Fermat's Library | The Epigenotype annotated/explained version.

#### TL;DR C.H. Waddington was the first biologist to say explic...

Conrad Hal Waddington was a British developmental biologist, geneti...

**Genotype:** The genotype of an organism is a description of that...

The term epigenetics is the study of how your behaviors and environ...

Waddington would later substitute the word epigenotype for the epig...

> ***"Thus genetics has to observe the phenotypes, the adult charac...

The species Drosophila melanogaster - often referred to as the frui...

> ***"Genes are not interlopers, which intrude from time to time to...

REPRINTS AND REFLECTIONS

The Epigenotype

C. H. Waddington*

The adult characteristics of animals, i.e. their phenotypes, must be studied in

order to reach conclusions about the genotypes, i.e. the hereditary constitutions

which form the basic subject-matter of genetics. But between genotype and

phenotype lies a whole complex of development processes, for which Dr

Waddington proposes the name ‘epigenotype.’ He here describes some of the

general characteristics of an epigenotype, with special reference to the fruit-fly

Drosophila melanogaster.

Of all the branches of biology it is genetics, the sci-

ence of heredity, which has been most successful in

finding a way of analysing an animal into represen-

tative units, so that its nature can be indicated by a

formula, as we represent a chemical compound by its

appropriate symbols. Genetics has been able to do this

because it studies animals in their simplest form,

namely as fertilized eggs, in which all the complexity

of the fully developed animal is implicit but not yet

present. But knowledge about the nature of the ferti-

lized egg is not derived directly from an examination

of eggs; it is deduced from a consideration of the

numbers and kinds of adults into which they develop.

Thus genetics has to observe the phenotypes, the adult

characteristics of animals, in order to reach conclu-

sions about the genotypes, the hereditary constitutions

which are its basic subject-matter.

For the purpose of a study of inheritance, the rela-

tion between phenotypes and genotypes can be left

comparatively uninvestigated; we need merely to

assume that changes in the genotype produce corre-

lated changes in the adult phenotype, but the mech-

anism of this correlation need not concern us. Yet this

question is, from a wider biological point of view, of

crucial importance, since it is the kernel of the whole

problem of development. Many geneticists have

recognized this and attempted to discover the pro-

cesses involved in the mechanism by which the

genes of the genotype bring about phenotypic effects.

The first step in such an enterprise is – or rather

should be, since it is often omitted by those with an

undue respect for the powers of reason – to describe

what can be seen of the developmental processes. For

enquiries of this kind, the word ‘phenogenetics’ was

coined by Haecker

. The second and more important

part of the task is to discover the causal mechanisms

at work, and to relate them as far as possible to what

experimental embryology has already revealed of the

mechanics of development. We might use the name

‘epigenetics’ for such studies, thus emphasizing their

relation to the concepts, so strongly favourable to the

classical theory of epigenesis, which have been

reached by the experimental embryologists. We cer-

tainly need to remember that between genotype and

phenotype, and connecting them to each other, there

lies a whole complex of developmental processes. It is

convenient to have a name for this complex: ‘epigen-

otype’ seems suitable

We know comparatively little about the general

characteristics of an epigenotype. One general feature,

however, is that it consists of concatenations of pro-

cesses linked together in a network, so that a disturb-

ance at an early stage may gradually cause more and

more far reaching abnormalities in many different

organs and tissues. Some very beautiful examples of

such effects have recently been described by

Gru¨neberg

3,4

based on mutations in his mouse

colony at University College, London. One gene, the

‘grey-lethal’, brings about a lack of yellow pigment in

the fur, and a failure of the absorption of bone which

normally accompanies growth. The latter effect entails

a whole host of secondary consequences. Thus the

minerals of the body are immobilized in the bones

and cannot be used for new growth, so that the

teeth are incompletely calcified and unable to masti-

cate solid food. Again, the lack of bone absorption

leads to pressure on some nerves, particularly those

serving the lower jaw; this presumably gives rise to

neuralgic pain, the animals are disinclined to take

even liquid nourishment, the starvation affects the

thymus gland, and the animals eventually die.

Another lethal gene, this time in the rat, brings

about even more manifold and at first sight uncon-

nected abnormalities. The first noticeable effect is an

abnormality in the development of cartilage, which

affects the ribs, and thus the lungs, circulatory

organs, and finally the growth rates of various parts.

* Waddington CH. The Epigenotpye. Endeavour 1942; 18–20

Reprinted with permission.

Published by Oxford University Press on behalf of the International Epidemiological Association

International Journal of Epidemiology 2012;41:10–13

doi:10.1093/ije/dyr184

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Complementary to the study of single genes and the

numerous effects which they produce is the study of a

single organ and the numerous genes which affect it.

Probably the most completely investigated instance is

the wing of that favourite genetical object, the

fruit-fly Drosophila me lanogaster. Following preliminary

work by Auerbach, Dobzhansky, and Goldschmidt, I

described the developmental actions of some thirty

geneloci

. It was found that during the first

forty-eight hours after the larva enters the pupa, its

wings undergo at least fifteen different processes,

each of which is affected by some known gene. We

Figure 1 Diagrammatic drawings of sections of the developing wing in the fruit-fly Drosophila. Notice how the wing is at

first quite solidly constructed. (Figure 1b is of about the same age as figure 2A.) Then it becomes hollow (figure 1d, which

corresponds to figure 2B), contracts again (figures 1e, f, g), and finally becomes folded (figures 1h, i).

Figure 2 Four stages in the development of the wing in Drosophila. Figure A shows the wing shortly after the puparium is

formed; in B the wing has become inflated, and its venation is obliterated; in C and D it contracts again and its final

venation appears. Just after the stage shown in D, the wing becomes folded and remains thus until just after the fly

emerges from the pupa.

REPRINTS AND REFLECTIONS

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have here, in fact, a concrete example of something

which has always been obvious in theory, namely that

the genotype is continual and unremitting control of

every phase of development. Genes are not inter-

lopers, which intrude from time to time to upset the

orderly course of a process which is essentially inde-

pendent of them; on the contrary, there are no devel-

opmental events which they do not regulate and

guide.

The alterations in development produced by genetic

changes can be used, as the experimental embryolo-

gist uses those which he produces by his operating

needle, as a means of analysing the causal mechan-

isms of development. We find, for instance, that is the

two sheets of epithelia which build up a Drosophila

wing fail to come together as they normally do, the

cavity left between them may differentiate into a

wing-vein instead of into the normal wing surface.

Or, again, we find that if the two epithelia are

folded together in an abnormal manner, the position

of the wrong veins is determined by the upper-

surface, and impressed by that surface on to the

lower one. These deductions from the ‘natural experi-

ments’ performed by genes can be checked by

Figure 3 Some genetically controlled abnormalities in the contraction-phase of wing-development in Drosophila. Figures A,

B, and C show wings of the mutant race net in which there is a partial failure of contraction, which causes the formation of

extra veins in some regions. In figures D and E the failure of contraction is much more complete, and bubbles of fluid are

left between the two wing-surfaces, which remain so far apart that in many areas no veins appear (the mutant bloated).In

figures F, G, and H the contraction does not fail, but is abnormal, so that a wing of characteristically elongated form is

produced (the mutant blade in D. pseudo-obscura).

12 INTERNATIONAL JOURNAL OF EPIDEMIOLOGY

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experiments of the conventional kind; one can make

operations on the developing wings, using fine glass

needles and the other micro-surgical instruments of

experimental embryology. A considerable series of

such operations has been made by Lees

who was

able to confirm, and in some cases to extend, many

of the previous deductions.

For this particular organ there remains very little of

that gap between genetics and experimental embry-

ology which has been so frequently lamented as one

of the main flaws in the structure of biological theory.

As would be expected, many of the general principles

of experimental embryology reveal themselves again

in the epigenetical analysis. For instance, we are fa-

miliar with the fact that there are critical periods in

development, such as the time of gastrulation at

which the primary organizer is active. Similarly we

find that in the developmental of the wing there are

certain periods at which many deviations of develop-

ment, which had previously seemed of only minor

importance, suddenly entail radical and far-reaching

consequences. To give a concrete example: the wing is

essentially a sac the two surfaces of which are, at one

period, forced apart by a considerable pressure of the

contained body-fluid, which is later withdrawn so

that the two epithelia come together again. The pro-

cess of contraction is a critical one. Slight irregulari-

ties in it are responsible for most of the abnormalities

in the development of the wing-veins, and minor de-

viations in the relative positions of the wings and legs

may, by impeding the flow of body-fluid, lead to crip-

pling malformations of those organs.

It would take us too far to attempt to discuss in

detail the general characteristics of such epigenetic

crises as these. We should find ourselves involved

with the same highly complex and little-understood

series of problems which confront the experimental

embryologist; with the problem of structures of vari-

ous ranges of size, with the differentiation of cells and

of tissues, and with the question of whether differen-

tiation is into sharply contrasted alternatives or into a

continuously varying range of products. Without at-

tempting to answer any of these questions here, we

may be content to point out that the analysis of the

effects of genes has now progressed far enough to

become merged with experimental embryology. The

two methods of analysis who rapprochement has for

so long been no more than a pious hope can now

actually and in practice come together in an attack

on the still unresolved problems of the epigenotype.

References

Haecker V. ‘Entwicklungsgeschichtliche Eigenschaftsana-

lyse,’. Phaenogenetik Jena.

Waddington CH. ‘Pupal Contraction as an Epigenetic

Crisis in Drosophila. Proc. Zool. Soc. Lond. (in press) [sic].

Gru¨neberg H. ‘Some New Data on the Grey-lethal

Mouse,’. J. Genet 1938;36:153.

Idem. ‘An Analysis of the ‘‘Pleiotropic’’ Effects of a New

Lethal Mutation in the Rat,’. Proc. Roy. Soc., [B] 1938;125:

123.

Idem. ‘The Genetic Control of Wing Development in

Drosophila’. J Genet. 1940;41:75.

Lees A.D. ‘Operations on the Pupal Wing of Drosophila’.

J Genet. 1941;42:115.

Published by Oxford University Press on behalf of the International Epidemiological Association

International Journal of Epidemiology 2012;41:13–16

doi:10.1093/ije/dyr183

Commentary: The epidemiology of epigenetics

David Haig

Department of Organismic and Evolutionary Biology, Harvard University, 26 Oxford Street, Cambridge, MA 02138, USA

E-mail: dhaig@oeb.harvard.edu

Accepted 22 July 2010

We are in the midst of an epidemic of the words

‘epigenetic’ and ‘epigenetics’. In the database of ISI

Web of Knowledge, more than a 1300 articles pub-

lished in 2010 contain epigenetic(s) in their title,

whereas the corresponding number for each year

prior to 2000 is less than a hundred. Figure 1 illus-

trates the long-term trend using an index designed to

correct for changes in the size and composition of the

database. Roughly speaking, there was little change in

relative frequency from the 1950s until 1999, but

EPIDEMIOLOGY OF EPIGENETICS 13

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Discussion

#### TL;DR C.H. Waddington was the first biologist to say explicitly that the ***development of a phenotype is the sum of genetic expression and tissue interactions***. Presenting genes as responsible for guiding the mechanics of development was an astounding conclusion and a paradigm changing idea. Waddington's view of development was very different from that of most biologists and embryologists. He believed that to understand development one has to have detailed knowledge of genetic mutations and one has to be able to link the expression of these genes to precise moments of organ development. What Waddington summarizes in this three-page paper is a truly revolutionary view of biology, he concludes that: - genes are responsible for guiding the mechanics of development. - genes act together to cause particular phenomena to take place. - genes act during development and that they do not merely "fine-tune" an autonomous developmental trajectory. **Genotype:** The genotype of an organism is a description of that organism's complete set of genes. **Phenotype:** Phenotype refers to an individual’s observable traits, such as height, eye color and blood type. A person’s phenotype is determined by both their genomic makeup (genotype) and environmental factors. Learn more here: - [Genotype](https://www.genome.gov/genetics-glossary/genotype) - [Phenotype](https://www.genome.gov/genetics-glossary/Phenotype) The term epigenetics is the study of how your behaviors and environment can cause changes that affect the way your genes work. Learn more here: [Epigenetics](https://en.wikipedia.org/wiki/Epigenetics) The species Drosophila melanogaster - often referred to as the fruit fly - is often used as a model organism in biological research, particularly in genetics and developmental biology. Learn more here: [Drosophila melanogaster](https://en.wikipedia.org/wiki/Drosophila_melanogaster) !["fruit fly"](https://upload.wikimedia.org/wikipedia/commons/4/4d/Drosophila_melanogaster_-_top_%28aka%29.jpg) > ***"Genes are not interlopers, which intrude from time to time to upset the orderly course of a process which is essentially independent of them; on the contrary, there are no developmental events which they do not regulate and guide."*** Conrad Hal Waddington was a British developmental biologist, geneticist and author who laid the foundations for systems biology, epigenetics, and evolutionary developmental biology. You can learn more here: [C. H. Waddington](https://en.wikipedia.org/wiki/C._H._Waddington) !["waddington"](https://upload.wikimedia.org/wikipedia/en/9/9d/Conrad_Hal_Waddington.jpg) > ***"Thus genetics has to observe the phenotypes, the adult characteristics of animals, in order to reach conclusions about the genotypes, the hereditary constitutions which are its basic subject-matter."*** Waddington would later substitute the word epigenotype for the epigenetic landscape, "the symbolic representation of developmental processes."

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