reacted to conditions. In other words, the meanings of genotype,
phenotype, and their distinction again make sense as an abstraction
through practices of control over biological materials and conditions
in agricultural and laboratory breeding and the allied use of models
and analysis of data.



It should also be noted that, in agricultural breeding, the lines or
other genealogically defined groups became called genotypes as well.
Genotypes in this sense are classes of individuals related by
genealogy from a common ancestor or set of ancestors. The relatedness
takes a variety of forms--not only pure (inbred or cloned) lines,
but also offspring of a given pair of parents or a set of ancestors or
an open pollinated plant variety in which the genes vary within
replicable bounds among the generations of individuals in the class.
The corresponding phenotype is then the range of values of the trait
or set of traits as they are observed to vary for the genealogically
defined line or group in the given location(s) or situation(s). In
this sense the phenotypes from different lines may overlap; organisms
are divisible into phenotypes as classes for the purpose of
quantitative genetic analysis not through "finer methods of
measuring or description", but because the lines or groups are
separable. (Quantitative genetics extended to humans does not involve
controlled breeding, but does rely on relatedness that differs
between, say, monozygotic and dizygotic (i.e., fraternal) twins. Even
though a twin pair is not conventionally referred to as a genotype,
human quantitative genetics has followed the same idea for data
analysis as used in agricultural breeding.)


### 3.4 Continuous Variation; Particulate Factors



The mathematical models of quantitative genetics could be readily
extended from selective breeding to evolutionary change by having
theoretical genotypes from a large number of loci each contribute to
parameters for surviving and leaving offspring--so-called
*selection coefficients*. Data on the variation for a trait in
a specific group or population could be analyzed so as to estimate the
parameters in the model that would generate the observed changes in
the average value of the trait over time. Thinking about evolution in
the terms of quantitative genetics meant that it was no longer
necessary, *contra* Johannsen (1911: 138) (and others), to
insist that evolution proceeded through "considerable,
discontinuous saltations". Notice, again the separate
theoretical genotypes and their contributions, this time to selection
coefficients, remain unobserved; the focus of the data analysis could
be on differences in the trait, not the mechanisms of trait
development. The complexity of developmental mechanisms, which involve
interactions with the environment, was collapsed in the models into
the selection coefficients modulated by parameters for dominance
between alleles (i.e., variants of a gene) within, and epistasis
between, theoretical genotypes.



A parallel development, initiated again by Fisher and Wright, as well
as by J.B.S. Haldane, involved mathematical models of theoretical
genotypes at one or a few loci each contributing to the parameters for
surviving and leaving offspring. In this field, which came to be known
as Population Genetics, estimation of selection coefficients of
genotypes inferred from distinct phenotypes was possible, albeit more
readily when the populations were subject to artificial selection in
the laboratory than when frequencies or changes over time were
observed in the wild (which was studied in the new field of
*ecological genetics*). Just as in quantitative genetics, the
focus in population genetics was on *difference* in traits;
complexities of development in its ecological context were typically
collapsed into the parameters of the models.


### 3.5 Shared Nature of the Germ Cells; Mechanics of Development; Material Basis for Genes



Some Mendelian researchers extended the investigation of the material
basis for genes to their role in developmental processes. For example,
the eyes of fruit flies, normally red, are sometimes white.
Geneticists identified the location on the chromosomes that
corresponds to the white-eye mutation (Morgan 1919) and later
investigated the pigment-formation metabolic pathway and the enzymes
(proteins that modulate biochemical interactions) involved as fruit
fly eyes develop the normal or mutant color (e.g., Beadle &
Ephrussi 1936). Research since World War II that came to be known as
*molecular genetics* or *molecular biology* went on to
identify DNA as the chemical basis of genes and the mechanisms of DNA
replication, mutation, transcription to RNA, and translation to
polypeptides (components of proteins). Researchers probed the feedback
networks that regulate these mechanisms, first in viruses and
bacteria, then in complex, multicellular organisms; mapped and
modified the specific DNA sequence of organisms; compared sequences
among *taxonomic groups* (i.e., groups in different branches of
the classification of life) so as to assess the degree of genetic
variation in populations and to classify taxonomic groups into
phylogenies; traced where and when in development specific genes are
active; and examined the role of DNA sequences not associated with
genes (Griffiths & Stotz 2013). Such research, which now occupies
the center of biology, renders it plausible to many researchers and
commentators that development of traits will eventually be understood
in terms of a composite of the influences on the organism over time of
identified DNA variants (see entry on
 gene).


## 4. Philosophical Issues Brought into Play by Attention to Control of Biological Materials and Conditions



Johannsen, as noted earlier (and conveyed in the contrast between the
method of
 figure 2
 and the theory of
 figure 1),
 provided no method to divide a natural varying population into
phenotypes as classes of organisms, let alone to use these classes to
identify genotypes as classes within such populations. What would be
required then in order to apply his terms and distinction in the study
of heredity for natural varying populations? A number of pathways can
be delineated: 


1. *reintegrate*--develop methods to bring back and tie
together what had been de-emphasized through the control of biological
material and conditions employed in the experiments that provided the
basis for his original presentation of genotype and phenotype and for
subsequent developments in the study of heredity;
2. *engineer*--retain the experimental control within an
increasing range of contexts;
3. *generalize theoretically*--use the theory and models
that inform the control and engineering as a basis for explaining
and/or intervening more broadly (Hacking 1983; Cartwright 1999; entry
on
 the structure of scientific theories);
4. *liken*--think or act as if observations in natural
varying population or less controlled situations derived from similar
theory and models; and
5. *experiment more*--do not pursue reintegration, but
continue to employ Mendelian methods to learn more about the biology
of organisms (Waters 2004).



As a sociological, not a logical matter, success in engineering may
underwrite theoretical generalizing and both may, in turn, make more
plausible any assumed extension to naturally varying populations.
Together with further experiments, these pathways may eventually lead
to success in re-integration. It could be imagined that the processes
exposed in controlled conditions would eventually explain heredity in
naturally varying populations. This might happen by researchers
identifying the material constituents of the genotype passed to the
organism by its parents and then tracing how all these constituents
influence the development over time of the organism's traits or
phenotype--perhaps first in controlled conditions, and then in
variable ecological situations (see entry on
 reductionism in biology).
 However, there is no guarantee that the original experimental basis
for the genotype-phenotype distinction or subsequent developments must
lead to effective engineering, theoretical generalization, or likening
that clarifies. Indeed, as a sociological not logical matter, pursuing
such steps may distract attention from the project of re-integration.
 Section 5
 reviews what would be entailed in reintegration, doing so in order to
problematize the status of the original experimentally based
distinction as a basis for the study of heredity for natural varying
populations. The rest of section 4 points to several areas of
philosophical discussions brought into play and extended by
experiments followed by the pathways and steps above.



The "New Experimentalism" counters or complicates a
traditional emphasis in philosophy of science on theories by studying
what goes on in laboratories, or, more generally, the practical
methods of achieving reliable results (see entries on
 experiment in biology
 &
 the structure of scientific theories).
 As noted earlier
 (section 2),
 attention is also warranted to the ways that an area of biology, such
as the study of heredity, becomes experimental in the first place.
Experiments in biology may lead to the engineering of new phenomena or
objects, such as knockout mice (i.e., a line with a specific gene
deactivated), but, at the same time, they leave open the question of
the significance of what gets de-emphasized through the control of
biological material and conditions employed in the experiments. To
continue the knockout example: does the effect of a gene knocked out
in a highly inbred line of mice extrapolate to its effects in
naturally variable populations of mice, let alone other species? In
other words, the demonstration of genes in knockout lines that have
defined effects could be a textbook case of something
represented--the DNA sequence as gene--warranting the status
*real* given the reliable effect of its absence. Yet
antirealists could point to what has not yet been observed given the
special experimental conditions of Mendelian research and subsequent
molecular biology (see entry on
 scientific realism).
 Such an objection notwithstanding, if there is a method that is
productive of results, there will be scientists who apply it even if
the results do not address questions that once motivated their line of
inquiry (as evident, for example, when, as noted earlier, the study of
heredity came to focus on differences not similarity and development).
How is any such pragmatism to be viewed?--are experiments in
biology like a philosophical pragmatism concerned with truth or one
concerned about achieving goals and formulating further goals that can
be pursued in practice (see entry on
 pragmatism).
 Or is it a pragmatism highlighted more in sociology than philosophy
of science, in which the researcher or the interpreter of science
considers how difficult it is *in practice* to modify what has
been established as knowledge (Latour 1987)? The last sense fits well
with this entry's attention to abstraction in the form of the
*material* practices of *control* over biological
materials and conditions advanced in modern experimental biology and
agricultural breeding. It should be noted, however, that this form of
abstraction centers on objects that are concrete, not therefore
conforming to the contrast abstract versus concrete (see entry on
 abstract objects).
 



The interrelated issues concerning pragmatism, scientific realism, and
abstraction become even more pertinent when the theory and models that
inform experiments, such as the genotype-phenotype distinction in
Mendelian research, are extended to less-controlled situations, such
as agricultural breeding trials, and to analysis of data derived from
them. As noted earlier, quantitative genetics relies on models of
contributions from unobserved, theoretical genotypes. Analyses of data
using those models allow breeders to decide which traits to enhance
through selection even though they have no evidence independent of the
data to *confirm* the assumption in their models about
theoretical genotypes and their contributions (Lloyd 1988). Yet, as publications,
careers, release of varieties, software packages, and so on get built
on such a foundation, it becomes ever more difficult in practical
terms for researchers to promote alternatives that do not rest on the
unobserved and unconfirmed entities and properties. Indeed,
*unconceived alternatives*, the possibility that Stanford
(2006) highlights, may well include theories that entail methods that
are, for various reasons, *impractical*. The pragmatic issue of
needing a practical method applies in turn to philosophy: When
philosophers make distinctions or otherwise point to issues that
scientists have left unclear or under-examined, by what means do they
envisage influencing the scientists to change their views or
practices? That question is left open by this entry. The
genotype-phenotype distinction has been positioned in this entry in
relation to control of biological materials and conditions, thus
drawing attention to the challenge of reintegrating what had been
de-emphasized through that control. Yet, no method is provided for
philosophers to get the challenge taken up beyond the implication that
the description--the framing--would be a helpful starting
point. In other words, the entry has positioned the genotype-phenotype
distinction in line with the *descriptive* emphasis in the New
Experimentalism on scientific practice, a *prescriptive*
possibility of reintegration, and an open question about the method
needed to shift actual practice. (The contrast of descriptive versus
prescriptive perspectives is explored in Stegenga's 2009 review
of Weber's contribution to philosophy of experimental
biology.)



The description versus prescription contrast also comes into play in
relation to the different kinds of meaning given to the
genotype-phenotype distinction. Should philosophers descriptively
trace the shifts in meaning from Johannsen to the current day, or
should they prescriptively disambiguate different meanings that may
coexist among the work of different groups of researchers or even
within a given group (see entry on
 ambiguity)?
 Or should it be simply and descriptively noted that coexisting
meanings make the genotype-phenotype distinction a "boundary
object" that allows various fields (or "social
worlds") to interact even though the fields use the term to
different ends (Star & Griesemer 1989)? Perhaps the different
meanings given to the term serve as a reminder of the disunity of
science that follows once rationality and objectivity are seen not as
"universal or necessary [matters], but local and contingent,
relative to scientific interests and purposes" (entry on
 the unity of science;
 Cartwright 1999). Descriptively, philosophers could tease out the
different, sometimes incommensurable, interests and purposes that make
a line of inquiry rational. Prescriptively, they may highlight where
they disagree with a given field's interests and purposes, but
they could also advocate pluralistic acceptance of different sciences
that reflect 



> 
> 
> the complexity of the phenomena under investigation in interaction
> with the limitations of human cognitive capacities and the variety
> of... pragmatic interests in representations of those phenomena
> 
> 
> 
> 



(The Social Dimensions of Scientific Knowledge; on "pragmatic
interests", see also references on social and economic history
of heredity at the end of
 section 1).
 However, two other possibilities remain, namely, ambiguity in the use
of the genotype-phenotype distinction obscures shortcomings in
theories and methods and allows the advances in one field (e.g.,
molecular genetics) to be seen to render more plausible the
empirically and conceptually unrelated claims of another (e.g.,
quantitative genetics) (see sections
 5.2.1,
 6.4, and
 6.5).


## 5. Control and Reintegration



Sections
 2
 and
 3
 described how the original genotype-phenotype distinction was
operationalized under special, controlled conditions, namely, the
growing and crossing of inbred lines raised under uniform conditions.
 Section 4
 laid out pathways from the experimentally based distinction:
reintegrate, engineer, generalize theoretically, liken, and experiment
more. Yet biology and philosophy of biology have not emphasized the
need to reintegrate what has been abstracted away as a necessary step
if the genotype-conception of heredity is to be extended beyond those
special conditions (Figures
 2
 and
 3)
 and applied to the study of heredity for natural varying populations
 (Figure 1).
 Therefore, to highlight the implications of basing the
genotype-phenotype distinction in controlled conditions, this section
considers what control and possible reintegration might entail in the
different realms reviewed so far.


### 5.1 Experimental Genetics


#### 5.1.1 Inbred Lines



For inbred lines, in contrast to the realm of natural varying
populations, the phenotype-as-class is not used to identify the
genotype-as-class; indeed it is recognized as a phenotype because the
genotype, which is the inbred line, is given. As far as
Johannsen's experiments could discern, the
genotype-as-material-constituents could be the whole germ cell or
seed. Reintegration would entail conceptualizing the action of these
constituents of the genotype-as-whole-cell and finding methods to
investigate their influence on the development over time of the
organism's traits (see entry on
 developmental biology).
 Such a program had proponents, especially in the first half of the
twentieth century, but came to be eclipsed by Mendelian genetics and
discounted by historians and philosophers of heredity (Sapp 1987).


#### 5.1.2 Mendelian Crosses



Mendelian experiments require further control than for inbred lines,
because the lines have to be raised in uniform conditions, crossed,
and self-pollinated. Phenotypes can then be used to discriminate among
multiple hypotheses about genotypes, where the phenotype is a class of
organisms that share only some part of the whole set of the
organisms' traits and the genotype is a class or organisms that
have some part of their germ cells in common. The relevant part of the
genotype was shown to be pairs of genes located along chromosomes as
long as, given the control entailed by Mendelian experiments, the
focus lay on *differences* in traits, not on how an offspring
develops to have the trait at all. Recall, as Johannsen noted, that
Mendelian experiments are limited in examining the species-typical
aspects of the germ cells and subsequent development. Again, a program
for reintegrating what is abstracted away through experimental control
can be imagined: researchers identify the material constituents of the
genotype and then trace how all these constituents influence the
development over time of the species-typical traits. From the
composite of these influences the organism as a structured whole might
emerge. Two emerging features of the study of heredity, however, work
against such a reintegration program: Heredity, as mentioned earlier,
has become equated with the transmission of and cross-generational
patterns in the differences. That means development became a separate
and secondary matter (Sapp 1987); analysis of the dynamics of
species-typical development of morphological structure was eclipsed by
genetics.



It is not strictly correct to assert that Mendelian experiments are
unable to examine species-typical traits. For example, all individuals
of all species of the fruit-fly genus Drosophila have exactly three
simple light receptors, *ocelli*, arranged in a symmetrical
triangle on the midline of the top of their heads. The simplest
assumption is that there is no variation in genotypes (in the sense of
material constituents) that influence this trait and its development
is resistant to normal environmental disturbance. However, if the
development of the fly is sufficiently disturbed, some flies with two
or fewer ocelli are observed. If those with fewer than three ocelli
are used as parents for the next generation, they produced more
abnormal flies than the parental generation. When the process of
selective breeding from abnormal flies is continued over many
generations, a line of flies is produced that consistently has two
ocelli, even in the absence of any external disturbance of development
(Maynard Smith & Sondhi 1960). The success of this and other
selection experiments in the same vein shows that the original
uniformity of the trait is not an indication that there is uniformity
in all of the genotypes that may, under certain conditions, influence
the trait's development (Rendel 1967). Any investigation of how
the diverse genotypes result in the development of the typical
three-ocelli pattern now has to explain the occurrence of the aberrant
pattern as well.



Although Johannsen (1911) gave almost no attention to the dynamics of
development, recall (from
 section 2)
 that he wanted the genotype to be seen as a whole and saw no value in
the idea that "discrete particles of the chromosomes are
'bearers' of special parts of the whole inheritance in
question" (1911: 131-2). Yet, Mendelian experiments seemed
to show that the discrete-particles idea was justified. 


#### 5.1.3 Molecular Genetics



Much progress in restoring what was abstracted away has come through
the productive research program of molecular genetics (as summarized
at the end of
 section 3).
 This is not to say that any catalog or database of genes and DNA
variants for any organism remotely resembles a *literal*
"blueprint" or "program" for its
*development*. Nevertheless, with ever-improving knowledge
about genetics at the molecular level and technologies to manipulate
DNA, the field of genetics is now involved, not only in accounting for
how one organism differs in a trait from another, but also in
illuminating the networks of gene activity and feedback (*gene
regulation*) and the major branch-points of development of the
organized structures--biochemical, physiological, and behavioral,
as well as morphological--which phenotypes-as-traits are variants
of. Whether this progress eventually leads to an account of the
operation of the genotype as a whole (or even of some delimited parts
of the genotype), and then to the species-typical development of
structure, remains to be seen (Robert 2004, entry on
 developmental biology).
 The need for such reintegration is, however, often discounted. This
is evident when, for example, it is assumed that genes descended from
a common ancestor (*orthologs*) should have the same function
and influence the same traits across taxonomic groups descended from
that ancestor (e.g., PAX6 gene in relation to the eyes of mammals and
fruit flies). What that assumption overlooks is the possibility that
traits depend on the genotype as a whole in the development of the
organism as a whole and the possibility that a gene may be conserved
through roles that shift in the evolving lineages.



Notwithstanding the advances of molecular genetics, its methods
involve another significant form of control. The uniform conditions
typical in molecular genetics exclude dynamics of development in
ecological context, a context, moreover, that the organism, with its
traits, helps shape (Gilbert & Epel 2009; Lewontin 1983). It could
be imagined that genetic investigations of the hereditary basis of
traits--or, at least, of *differences* among
traits--for inbred organisms in tightly controlled situations
might permit successful extrapolation to the development of traits in
an ecological context (as pursued, for example, in investigations of
strategies of growth and reproduction over the life course and
plasticity of traits under environmental variation ["phenotypic
plasticity";
 developmental biology]).
 Yet, again, the need for reintegration of these aspects of naturally
variable situations may readily get discounted. Consider animal
experiments viewed as models for human medicine. Questions are
routinely raised about the validity of, say, mice as a model for
humans. However, even to speak of "mice" and
"humans" is an abstraction that discounts the variation
among mice and the variation among humans. If, instead, the variation
were paid attention to, the first step would be to note that highly
selected strains of laboratory mice are less variable than
undomesticated populations (Rader 2004) and experiments made on such
mice involve tightly controlled situations. To what extent, it could
then be asked, do experimental observations hold for individuals from
undomesticated populations raised in varied and far more complex
situations? If mechanisms have been exposed using laboratory mice
(Tabery 2014), to what extent do they depend on the controlled value
of factors that are not typically enumerated when describing the
mechanism? Of course, this line of questioning is preempted when
biotechnology expands its capacity to control conditions and harness
genetically engineered organisms to produce desired products.
(Biotechnology can be seen as the industrial manifestation of
*analytic biology*, the program that seeks to understand
organisms by cutting them up into some appropriate small parts.
Relevant here are the politics, economics, and cultural dimensions of
the rise of biotechnology and, before that, genetics itself in the
areas of agriculture, health, food science, the legal system, and
more. All that lies beyond this entry's scope; see
Muller-Wille & Brandt 2016.)


### 5.2 The Use of Models for Selective Breeding



The use of models in quantitative genetics and population genetics is
also based on control of biological materials and conditions. For
these fields, as indicated in this section, it is more difficult to
formulate programs that reintegrate what had been de-emphasized.


#### 5.2.1 Quantitative Genetics



Mendelian experiments crossing inbred lines met the goal of Johannsen
(and biologists following him) of giving repeatable outcomes and
exposing hidden processes, but quantitative genetics, designed to
analyze continuous traits (see sections
 3.3
 and
 3.4),
 bore an ambiguous relationship with that goal. Models allowed
breeders to *predict* outcomes under different mating designs;
the outcomes were not strictly *repeatable* given that what was
actually achieved typically varies from what was predicted. Moreover,
while researchers could *imagine* that the hidden processes
were like the theoretical ones in the models, the theoretical
genotypes forming the basis for quantitative genetic models were
unobservable (see entry on
 scientific realism).
 Nevertheless, material practices of control of materials and
conditions ensure that the model-based analyses continue to be useful.
In particular, when there are discrepancies between outcomes and
predictions, which may result from the hidden processes being
*unlike* the theoretical ones in the models, breeders can
always compensate: they can discard the undesired offspring and breed
from the desired ones. And, as breeding programs are elaborated that
build on the models (e.g., Holland et al. 2003), it becomes ever more
difficult in practice to implement data analysis that would build up
from an alternative model (see entry on
 pragmatism
 and
 section 4).
 Note, because quantitative genetics involves statistical analysis of
data on continuous traits, it must be possible to analyze the data on
trait variation using models that avoid reference to what is
*not* observed (Taylor 2012). However, this possibility has not
been pursued in quantitative genetics (and thus becomes a potential
case of Stanford's [2006] unconceived alternatives mentioned
earlier). Indeed, the difficulty of applying any alternative to
quantitative genetic models extends to analysis of data on variation
in human traits, even though in that realm breeding is not an option
and control of biological material and conditions is minimal. 



If it is difficult in practice to implement breeding programs and data
analysis based on models that avoid reference to what is not observed,
it is difficult to conceive such alternatives without the following
prescriptive disambiguation. Here a *restoration* more than a
reintegration can be entertained, that is, to insist on the
distinction between variance in actual observable genotypes and
*genotypic variance* (sometimes shortened to *genetic
variance*, where variance is the statistical measure of variation
in a given quantity). The latter term stems from breeders using the
term *genotypic value* for the average value of a trait over
all locations in which they raise or grow the genotype (in the sense
of classes of individuals related by genealogy from a common ancestor
or set of ancestors; see
 section 3).
 The variation among these genotypic values is, as shorthand, called
the genotypic variance. In other words, the quantity derives from
statistical analysis of variation among related and unrelated
individuals in their phenotypes (in the sense of observed
*traits*), not in their genotypes (in the sense of DNA). Not
only does genotypic variance vary with the mix of genotypes and
locations, its statistical estimation does not reference measurable
genetic or environmental factors influencing the development of the
traits. Unfortunately, it is common for researchers and commentators,
including philosophers, to speak of genotypic or genetic variance in
terms like the "contribution of genetic differences to observed
differences among individuals" (Plomin et al. 1997: 83) as if
variation in traits and variation in genotypes had some obvious
relationship. The conflation may derive from quantitative genetic
models being based on genotypes (in the sense of pairs of genes). But
those are theoretical genotypes, unobserved and, as noted above, not
essential to the analysis of trait variation. (To add to the potential
for confusion, the technical term for the ratio of the genotypic
variance to the total variance observed in the trait in question is
Heritability, which has no relation to the existence of a connection
between parent and offspring traits through transmission of genes
[Taylor 2012].)



To enhance the disambiguation, Taylor (2012) recommends the use of
terms familiar in agricultural trials: *variety* instead of
genotype (in the sense of classes of individuals related by genealogy
from a common ancestor or set of ancestors), *location* instead
of environment, and *trait* instead of phenotype (given that
this last term implies a connection with a set of genotypes, in the
sense of pairs of genes). Whether or not the alternatives terms get
more widely adopted, once the gap between statistical patterns from
quantitative genetics and measurable underlying factors is recognized
*and consistently observed*, it becomes difficult to follow the
reasoning of accounts that conflate or slip between the disparate
meanings of "genetic". This difficulty extends to accounts
of the *interaction* between genes or genotypes and environment
that overlook the distinction, proceeding then as if interaction as
defined in quantitative genetic analyses of variation has some
conceptual or empirical connection with statistical interaction
between measured presence of genes and environmental variables. (It is
beyond the scope of this entry to review such accounts by scientists
or philosophers; see Taylor 2015 as well as discussion in
Section 6.5 on what the conflation or ambiguity signifies.)



There is an alternative to restoration of the distinction between
genotypic variance and variation in actual genotypes, which is to
focus on the latter. As determining the sequence of DNA at any stretch
of the genome (i.e., of the genotype-as-material-constituents) has
become routine, Genome-Wide Association (GWA) studies allow estimation
of the fraction of the variation in the trait that is associated with
measurable genetic variants. (The variants studied are
single-nucleotide polymorphisms [SNPs], which are not held to be the
DNA influencing the trait, but simply somewhere close to those factors
on the genome.) It turns out, however, that, even when many genetic
variants are examined together, only a small fraction of the variation
in the trait is associated with--or in statistical terms,
"accounted for" by--the genetic variants (McCarthy et
al. 2008). This finding has led to discussions about *missing
heritability* (e.g., Manolio et al. 2009). This new heritability
has, however, no conceptual or empirical connection with the
heritability of quantitative genetics. To the extent that the
additional ambiguity in use of the term heritability is associated
with the unfulfilled expectation that high heritability means genetic
variants might account for a large fraction of trait variation, the
restoration identified in the previous paragraphs is warranted. 



One plausible explanation of the limited success of GWA studies
depends on the distinction between genotypic variance and variance in
actual genotypes being clearly made. Even if the classical
quantitative genetic heritability is high and similarity between twins
or a set of close relatives is associated with the similarity of
yet-to-be-identified genotypes or genetic factors, *the factors may
not be the same from one set of relatives to the next, or from one
location (environment) to the next*. In other words, the
underlying factors and the pathways of development that they influence
may be *heterogeneous*. It could be that pairs of alleles, say,
AAbbcbDDee, subject to a sequence of environmental factors, say,
FghiJ, are associated, all other things being equal, with the same
outcomes as alleles aabbCCDDEE subject to a sequence of environmental
factors FgHiJ (Taylor 2012). The possibility of heterogeneous factors
underlying similarity in traits obviously recedes if the biological
materials and locations are close to the original set of relatives and
environmental factors. The corollary is that, when users of
quantitative genetic models overlook that possibility, they are, in
effect, assuming tight control of biological materials and
conditions.



Some degree of reintegration of what is unobservable in the classical
use of quantitative genetic models has occurred through the technique
of mapping quantitative trait loci (QTL)--regions of the genome
containing genetic factors associated with variation in a continuously
variable trait. Yet QTL mapping has had most success in animal and
plant varieties that can be replicated and raised in controlled
conditions; reliable QTL results for human populations are few
(Majumder & Ghosh 2005; but see the Wellcome Trust Case Control
Consortium 2007). Indeed, reintegration of the complexities of
development in its ecological context, which are collapsed into the
parameters of the models, remains scarcely developed in quantitative
genetics (as evoked for the human case by Turkheimer 2004).


#### 5.2.2 Population Genetics



In population genetics, the complexities of development in its
ecological context are also collapsed into the parameters of the
models, such as the parameters for surviving and leaving offspring.
Not surprisingly then, the estimation of the selection coefficients of
genotypes (in the sense of pairs of genes) is more readily done when
the populations are subject to artificial selection in the laboratory
than when frequencies or changes over time are observed in the wild.
Lewontin (1974a) provides grounds for doubting the likelihood of some
day restoring what is abstracted away in those selection coefficients.
Measurements of selection coefficients and other parameters of the
model are possible, Lewontin concludes, only when a single allelic
substitution is associated with a large difference in the trait, not
when the effects of gene substitutions make only small differences.
This led him to remark that: "What we can measure is by
definition uninteresting and what we are interested in is by
definition unmeasurable" (1974a: 23). The problem of relating
population genetic models to observations becomes astronomically worse
when there are multiple, linked loci (1974: 317). He suggests that
population genetics should shift its attention to the selection
coefficients for long segments of chromosomes. This program, like
Johannsen's wish that the genotype be seen as a whole, has
scarcely been pursued. Even if it had been, ecological genetic
analysis of variation in natural populations, with all its complexity
(e.g., Clausen et al. 1948), would still be needed to begin to
reintegrate ecological context into population genetics. 


## 6. What the Genotype-Phenotype Distinction Signifies



That special experimental conditions are entailed in the original
formulation of the terms genotype, phenotype, and the distinction
between them also has implications for the issues that might seem to
have been settled by the adoption of Johannsen's
genotype-concept of heredity.


### 6.1 Barrier Between Traits and What is Transmitted to the Next Generation



To the extent that the DNA transmitted to the next generation has been
shielded from most of the interactions that occur during the
organism's lifetime (both within the organism and with the
environment), there is a barrier to "peculiar" traits
(Johannsen's label for traits acquired during the specific
development of the parents) being passed on to their offspring. (A key
part of this shielding is the one-way transcription of DNA to RNA
[which then codes for the amino acids that make up proteins], not, in
general, transcription in the other direction.) While the
genotype-phenotype distinction can be seen to *signify* the
existence of this barrier, there is a long history of researchers
claiming to show ways around it. Most notably, the modern science of
epigenetics, building on ever-increasing information about DNA
sequences and how genes function, shows how chemicals from outside the
cell can modify the activity of genes for the rest of an
organism's life and sometimes even into subsequent generations
(Stotz 2006). 



Developmental Systems Theory (Oyama, Griffiths, & Gray 2001),
Evolutionary developmental biology ("evo-devo") (Moczek et
al. 2015), and a Post-genomic Synthesis in Behavior and Cognition
Research (Stotz 2008) also argue for attention to *extended
inheritance*, which includes transmission not only of epigenetic
modifications, but also of resources outside the organism, such as
when reptiles lay their eggs in places that ensure the right
temperature for incubation. This last example also fits under the
ambit of Niche Construction theory (Odling-Smee et al. 2003). This
field investigates the significance of organisms shaping the
ecological context in which they develop their traits, survive, and
reproduce, as epitomized by beavers living in the ecosystem of ponds
formed by the dams that they build and maintain. (Whether or not
epigenetic and extra-organismal resources have the same causal status
as genes is a matter of philosophical debate beyond the scope of this
entry; see Waters 2007; Stotz 2006; Griffiths & Stotz 2013; entry
on
 inheritance systems,
 and
 section 7
 below.)


### 6.2 Evolution Defined as Change in Gene Frequencies



Biological evolution, in its most general construal, is modification
by descent, that is, change over time in frequency of observed traits
or forms in a population or a taxonomic group derived from a common
ancestor. A narrower definition, however, arose with the rise of a
genotypic conception of heredity, namely, only with changes in
frequencies of genes is evolution deemed to be happening. The barrier
to so-called inheritance of acquired characteristics is held to make
irrelevant any changes in forms without changes in gene frequencies.
Exponents of extended inheritance disagree, including in their
definition of evolution the changes in the developmental system and
its constructed niche (Griffiths & Stotz 2013). Adjudication of
the disagreement comes down, in part, to a matter of quantity: How
significant are resources other than the genotype (in the sense of the
DNA of the whole genome) in development of traits that influence
survival and reproductive success? Significance may depend on the
number of generations that the resources are transmitted. The
disagreement, however, becomes qualitative, even radical, if attention
is given to the dynamics of development in an ecological context that
had been abstracted away in demonstrating the original genotype
conception of heredity. Reintegrating developmental dynamics entails
more than noting the existence of developmental noise, such as when
Drosophila individuals are not symmetric in the number of bristles on
each side. The next subsection elaborates.


### 6.3 Development as a Genotype to Phenotype Relationship



Several of the programs of reintegration sketched in
 section 5
 rest on the idea that development of traits will eventually be
understood in terms of a composite of the influences of DNA variants
on the organism. An alternative approach is to observe that germ cells
are organized structures, which means that development is always a
process of further organization emerging from initial organization.
That emphasis was evident, not only in developmental mechanics
(*Entwickslungsmechanik*), but also in a mid-twentieth century
form of epigenetics centered on embryological or developmental
pathways. Conrad Waddington, for example, undertook experiments on
variation in certain characters that was originally seen only in
response to an environmental stress, e.g., enlarged anal papillae (a
fleshy protuberance) of *Drosophila* larvae that arose in
higher salt concentrations (Waddington 1959). In populations that had
been selected for that responsiveness, eventually the trait occurred
even when that stress was withdrawn. Waddington's interpretation
is that a genotype (in the sense of a specific set of pairs of genes)
had arisen in the population that switched on development of large
papillae. Presumably, this could happen through reassortment of genes
into new genotypes, not a random mutation. An alternative hypothesis,
which places more emphasis on the dynamics of development, is that, if
many pathways in a non-inbred population can produce the same response
(e.g., enlarged anal papillae in response to salt), selection results
in a population of individuals that have a concentration or redundancy
of the various pathways. *If* pathways arise within this
concentration where large papillae develop without the salt stress,
that is not a logical process to be modeled by population genetic or
quantitative genetic models, but a contingent outcome of the dynamics
of development in a realm in which a variety of genotypes can
influence a variety of paths to a trait. In this light, to call traits
phenotypes, and thus suggest that they have a direct association with
a specific genotype, is to make it more difficult to conceive and
pursue a program of reintegration in which researchers examine cases
of traits that are acquired as an appropriate response to
environmental condition and then increase in frequency in a
population. Moreover, even if such cases turn out not to be common,
they trouble the premise that the *individual-to-individual
barrier* to a trait being transmitted back into the genotype
barrier means that acquired characters cannot increase in a
*population* during evolution.


### 6.4 What Counts is Underneath or Inside the Observable Surface



The genotype-phenotype distinction can also signify that the
surface--phenotype--is mere appearance; what is underneath
or inside that surface--the genotype--is what counts. A
small irony, given that the phenotype originated in relation to
inferring genotypes (in the sense of a class that shared something
unobservable), is that, to the extent that molecular biology has made
DNA sequences observable, especially at sites in which the sequences
vary from one group to another, each genotype (in the sense of a pair
of genes or DNA sequence) becomes another phenotype (Nachtomy et al.
2009). During the development of an organism, each of these
genotypes-as-phenotypes at time 0 interacts with the rest of the
phenotype and environmental factors to produce the phenotype at time
1, 2, and so on. It may well be the case that germ cells arise at some
point in the life course that are buffered from most of these
interactions. However, with respect to conceptualizing development
from time 0 till death, nothing logically makes the genotype not also
a phenotype.



In any case, the view is widespread that what counts is underneath or
inside. It is evident in the definition of evolution as change in gene
frequencies and the idea that development of traits will eventually be
understood in terms of a composite of the influences of DNA variants
on the organism. It can also be seen in many other features of
discourses around heredity, such as the following:


1. An oft-repeated assertion is that random mutations in genes are
the ultimate source of variation on which evolution builds. This
assertion discounts the reassortment of genes into new combinations of
genotypes (in the sense of pairs of genes) that occurs with every
sexual reproduction and with the recombination after crossing over of
chromosomes that occurs in many species, as well as with niche
construction and novel response to environmental conditions that can
occur during development.
2. Discussions of the unit of selection, typically a gene or
genotype (in the sense of a specific pair of genes), often assume or
imply that, when organisms are shown to enjoy differential survival
and reproductive success because of the effect of some trait they
possess, it is actually because they possess some gene or genotype. In
some accounts, the organism becomes the "selfish"
gene's way of making copies of itself. Such a picture is a
variant of a theme with a long history, namely, the living being is an
agent directed by some other agent, such as in theology when the soul
is given by the grace of God.
3. The use of the term phenotype for a trait suggests a direct
association with some genotype even when there is no program, let
alone a method, to expose which genotypes influence the trait.
4. The claim is made that all disease is genetic. The corresponding
programs of genetic medicine, personalized genomics, and precision
medicine, propose or promise to identify and make therapeutic use of
genetically determined disease susceptibility in individual patients.
Not only do such programs discount the environmental and social
aspects of epidemiological trends in many diseases, but, as evident
when genetic oncologists use the term "familial cancer" in
contrast to hereditary cancers, this conception of heredity brings
back what Johannsen had sought to expunge, namely, thinking about the
transmission of peculiar or acquired traits.
5. Invocation of "genetic tendency" without a method to
infer it from analysis of traits--even when done by commentators
critical of claims made about genetics, as in "simply because a
genetic tendency exists does not mean it will be phenotypically
expressed" (Jesser 2002, 42).
6. It is now popular to boast that "it's in our
DNA", in the sense of a core value that is beyond question for
an organization or group.


### 6.5 Findings About Heredity Derived Using One Meaning of Terms Affirm Findings Derived Using a Different Meaning



With genetics held to get at the fundamental thing that counts in
heredity, it makes it plausible to take research using methods based
on one kind of meaning of the terms genotype, phenotype, and the
distinction between them to affirm research based on another
meaning--they are all contributing to an understanding of that
fundamental something. In this spirit, the ascendance of the
predominant current meaning--DNA versus traits--has not
necessitated rejection or even disambiguation of the other meanings of
the terms evident in Johannsen (1911) and that have coexisted
since--class, abstraction, or material constituents; whole or
part; natural units or products of experimental control
 (sections 1-3).
 Not being troubled by the ambiguity of different meanings and methods
is especially evident when commentators speak of "the
nature-nurture debate" as if it were unimportant to specify
which nature-nurture science is being debated. In practice, at least
five nature-nurture sciences can be readily distinguished (Taylor
2015):


1. Researchers in laboratory and agricultural breeding or human
quantitative geneticists compare how much variation in a trait is
associated with differences among means for varieties, locations,
variety-location combinations, and residual contributions (i.e.,
genotypic, environmental, genotype-environment interaction, and
residual variance where genotype here means a line or genealogically
defined group; see
 section 3.3)
2. Researchers compare how much variation in a trait is associated
with differences in measured genetic factors, environmental factors,
gene-environment interaction, and a residual component (where the
genetic factors are typically genotypes in the sense of a pair of
genes).
3. Through either of the above forms of analysis, researchers try to
compare the variation within groups (e.g., among Euro-Americans and
among African-Americans) to the difference between the averages for
the groups.
4. Through investigations that might extend any of the preceding
kinds of analysis of observational data, researchers piece together a
picture of the processes of development of a trait and, on that basis,
speak to the fixity versus flexibility of traits. (The multiple
meanings of genotype, summarized above, arise in research and
discussions on this topic.)
5. Researchers provide an evolutionary account of the increase in
frequency of a trait through natural selection based on the
trait's superior function in the environment (see
 section 6.2).



These nature-nurture sciences entail not only different methods but
also different control of materials and conditions, so, in practice,
results are difficult to translate from one of them to the next.
Discussion of *the* nature-nurture debate (even in critical
accounts where nature and nurture are said to interact or shape each
other) signifies, among other things, that the specialness of the
conditions involved in the original formulation and demonstration of
the genotype-phenotype distinction may be overlooked. As a
consequence, for example, control of materials and conditions that is
practical in laboratory and agricultural breeding gets built into
evolutionary thinking when the latter uses models and terms from
breeding as if there were also a selector in naturally variable
populations. 



Granted, as noted earlier, biotechnology has a growing capacity to
control conditions and harness genetically engineered organisms to
produce desired products. However, to the extent that biological
theory is still meant to address naturally variable populations, then
concepts, methods, and models are needed through which what has been
controlled or de-emphasized might be brought back and
*re-integrated* into the scientific accounts. The framing of
this entry in terms of control and reintegration has been designed to
draw attention to the space around the genotype-phenotype distinction
that remains open for conceptual clarification and methodological
advances.


## 7. Coda on Causality



The introduction noted that, if the genotype-phenotype
*relationship* had been the focus of this entry, more attention
would need to be given to philosophical arguments about causality and
about abstraction as it relates to causal claims. Yet, realizing any
of the programs of reintegration mentioned in this entry would entail
rich causal analyses: networks of gene regulation linked to organized
structures that branch into more organized structures, epigenetic
modifications during and across lifespans, organisms shaping the
dynamics of the ecological context in which they develop their traits,
and frequencies of traits changing in populations over generations.
This said, in realms of experimentally controlled biological materials
and conditions, a simpler sense of causality may seem plausible,
namely, a *difference that makes a difference* (see entry on
 causation and manipulability).
 (The serious debate about whether statistical analysis can
distinguish causal from non-causal differences that "make"
a difference should be noted; Hernan et al. 2002.) The
connection between an association within some population and causal
mechanisms is susceptible to disconfirmation by experiments. At the
same time, doing such experiments invites scrutiny of the relationship
of experimentally altered dynamics to the original dynamics that
generated the data that were analyzed to show the original statistical
association (Taylor 2015). 



Most importantly given the framing of this entry around control and
reintegration: Any experimental as well as statistical association is
also *conditional* on the subset of the population or species
studied and the situations where they are observed (Lewontin 1974b).
Understanding associations and formulating manipulations based on them
requires attention to what has been experimentally or, at least,
statistically held constant. In other words, in controlled conditions
the direction of the arrow labeled identification in Figures
 2
 and
 3
 may be reversed and given a causal connotation, but the causality is
conditional on the factors, including the rest of the organism, held
constant. The understanding and manipulations may well extrapolate
beyond the original, controlled population and situations (and thus
match the general theory summarized in
 Figure 1),
 but, absent an actual program of reintegration, there is no basis for
assuming that they will. While Waters (2007), Tabery (2014) and others
would give greater status to differences that have *actually*
been observed to make a difference (Griffiths & Stotz 2013), this
entry has pointed to the control of biological materials and
conditions that *excludes many factors*--genetic as well
as environmental, structural as well as particulate--*from
being* seen *to make a difference*. Ironically, if
appearances are not to mislead and obscure, or be spun into
speculative theories
 (section 2),
 the science of heredity needs methods that bring back what was
abstracted away under the experimental control that made
Johannsen's original genotype-conception meaningful.