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Evolution of Genes and Genes in Evolution
THEODOSIUS DOBZHANSKY
Department of Zoology, Columbia University, New York City
"Even though the genius of man might make various inventions, attaining the same end by various means, it will not invent anything more
beautiful, or more economical, or more direct than nature, for in nature's
inventions nothing is wanting and nothing is superfluous."
Leonardo da Vinci
HUMAN DIVERSITY AND THE GENETIC CODE
Modern man is disinclined to concede to nature
as unstintingly as Leonardo did a sweeping
superiority over human invention. The suppleness
of the genetic mechanisms which transmit heredity from one generation to the next is, however,
unequalled among human exploits. The evidence
now available is overwhelmingly in favor of the
view that the genetic information transmitted
through the gametes is encoded primarily, though
perhaps not exclusively, in deoxyribonucleic acids.
The volume of these extraordinary substances in
a human gamete amounts, according to the
figure quoted by Muller (1958), to about four
cubic microns, and the weight to a mere 4 X 10-~2
grams. The number of persons living will soon
reach three billion, or 3 X 109 people. They will
have arisen from 6 N 109 gametes. It follows that
the total volume of the physical carriers of the
genetic information which the species Homo
sapiens will have received from its ancestors will
amount to a paltry 2.4 mm ~, and the aggregate
weight will be some 24 mg. This is about equal
to a raindrop.
How can the genetic individuality and distinetiveness of every human being in the whole
world reside in so minute an amount of material?
To resolve this mystery has been, and still continues to be, the main task, or at any rate one of
the main tasks, of genetics. The efforts of Mendel,
Morgan, Muller, and of many other geneticists,
biologists, and biochemists, extending for almost a
century up to the present, have cleared up large
segments of the mystery, or at ]east made them
less baffling. It will be convenient for our purpose
to begin the consideration of the problem with one
of the most recent advances, rather than in the
historical order.
A detailed exposition of the brilliant hypothesis
of Watson and Crick (1953) and Crick (1954,
1957) is quite unnecessary for our present purpose.
Its essentials are that deoxyribonucleic acids
(DNA) consist of a double helix of polynueleotide
chains; the two chains of the helix are held
together by hydrogen bonds between their component purine and pyrimidine bases; two purines,
adenine and guanine, and two pyrimidines, cytosine and thymine, are found; adenine in one
chain is always linked to thymine in the other,
and guanine to cytosine. Analysis of DNA from
different organisms has shown that the adenine:
guanine and thymine:cytosine ratios vary from
species to species, while the adenine:thymine
and guanine:cytosine ratios are always close
to unity.
According to Dunn and Smith (1958), a part of
the adenine in the DNA of at least some strains of
the bacteria Escherichia colt, Aerobacter, Mycobacterium, and some others is replaced by a related
compound, 6-methytaminopm'ine. Similarly, a
part of the cystosine in the DNA of some higher
animals is replaced by 5-methylcytosine.
Innumerable words can all be represented by
different combinations of the 26 letters of the
Latin alphabet. The genetic "alphabet" contains
only four "letters"--the four nucleotide bases. It
is nevertheless capable of specifying the differences
between countless genes. Suppose that a gene is
a section of the helix covering only ten nucleotide-pairs. The number of possible permutations
of four letters in a ten-letter "word" is 4'% or
1,048,576. A gene may actually contain hundreds
or even thousands of linearly arranged nucleotides.
Provided that there are no restrictions on the proportions or on the order of the nucleotide-pairs,
the numbers of the possible variant structures
(alleles) of genes is immense.
Muller (1958) goes daringly much beyond this,
basing his speculation on Benzer's (1955, 1957)
brave hypothesis that a mutation, at least in the
bacteriophage, may involve substitution, loss, or
insertion of a single nucleotide-pair in the WatsonCrick double helix. Muller assumes that the
entire 4 N 10-12 grams of DNA in the haploid
chromosome set in a human gamete is uniquely
represented genetic material (concerning the validity of this assumption see, however, below). Since
the mass of one nucleotide pair is about l 0 -2'
grams, there must be some 4 X 109, or four billion, nucleotide pairs in a human gamete. With
four kinds of nucleotides, and making the same
assumptions as above, this makes four to the
four-billionth power, or about 102,~~176176176176
possible
genetic endowments. This is as good an "infinity"
as ever envisaged for anything.
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DOBZHANSKY
ORGANIC DIVERSITY
Mankind is certainly not the most numerous
species on earth. Dr. C. B. Williams (private
communication) estimates that the number of
existing species of insects may be of the order of
2 • 106, and of living individual insects of the
order of 1018. This would mean an average of
about 5 X 101I individuals per insect species, but
some species are undoubtedly much more numerous, and many others much less numerous than
the average. Both the numbers of species and of
individuals of animals which stand in the zoological system higher than insects is virtually
negligible compared to the diversity and the
abundance of the insects.
I can find no estimates, however rough, of
numbers of individuals of higher plants, but
they can hardly exceed the insect populations by
more than one or two orders of magnitude. Lower
animals at least equal the insects in numbers of
individuals, though certainly not of species. Thus,
soil nematodes seem to be, according to some
counts, more numerous than insects in at least
some climates. Among microorganisms, the numbers of individuals are surely much greater than
among the higher forms of life. And yet, the
potentialities of genetic mechanisms to generate a
diversity of genotypes are more than ample to
confer genetic individuality even on microorganisms. Thus Benzer (1957) estimates that the
genetic material of the bacteriophage T-4 particle
consists of between 2 X 105 and 8 X 10 ~ nucleotide pairs. Even if every bacteriophage particle
had a genotype different from every other, they
would embody only an insignificantly small fraction of the possible genotypes (48~176176176
or more,
using Muller's method of computation). Of course
where asexual reproduction is the usual or the
exclusive method of propagation, as it is in many
lower organisms, clones are formed which consist
of individuals which, barring mutation, have the
same genes.
The four-letter "genetic alphabet" is, to use
Leonardo's words, a beautiful, economical, and
direct means to create an ample supply of genetic
raw materials from which evolutionary changes
can be constructed. This is evident despite the
many uncertainties in the above speculations and
calculations. Perhaps one of the gravest uncertainties concerns the assumed identity of the
entire mass of D N A in a gamete, or in a cell in
unicellular organisms, with the unique carriers of
the genetic information. We see nothing strange in
the assumption that a human gamete carries some
four billion nucleotide pairs, or at least 10,000
times as much as is found in a bacteriophage.
Man, the crown of creation, is entitled, we feel,
to have more, and more complex, genes than a
lowly bacteriophage. However, comparison of a
wider variety of organisms discloses some unexpected situations, as illustrated by Table 1
(compiled from the publications of Mirsky and
Ris, 1951, and Vendrely, 1958).
TABLE 1. D N A CONTENT, IN MG X 10-9, PER DIPLOID
NUCLEUS IN DIFFERENT ANIMALS
(After M i r s k y a n d Ris, a n d Vendrely)
Organism
Sponge
Jellyfish
Sea urchin
Limpet
Crab
Shark
Sturgeon
Carp
Trout
Lungfish
Amphiuma
Necturus
Frog
DNA
0.11
0.66
1.96
1.00
2.98
5.46
3.2
3.5
4.9
100
168
48
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Organism
Toad
Green turtle
Alligator
Fowl
Goose
Rabbit
Guinea pig
Rat
Horse
Cattle
Pig
Dog
Man
DNA
7.3
5.3
5.0
2.3
2.9
5.3
5.9
5.7
5.8
6.4
5.1
5.3
6.0
Man and other mammals have about twice as
much D N A in their nuclei as a crab has, three
times as much as a sea urchin, five to six times as
much as a limpet, and some fifty times as much as
a sponge. So far so good; but the frog exceeds man
by a factor of more than two, the lungfish Protopterus by at least sixteen, and the urodele amphidian, Amphiuma, by more than twenty five. The
D N A contents of the nuclei tend, on the whole, to
parallel the cell size, and the cells of Necturus, Protopterus, and Amphiuma are remarkably large.
Cells are usually larger in polyploids than in the
diploids from which they are derived. There is,
however, no reason to believe that any of these
animals are high polyploids, and it is hard to
make sense of the supposition that they need
more numerous or more complex and larger
genes than man does. Other possible surmises
are about equally unattractive. One may suppose
that only a part of the D N A contained in a
chromosome is the carrier of the genetic information which replicates itself, while the remainder
is not replicated. Or else, a part of the DNA,
though it does replicate itself, represents "nonsense combinations" of the nueleotides, a sort of
a useless ballast in the chromosome. It is also
possible that, at least in some organisms, chromosomes contain not one double helix of polynucleotie chains but several or many replicate helices
held together like separate wires in an electric
cable. The first of these conjectures is not easily
reconciled with certain observations on the autoradiographic behavior of chromosomes labeled
with tritiated thymidine (Taylor, Woods, and
Hughes 1957). The third is not in accord with the
fact that most gene mutations induced in the
gametes by X rays and other means alter the
whole bodies, and not only parts, of the bodies of
the zygotes which arise from such m u t a n t gametes. One can only conclude that as yet no satisfactory understanding of the situation has been
reached.
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EVOLUTION OF GENES AND GENES IN EVOLUTION
CONCEPT OF PARTICULATE HEREDITY
Unfashionable though such an idea may be in
this day of molecular biology, it should be kept in
mind that a living body is more than a container
for a mixture of chemicals. Knowledge of the
chemical composition would, by itself, tell us
about the organism roughly as much as a chemical
analysis of an automobile would about the motor
vehicle. This is obviously not to deny that the
component parts of an automobile must be made
of proper materials to function properly. Organization as well as composition of the protoplasm are
essential for life, and both have developed and
become perfected in the process of evolution.
The methods used to secure an understanding
of the nature of the genetic code fall into two
classes. The first is the Mendel-Morgan method
of crossing and analysis of hybrid generations,
from which inferences are drawn concerning the
architecture of the germinal materials. The second
is the method of chemical and physical investigation of these materials. An entirely satisfactory
synthesis of the results of these two types of
studies is probably not yet in the realm of what is
achievable. However, it is not premature to survey
the outlines of the situation which is emerging,
and such surveys have been attempted from time
to time, with varying degrees of success by many
geneticists. One of the most recent and most
successful is that of Pontecorvo (1958). In the
present Symposium, our interest in this matter is
perhaps tangential but nevertheless very real.
Since evolution is a change in the genetic structure of living matter, an at least provisional
genetic theory free of overt contradictions is an
indispensable part of the twentieth century Darwinism.
The enduring achievement of Mendelian-Morganian genetics is the demonstration that the
hereditary materials transported in the gametes
are arrays of discrete units known as genes.
("Mendelian-Morganian" genetics is sometimes
contrasted with Michurinist-Lysenkoist pseudogenetics. Since the latter belongs to the category
of superstition rather than science, MendelianMorganian is a fair label to describe that part of
genetics which uses analysis of hybrid generations
as its most distinctive tool). Even though the
gene-particles are not quite the windowless
monads envisaged by classical geneticists, at
least some discontinuity in the germinal materials
is incontrovertible. The raw materials of evolution
are, accordingly, changes in structure, number,
or relative position of the genes. These raw materials are acted upon by sexual recombination,
natural selection, and random genetic drift. Interactions of these factors lead to changes of frequencies, or to substitutions of one or more genes
in living populations. Such alterations are the
elementary evolutionary events. (Not enough is
known about changes in the cytoplasmic germinal
materials to have their proper places assigned
17
among the raw materials of evolution and among
the elementary evolutionary events. It appears
likely that most, or even all, cytoplasmic genetic
materials will be shown to be self-reproducing
particles. If so, their eventual inclusion among
the components of the evolutionary process should
present no great difficulty).
Mendelian-Morganian genetics has made it
exceedingly probable that evolutionary changes
are reducible ultimately to gene changes. This
indeed is important enough. But genetics has
accomplished something else as well; it has
clarified the evolutionary role of sexual reproduction. A majority of species of organisms now
living reproduces sexually; this has been the case
apparently since Cambrian times, or earlier.
Mechanisms which bring about exchanges of
germinal materials between different strains within
a species have in recent years been discovered
even in forms in which true sexual reproduction is
lacking. What, however, are the consequences of
such exchange? Seeing that children are usually
intermediate between the parents, pre-Mendelian
biologists inferred that the heredities of the
parents commingle and blend in the offspring.
This seemed reasonable enough to many physiologists, even to so brilliant a one as Jacques Loeb.
Darwin, though very reluctantly, made the
same inference. But if the parental heredities
really blended in the offspring, then sex would be
a conservative force, a great leveler, and at least
a brake if not a complete checkmate on evolution.
A newly arisen mutation would, in a few generations, be dissolved in the prevalent type, like a
drop of ink in a sea. Worse still, starting with a
genetically variable population, for example a
population containing large and small, or dark
and light individuals, some generations of sexual
interbreeding would yield a genetic uniformity-an intermediate pure race. The concept of particulate heredity changes the situation completely.
Particles do not blend or dissolve, they segregate.
This is a direct corollary of Mendel's discovery.
To us, having the advantage of hindsight,
this deduction seems crystal-clear, almost to the
point of banality. It was, in fact, arrived at but
slowly. As is generally known, Hardy and Weinberg, independently but in the same year, 1908,
pointed out that the genetic composition of a
sexually-reproducing population should remain
constant through a series of generations. The full
evolutionary implications of this constancy were
first realized, and clearly expounded, in a remarkable but little known work of Chetverikov,
in 1926. The constancy, the genetic equilibrium
discovered by Hardy and Weinberg, describe the
statics of the population. They obtain in the
absence of disturbing factors, mutation, selection,
and random genetic drift. These disturbers of the
equilibrium are the dynamic forces acting on
populations. They are the causes of evolution. A
translation of a part of Chetverikov's work is
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DOBZHANSKY
found in an appendix to the present article. The
same ground was traversed again, with much
mathematical elegance and refinement, in Fisher's
well-known book in 1930. This was followed by
Wright's analysis in 1931. Population genetics
was thus launched.
Heredity being particulate, sex is not only
exculpated of any suspicion of being a brake on
evolutionary change; sexual reproduction becomes
one of the most important evolutionary mechanisms. Under asexual reproduction, every mutational change yielding the components of a new
adaptive genotype must arise in the same line of
descent. In sexual Mendelian populations, mutants arisen in different places and at different
times may be combined in a single genotype,
owing to Mendelian recombination. Furthermore,
astronomical numbers of genotypes become potentially possible. Recombination in the progeny
of hybrids heterozygous for n genes may yield 3"
genotypes, 2 n of them homozygous ones. 1
Be it noted that Hardy-Wemberg-Chetverikovian deductions are valid regardless of whether
genes are absolutely discrete "beads-on-string",
as they were pictured in classical genetics, or
merely functional blocks of nucleotide pairs in the
Watson-Crick double helix. The point crucial for
these deductions is that the genes segregate and
recombine, as shown by Mendel and as seen in
countless experiments made following the Mendelian discovery. Nevertheless, genes are not only
atoms of evolution but are themselves evolving
organic systems. The nature of these systems is
clearly one of the modern evolutionist's concerns.
CONTINUITY AND DISCONTINUITY OF GENES
The ideas held by geneticists concerning the
genes have been undergoing a progressively accelerating, and on the whole progressive, evolution
for almost a century. Mendel's great work describes the inheritance of "characters"--colors,
shapes, and sizes of pea plants. He realizes, however, that the "characters" must be somehow
present in the generative elements as well as in
the mature plants: " . . . . The theory is confirmed
that the pea hybrids form eggs and pollen cells
which, in their constitution, represent in equal
numbers all constant forms which result from the
combination of the characters united in fertilization." And towards the end of his paper, almost
1Pontecorvo (1958), p. 134) writes: " . . . T h e discovery of the versatility of recombination has made nonsence of the specious arguments which used to be
produced for reconciling with neo-Darwinism the
widespread occurrence of asexual microorganisms. We
realize now that, if in an organism there is no obvious
sexual cycle, we had better find out which other process
of recombination is operating". This, I submit, is a
misunderstanding. Gene recombination, by whatever
process, may unite genetic variants arising in different
lines. If, however, organisms in which no genetic recombination takes place are frequent, then the "specious
arguments" remain necessary. If they are rare the problem ceases to exist.
as an afterthought, Mendel adds: " T h e differentiating characters of two plants can finally, however, only depend upon differences in the composition and grouping of the elements which exist in
the foundation cells of the same in vital interaction."
After the rediscovery of Mendel's work in 1900,
his chaste "characters" did not long remain unentangled with doctrines of a cruder material sort.
In 1903, Sutton and Boveri independently guessed
that the Mendelian "characters" must be borne
in the chromosomes of cell nuclei. This was a
remarkably lucky guess, considering the time
when it was made; it served to open a whole new
field of studies, cytogenetics. Johannsen, who
coined the word gene in 1909, wanted, however, to
be as puritanical about his gene concept as a
crusty Calvinist elder. To him, " T h e word gene is,
thus, fully free from every hypothesis. It expresses only the fact that at least many properties
of the organism are determined by special, at
least partly separable, and therefore to some
extent independent "states", "factors", "units",
or "elements", in short by what we shall call
genes, which are present in the gene cells."
The puritanical, abstract genes rapidly got
out of fashion. In 1919, Morgan wrote that "We
are led, then, to the conclusion that there are
elements in the germplasm that are sorted out
independently of one another . . . . These elements
we call genes, and what I wish to insist on is that
their presence is directly deducible from the genetic results (segregation in hybrids), quite independently of any further attributes or loealizations
that we may assign to them. It is this evidence
that justifies the theory of particulate inheritance." But further attributes are assigned to the
genes on the very next page: " . . . . The gene is a
certain amount of material in the chromosome
that may separate from the chromosome in which
it lies, and be replaced by a corresponding part
(and by none other) of the homologous chromosome." Moreover, Morgan definitely broke away
from the old preformlst notion, that a gene
"represents" in germplasm a part, or a "character", of the adult body. He wrote that "first, each
gene may have manifold effects on the orgamsm,
and, second, that every part of the body, and
even each particular character, is the product of
many genes . . . . I t m a y also be well to point out
that even if the whole germ plasm, the sum of all
the genes, acts in the formatmn of every detail of
the body, still the evidence from heredity shows
that this same material becomes segregated into
two parts during the maturation of the egg and
sperm, and that at this time individual elements
separate from each other largely independently
of the separation of other pairs of elements. It is
in this sense, and in this sense only, that we are
justified in speaking of the particulate composition
of the germ plasm and of particulate inheritance."
The "bead-on-string" analogy, representing the
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EVOLUTION OF GENES AND GENES IN EVOLUTION
genes as wholly independent particles, packed
in chromosomes in a fortuitous linear order,
arose perhaps as a text book oversimplification of
Morgan's conception. But it is only fair to point
out that, in the twenties and the early thirties,
this notion probably had the virtues of a working
hypothesis. It was pushed as far as it could go
without meeting stubborn resistance of incompatible facts. Such faets began to appear with Sturtevant's discovery in 1925 and 1928 of the position
effects at the Bar "locus" in Drosophila, which a
few years later was shown, by Bridges and by
Muller, Prokofieva-Belgovskaia, and Kossikov,
to be aetually a duplication for a short segment of
a chromosome. In the thirties, the discovery that
chromosomal aberrations are induced by X rays
opened up new possibilities of genetic and eytogenetic studies. Many transloeations and inversions were obtained in Drosophila, which carried
the same genes as "normal" flies, but arranged in
different linear orders in the chromosomes. In
many eases these genes were observed to act
differently when their arrangement in the chromosomes was altered. This began to look like real
interdependenee of genes which were neighbors
in the same chromosome.
A personal reminiscence may be in order here.
Late in 1932, I had an opportunity to demonstrate
to Professor R. Goldsehmidt some translocations
in Drosophila which yietded perceptible position
effects. His reaction was emphatic: such an hypothesis would mean the overthrow of the gene
theory! His repudiation of the gene theory came
soon thereafter (Goldschmidt 1935, 1938). Other
geneticists refused, however, to be impaled on the
horns of the dilemma--absolutely independent
genes or no genes at all. As instances of position
effects multiplied more and more (see especially
Dubinin and Sidorov 1934 and Lewis 1945), two
types of explanations of these phenomena were
ventured. Muller and Prokofieva (1935) pointed
out the possibility of " . . . . a higher degree of
interaction between locally more concentrated
products of gene aetivity than between more
distantly produced and either more diluted or
changed produets" (see also Lewis 1950). The
present writer (Dobzhansky 1936) ventured what
at that time seemed a less orthodox surmise,
namely that, "The genes may be pictured as
organic molecules united with each other in the
longitudinal direetion to form micelles, after the
fashion of the eellulose micelles. Breakage of such
a mieelle, and the formation of a new mieelle,
may involve modifications of the intergenic bonds
which may or may not be reversible in ease the
original gene order is restored."
Beginning particularly in the forties, genetic
studies on bacteria, viruses, and lower fungi
rapidly led to a tremendous refinement of what
Ponteeorvo (1958) aptly describes as the resolving power of genetic analysis. We have seen
above that the Morganian genes were elements "sorted out independently of one another."
19
In other words, they were units of Mendelian
segregation. But the segregation is observed in
heterozygotes which carry two variant forms, two
alleles, of a gene. Alleles arise by mutation, and
genes came to be regarded as units of mutation.
When a gene is observed to mutate repeatedly, its
different mutant alleles affect, as a rule, the same
trait or function of the body. Genes were believed
to be also units of function. This oversimplification has crumbled under the impact of the battering ram of the higher resolving power of genetic
analysis. The units of segregation, of mutation
and of function are not neeessarily coincident.
It would do injustice to the many ingenious
studies of the structure and function of the genetic
units which have appeared in reeent years to
attempt to single some of them out for review
here. I prefer rather to refer the reader to the short
but informative book of Ponteeorvo (1958), to
the relevant parts of the Cold Spring Harbor
Symposia on Quantitative Biology held in 1951,
1953, 1956, and 1958, to the Symposium on the
Chemical Basis of Heredity (W. D. MeElroy and
Bentley Glass, Editors, 1957), and to the collection of papers by Demeree et al. (1956). It should
also be pointed out that essentially convergent
information bearing on the problem of gene
structure has been obtained in organisms as
diverse as mice, Drosophila, maize, cotton, Aspergillus, Neurospora, yeast, Escherichia, Salmonella,
bacteriophage T4 and others.
The smallest genetical variables appear to be
mutational "sites". The lower limit of a mutational site is, as mentioned above, a single "letter"
of the "genetic alphabet", i.e., a single nucleotide
pair in a Watson-Crick double helix. The units of
recombination may or may not be larger than the
mutational sites. If they will prove to be larger,
this will mean that crossing over does not occur
indiscriminately between any two nucleotide pairs
but only between certain fixed blocks of them.
And finally, the genes as functional units contain,
at least sometimes and possibly always, several
to many units of recombination.
Different changes in the same gene were recognized in classical genetics because they behaved as
Mendelian alleles in crosses. Suppose that we
have several recessive mutants which more or less
resemble each other in phenotype. Recessive
mutants are regarded as allelic if they do not
complement each other's action in heterozygotes,
i.e., if the heterozygotes show the recessive
phenotype. Recessive mutants are non-allelic,
represent changes in different genes if they are
complementary to each other, and the double
heterozygotes have the "normal" dominant
phenotype. Now, mutations in adjacent mutational sites or recombination units may act as
so-called position pseudoalleles. Pseudoallelic recessive mutants complement each other when they
lie in the same chromosome (in the "cis" arrangement, i.e., rir2 in one chromosome and +1+2 in
the other chromosome), but are only partially
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20
DOBZHANSKY
complementary, or not complementary at all,
when they are in the "trans" arrangement (i.e.,
r1+2 in one chromosome and +1r2 in the other).
To quote Pontecorvo (1958): "Thus in the
cis-trans test we have an additional criterion to
that of non-complementarity for concluding that
the degree of functional integration between the
sites of one gene is more intimate than that
between the sites of two genes. We have, in fact,
an objective test, purely genetical and not requiring any biochemical analysis, for defining a
unit of function in heredity. . . . The difference
between allelism and non-allelism arises at the
transition between complementarity only in the
cis arrangement, and complementarity irrespective of arrangement. This transition defines the
'cistron' in the case of recessive mutants." The
possibility that the cistrons may sometimes be
overlapping is not excluded, and everything
points to the conclusion that every cistron contains more than one, possibly as many as a thousand or more, mutational sites, and perhaps several
to many recombinational units.
EVOLUTION OF THE G E N E STRUCTURE
The units of heredity have suffered the same
fate as the units of chemistry. The "indivisible"
atoms proved to be like miniature solar systems;
fixed numbers of planet-like electrons whirl around
a sun-like nucleus, which is in turn composed of
other subatomic particles. The "bead-on-string"
gene has resolved itself into a section of a string
of nucleotide pairs. This is, however, not an
undifferentiated string, for its sections are functional units; they are different genes or cistrons.
If the nucleotide pairs be likened to letters, then
a gene is like a word, or even a sentence. It is an
open question whether the words and sentences
in the genetic "message" are separated by spaces
and punctuation marks, or whether they follow
one after the other without interruptions, like
words in ancient inscriptions. It may even be that
the letters in the adjacent genetic "words" are
sometimes jumbled together.
It seems to me necessary to point out that,
contrary to what is sometimes alleged, the recent
developments in genetics have in no sense vindicated Goldschmidt's famous disallowance of the
existence of genes. Goldschmidt was a great
geneticist and a great mind; he performed well
and with dignity the important function assigned
by Goethe to Mephistopheles: to keep people, in
this case geneticists, intellectually on their toes.
This function is all too easily pre-empted by
failures in original scientific research, or even by
mountebanks, whose only qualification is their
intellectual sterility. However, Goldschmidt's
ideas that the genetic material in the chromosome
is functionally a continuum, and that rearangements of this continuum would result in so-called
systemic mutations, have at best a coincidental
resemblance to the new findings. This is not a
proper place to discuss Goldsehmidt's unconventional ideas about evolution, but there is no
escape from the conclusion that they have found
no confirmation eitherY
On the assumption that all life on earth is
ultimately monophyletic, the genes of a virus
particle and human genes are the products of
equally long evolutionary histories. (This assumption may be difficult to reconcile with the fact
that the genetic information in some plant viruses
is coded in ribonucleic acids, RNA, rather than
in DNA). In a sense, these histories may be
recorded in the gene structure. Some attenuated
version of the old-fashioned biogenetic law may
apply to gene structures as well as to embryonic
structures. However that may be, the gene
structure has certainly evolved, and the question
what this evolution was must sooner or later be
raised.
The origin of life is ground which angels, or at
least geneticists, fear to tread. Yet the splendid
work of Kornberg and his school (see Bessman et
al., 1958, and Lehman et al., 1958, for further
references) seems to contain a real promise that
the Riddle of the Sphinx may be answered in a
not too distant future. These authors have
obtained synthesis of DNA from four deoxynucleoside triphosphates (adenosine-, guanosine-, cytidine-, and thymidinc-triphosphates), in the presence of an enzyme isolated from the cells of colon
bacteria, of magnesium ions, and of a small
amount of a DNA "primer". The DNA synthesized has apparently the double-helical structure
demanded by the Watson-Crick model. But the
most remarkable fact is that the DNA synthesized resembles in composition the DNA used as
the primer. Primers obtained from different organisms cause the synthesis of their own copies. It
looks as if the primer DNA reproduces itself
from the raw materials (the four deoxynucleoside
triphosphates) supplied by the experimenter. This
comes closer to realization of the homunculus
dream then anything claimed since Paracelsus.
We do not know what the primordial genes
were like. They certainly synthesised their own
copies from materials drawn from their environment; they probably had a chemical constitution
related to the nucleic acids--DNA or RNA; and
just possibly they acted like Kornberg's primers.
Speculations concerning the origin of life on earth
assume that some organic compounds (such as
amino acids, and perhaps purines and pyrimidines) were formed in the primeval seas by nonliving agencies. The primodial life supposedly
2 Digressing for a m o m e n t from the sublime to the
ridiculous, one should take note of t h e efforts of
Lysenkoists to find a way of r e t r e a t from t h e i r indefensible positions. T h e y now claim t h a t the recent discoveries in genetics merely confirm w h a t M i c h u r i n was
saying long ago, a n d even w h a t Lysenko was saying more
recently. This line has been t a k e n in m a n y recent Russian publications (for example, N u j d i n 1958), a n d at
least one w r i t t e n in E n g l i s h (Michie 1958).
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EVOLUTION OF GENES AND GENES IN EVOLUTION
utilized these organic compounds for "food" and
as building blocks for self-reproduction. Since,
however, such compounds existed in only low
concentrations and were soon exhausted, natural
selection put a high premium on the ability of
genes, and eventually of organisms, to build
themselves from simpler substances.
An important achievement of the evolution of
life was the appearance of fully autotrophic
organisms, such as green plants, able to build
their bodies from inorganic salts, water, CO2, and
to utilize the energy of the solar radiations. It
seems plausible, although there is obviously no
direct evidence for this view, that the genes had
to evolve more complex structures as the complexity of the metabolic activities became more
and more advanced. A single virus-like gene was
no longer sufficient, and symbiotic groups of
them had to be formed to cope with greater
synthetic demands. Such groups of genes had to
form something like chromosomes, to insure
accuracy in reproduction. Gene recombination and
sexual reproduction were the next capital achievements of the evolutionary process.
The advent of gene recombination and of sex
made heavy demands on the gene structure. This
matter was discussed by Sewall Wright in his
Presidential Address at the Genetic Congress in
Montreal (thanks are due to Professor Wright for
his permission to quote his work before publication). The basic considerations are simple enough.
Where the reproduction is exclusively or at least
predominantly asexual, the chromosome may
really be nothing other than a succession of different functional sections of the Watson-Crick double
helix, following each other without interruptions.
The occurrence of meiosis, parasexuality, or
transduction may initially be compatible with
recombination taking place between any two
nucleotide pairs. Suppose, however, that, in an
organism like maize, Drosophila, or man, the
genes (cistrons) are sections of the helix containing
some 1000 nucleotide pairs, and that the populations carry many variable genes, each represented
by several or many alleles. Recombination within
a cistron would then cause changes resembling
mutations, and natural selection would be expected to act to promote a reasonable stability of
the adaptively successful gene alleles. This will
lead to a functional integration of the genes
(cistrons), and a restriction of the recombination
to the intergenic connecting links.
Several possible solutions of the above biological problem can easily be visualized. One of them
is that the genes, the physiologically significant
sections of the DNA helix, may be separated by
physiologically relatively inert stretches of the
same material. Crossing over would then occur
predominantly or exclusively, in these intergenic
connecting links of the helix. The genetic materials
in the simplest forms of life, such as viruses and
bacteria, may be little differentiated continua,
but this is quite unlikely in higher organisms. In
21
fact, we have conclusive evidence that the chromosomes in higher organisms consist of more or
less discrete segments, and this evidence is no
less conclusive because it is old and is, or at least
should be, well known. I mean, of course, the
chromomeric structure of the chromosomes in
meiotic prophases and in the giant chromosomes
of the salivary glands in Diptera. One of the
polemical footballs of cytology used to be whether
the chromomeres are actual thickenings of the
chromonema, or merely localized tighter coils of
that chromonema. This we may well leave to the
cytologists to settle; either way, the chromomeres
visibly and clearly testify that the chromosomes
of a Drosophila, maize, or a grasshopper contain
a succession of qualitatively different and discrete
segments linearly arranged. It is nature's fault,
not that of geneticists, that the microscopicMly
observable pictures do suggest the "bead-onstring" analogy. We do not, of course, know
whether the "string" as well as the "beads" may
carry some genetic information, but the discontinuity in the chromosome's components is evident enough.
GENE HOMOLOGY
The evidence presently available seems to show
that the DNA nucleic acids extracted from quite
dissimilar organisms are built of the same components, the two purine and two pyrimidine bases,
pentose sugars, and phosphoric acid. In this sense,
all genes in all organisms are alike in composition.
At least ignoring the RNA viruses, it might
appear that there has been no evolution at all in
the chemical components of the genes. All this
may well be true; nevertheless, it is more correct
to say that, as far as we know, no new "letters"
have been added to the genetic "alphabet" in
the course of evolution. The genetic "language"
has evolved entirely on the level of "words" and
"sentences", not on the level of the "letters". The
fact that the genetic "messages" transmitted
from generation to generation in amoeba and in
man are composed of the same "letters" is, however, not stranger than that the same alphabet
can be used for languages as heterogeneous as
English, Finnish, Turkish, and even Japanese.
I have hitherto, and quite deliberately, refrained from asking the obvious question, how
many and how profound are the gene changes in
evolution? There is no unanimity concerning the
answer among evolutionary geneticists. Two fairly
distinct views have emerged. The first is that
rather few mutations suffice to account for
evolution; the second proposes that most genes
must have changed many times, and, at least in
the aggregate, radically. The first, and the older
of the two views, goes back to Morgan and to De
Vries. De Vries believed that new species arose
through single mutations, but to him a mutation
did not mean a change in a single gene. Later on,
new races and species were supposed to incorpo-
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22
DOBZHANSKY
rate one or several lucky mutant genes or chromosomal changes, which happened to be favorable in
some environments. A great majority of the
genes composing a genotype were, however, assumed to be alike in at least closely related species,
and even in not so closely related ones. Perhaps
the most explicit recent statement of this view is
that of Sturtevant (1948). A not illogical corollary
was that similar genes may be found in quite
remote forms of life, and that, in fact, some
genes may have never changed in the evolution at
all. Evidence of this was seen in the presence of
similar or homologous organs, and particularly of
similar chemical constituents, in organisms remote
in the biological system. Yeast cells and human
cells have a number of similar enzymes; why not
also similar genes?
According to the second view, evolution involves far-reaching reconstructions of integrated
gene systems. Evidence of this comes, before all
else, from genetic analyses of differences between
related species, and also between subspecies or
races. At least in higher organisms, such differences, whenever adequate analysis is possible,
are shown to be compounded of not easily countable, but certainly numerous, polygene differences.
The gene pool of a Mendelian population usually
contains a multitude of unfixed genes. As a consequence, most individuals in such populations are
complex heterozygotes; different individuals differ
in many genes; and no two individuals, excepting
identical twins, are likely to have the same genotype.
Everyday experience shows that every person
is recognizably different from all other persons,
owing to numerous small differences in many
bodily features. These differences are conditioned
by genetic variations, mostly of polygenic nature.
I do not wish to be understood as suggesting that
gene differences with phenotypically discontinuous
effects are of no significance in evolution. Polygenes are certainly not a class of genes separable
from the so-called major genes. Some mutations
yield isoalleles which enter in the genetic causation of polygenic variability; other mutations of
the same genes give phenotypically discrete alterations. All intermediates also occur, and some
specific and racial differences include relatively
major genetic components. But the evidence is
clear that polygenic (isoallelic) variations are
predominant among the raw materials of evolution.
The statement that two or more organisms have
one or several identical or homologous genes
should have only one meaning: that the
organisms in question have inherited these genes
from a common ancestor. Suppose that we observe
vestigial wings in about one-quarter of a secondgeneration progeny from a cross of vestigial x
normal Drosophila flies. It is fairly certain that the
vestigial-winged flies have inherited copies of the
vestigial m u t a n t gene which the parent of the
cross had carried. Even here there is a possible
pitfall, since an occasional vestigial-winged fly
may contain a freshly arisen mutant gene at the
same or at a different locus. Human albinos may
be seen in New York and among the San Blas
Indians in the wilds of Panama. It is quite
improbable that these New Yorkers and Panamanians have inherited their albino alleles from
common ancestors. But their common ancestors,
probably very remote ones, did carry an allele a t
the albino locus, which produced normal pigmentation but which from time to time mutated
to the albino allele. The New Yorkers and the
Panamanians have inherited normal or albino
alleles of the same gene.
Now suppose that different species of Drosophila
are observed, in nature or in the laboratory, to
produce phenotypically similar mutants. We conclude that they have inherited from a common
ancestor a gene locus capable of undergoing similar
changes by mutation. This conclusion can be
verified for species which are able to cross and to
produce viable hybrids. If the mutants are recessive and they fail to complement each other in
the hybrids, it is reasonably safe to regard them
as allelic variants of the same gene; if they are
complementary they are changes of different
genes. Evidence of this sort is, however, difficult
or impossible to adduce for dominant mutants,
and for any mutants in species which cannot be
hybridized. The inference of gene homology must
then rest on more tenuous indications. Altogether
about a dozen Drosophila species have produced
sex-linked mutants which look more or less similar, and also produced some parallel autosomal
mutants. In the absence of the complementarity
tests, it is still reasonable to iudge that species of
Drosophila have many gene loci in common, and
that the process of mutation yields similar mutants. Genetic maps of chromosomes have been
worked out for several Drosophilae, and their
comparisons have produced some quite interesting
conclusions and speculations.
But here is a caveat--phenotypically similar,
or mimetic, mutants are produced also at different, fully complementary and not even linked
genes within a species. Among the classic mutants
in Drosophila melanogaster there are several nonallelic but visibly similar changes of the eye
color, the eye surface, bristle shape, etc. A few of
these mimetic genes may conceivably have arisen
in evolution through reduplication of the same
ancestral genes. But for a majority such a supposition is quite gratuitous. Our powers of observation are limited, and what to our eyes are phenotypically similar changes may actually be due to
different genes. These were, indeed, found in
number of instances, as in eye-color mutants when
these were studied physiologically and biochemically. Morphological mimics m a y often be distinguished physiologically. However, the difficulty
is exacerbated when mutants in different species
are compared. The more distinct the species, the
less the phenotypic similarity of even truly
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EVOLUTION OF GENES AND GENES IN EVOLUTION
homologous mutants, and the greater the chance
of error.
The difficulty is still further aggravated for
polygenes, within or between species. Traits like
the numbers of bristles on certain parts of the
body of Drosophila are modified by presumably
scores of genes, each producing only a small
effect, and not distinguishable from the effects of
other genes. H u m a n traits, like height, head
shape, intelligence, and even skin color have
genetic architectures presumably like the bristle
numbers in Drosophila. Whether or not size
variations in, for example, Drosophila melanogaster and D. pseudoobscura are due to the same
or to different genes remains outside the framework of our analysis, and no conceivable improvements of biochemical or physiological methods are
likely to change this situation. The MendelianMorganian method of analysis is simply not
practicable where polygenes are concerned, and
other methods, chiefly statistical, have to take
their place. This has even led Darlington (1956)
to entitle an essay, "Natural populations and the
breakdown of classical genetics", which certainly
does not err on the side of understatement.
In choosing to consider the polygenes (isoalleles)
in connection with the problem of gene homology
we are not being arbitrary. The raw materials
from which evolutionary changes are compounded
are in the main polygenic variants. This has a
consequence which was pointed out first apparently by Harland (1936). The eyes of all vertebrates, from fish to man, are homologous organs.
Despite their manifold differences they have the
same basic plan. In a sense, all vertebrates have
inherited their eyes from common ancestors. But
it does not follow that the eyes of a fish, a frog, a
lizard, a bird, and a mammal are formed by the
same genes. In the first place, the genes do not
form eyes or parts of eyes. Genes so canalize the
physiological processes that the egg, the embryo,
and the adult body develop in certain speciesspecific and genotype-specific ways. The presence
of homologous organs is, then, not necessarily
good evidence of persistence of identical, similar,
or even homologous genes. The genetic system
which brings about the development of the eye
in a fish is probably quite different from that in
a bird or in man.
What has been said above concerning organs
applies as well to their chemical constituents and
to enzymes. To an evolutionist, the fact that
certain enzymes are widely distributed in most
diverse organisms is very impressive. But to
conclude that these chemical constituents arc
produced everywhere by the same genes is going
far beyond what is justified by the evidence. In the
first place, what is really known is merely that
some enzymes extracted from different organisms
facilitate the same chemical reactions. These
enzymes are not necessarily identical in their
protein moieties. Secondly, the functional similarity of the enzymes is not necessarily conferred
23
upon them by identical genes in different organisms. The retention in the phylogeny of an
enzyme has the same meaning as retention of an
organ or a structure. Eyes are useful or essential
for survival in most vertebrates. Excepting in cave
animals, moles, and in a few others, natural selection opposes disruption of the eye function. The
enzymes of the Krebs cycle of the cellular respiration are perhaps even more indispensable than
eyes. The functional parts of these enzymes must
be preserved intact if life is to endure. This does
not make an evolution of enzymes any less likely
than an evolution of the organs of vision.
On the assumption that evolution was monophyletic, all organisms have inherited their genes
from the primordial life. Man and fish received
their genes from common ancestors of a more
recent vintage; the common ancestor of man and
chimpanzee is even less remote. In this, but only
in this sense, all genes everywhere are homologous.
But the genes have changed so many times and
so much during evolution that they differ in
kind they are different genes. Their residual
similarity may be solely that of D N A strands
with four and only four different kinds of nucleotides. To use again the language analogy--the
"letters" of the genetic alphabet have not changed
in biological evolution, but the words and the
syntax have changed, perhaps beyond recognition.
SEX AND CONTROL OF RECOMBINATION
Sex is perhaps the grandest of all inventions
achieved in the evolution of life. Above the level
of simplest viruses, any organism is a product of
symbiosis of many, in the higher forms probably
of tens of thousands, qualitatively different genes.
Gene recombination, which is a corollary to
sexual reproduction, permits gradual compounding of organic forms of superior adaptive
value from mutational building-blocks having
arisen in different places, times, and lines of
descent. As pointed out above, transduction,
parasexuality, and some other methods serve the
same biological function as sex does. All these
methods are trial experiments, among which
sexual reproduction, with syngamy regularly followed by meiosis, has evidently proven the most
successful one.
As a broad generalization, it may perhaps be
said that among the lower forms of life the different genes, which an organism has, are relatively
autonomous in their action (which is, of course,
not to deny the existence even in the lower organisms of chains of sequential physiological reactions). Progressive evolution has, on the whole,
led to a greater and greater complexity of the
developmental processes, and accordingly to more
and more interdependence and integration of the
gene-induced reactions. On the other hand, microorganisms often multiply to enormous numbers
of individuals, and they can afford to rely on the
occurrence of the right mutation at the right
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24
DOBZHANSKY
time to become adapted to changing environments. Where an individual does not count for
much, the destruction of masses of them does
not expose the species to a risk of extinction,
provided only that a variant adjusted to the new
environment appears in time to start building up
a new population. Among higher organisms individuals cannot be sacrificed with such impunity.
The challenges of the environment are then met
in two ways. On the individual level, the adaptedness lies in a homeostatic buffering of the developmental pattern. On the populations level, a great
array of genotypes is built to exploit the different
spatial and temporal facies of the environment.
Furthermore, sexual reproduction goes on eontinuously generating new genotypes. Some of
these may prove to be more homeostatic in the
old environments, or capable of holding forth in
new ones.
It is virtually certain that the different evolutionary patterns in lower and in higher organisms
are reflected in the architecture of their germinal
materials. At present we are, however, only
beginning to grope for understanding in this
field. It is, for example, certain that polygenic
variation exists among the lower as well as among
the higher organisms but it begins to look as
though it is less prevalent among the former than
among the latter. How much the recombination
of polygenic variants can do in an organism like
Drosophila can be gleaned from recent experiments
of Spassky, Spiess, Levene, and the writer (reviewed at the 1958 Symposium; see Spiess 1958).
In each of 3 different species of Drosophila, we
selected from natural populations 20 chromosomes which gave, in homozygous condition,
normally or near-normally viable flies. These
chromosomes were, thus, nearly alike as judged
from their phenotypie effects. We then obtained,
from each pair of the original chromosomes, ten
recombination products (i.e., 1900 "new" chromosomes per species). Homozygotes for these recombination chromosomes varied in viability all
the way from normality to complete lethality
(synthetic lethals).
The amount of the genetic variance released by
recombination can fairly be compared with the
total variance in viability found among the
chromosomes of the natural Mendelian population
from which the experimental chromosomes were
picked out. Such a comparison gives very impressive results. The variance among the recombination chromosomes amounts to between 25 % in
Drosophila persimilis and D. prosaltans to 43 % in
D. pseudoobscura of the total variance. In other
words, the recombination, in iust one generation, of the gene contents of chromosomes selected
for ostensible uniformity, re-creates from onequarter to four-tenths of the total variance
present in nature. It would seem that, in Mendelian populations of this sort, a temporary suspension of the mutation pressure would not
appreciably diminish the genetic variance for
quite some time to come.
Recombination, like mutation, is a two-edged
weapon. It produces novel adaptive genotypes.
On the other hand, it also breaks up the genotypes, old or new, with a fine impartiality as to
their adaptive values. A compromise must then
be struck between too much rigidity and too
much fluidity of the gene patterns. Reaching such
a compromise is especially difficult in higher organisms with their highly interactive genotypes.
Such genotypes can be arrived at only by a trialand-error mechanism operating on a grand scale.
But natural selection often produces genetic
death. The loss of individuals must be minimized,
for their supply is limited. Favorable gene patterns, once found, must be protected from disintegration.
SUPERGENES
The problem of the control of the amount of
gene recombination in evolution has too many
aspects to be considered here in its entirety.
Some of its aspects were discussed at the 1958
Symposium, particularly by Levitan, Carson,
White, Grant, and Stebbins. The remarks that
follow are restricted to recombination on the
gene-chromosome level only. Suppose that a
group of genes lying in the same chromosome is
adaptively favorable when present together, but
less favorable or unfavorable separately or in
other combinations. Tying together the successful
gene patterns is advantageous. The bond must
be strong enough to minimize losses through
break-up by recombination, but loose enough to
permit further improvement. A group of genes
"acting as a mechanical unit" has been called a
supergene by Darlington and Mather (1949).
Some of the sex-determining X- and Y-chromosomes are good examples of supergenes. Bisexuality arose independently, and in different
groups of organisms, both animals and plants,
from hermaphroditism. The original method of the
determination of sex in individuals, as female or
male, was probably monogenic. With monogenic
sex-determination, a pair of alleles of a gene acts
as a sex-differentiator, AA being a female and Aa
a male, or vice versa. However, when bisexuality
becomes firmly established in a phylogenetic
line, the sex-determination by a single gene is replaced by that of an integrated gene complex.
As pointed out particularly by Schmalhausen
(1949), trends from single gene determination to
polygenic determination of phylogenetically old
and adaptively important traits are rather general, at least among higher organisms.
The situation in Drosophila may serve as an
example. Excepting the heteroehromatin, all
parts of the X-chromosome of D. melanogaster
contain genes for femaleness. No short section
of the chromosome is by itself sufficient to transform one sex into another, as would be expected
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EVOLUTION OF GENES AND GENES IN EVOLUTION
with a single sex-differentiating locus. Since
crossing-over between the X- and Y-chromosomes
would generate sex-intergrades, polygenic sexdetermination can operate efficiently only if
recombination of the genes in the X- and Ychromosomes is excluded. Furthermore, a mechanism of the so-called dosage compensation has
developed, whereby the presence of two X-chromosomes in the female, and of only one in the
male, gives, apart from the sexual differences,
about similar developmental patterns (Muller
1950, Dobzhansky
1957). Duplications or deficiencies for parts of the X-chromosome
may
cause, however, gross phenotypic disturbances
or even lethality.
Chromosomal polymorphism, observed in many
Mendelian populations of both animals and
plants, includes a variety of examples of the formation of supergenes. It is well known that the
populations of many, though not all, species of
Drosophila are polymorphic for inversions of
sections of chromosomes. Thus, in D. willistoni
as many as 50 different inversions have been
found in nature, and in certain populations in
central Brazil an individual is heterozygous for,
on the average, nine inversions. Several convergent lines of evidence have shown that the inversion polymorphism is maintained, at least as
a rule, by adaptive advantages of the inversion
heterozygotes. It is a balanced polymorphism
maintained by heterosis.
We are, however, interested in a different aspect
of the situation. Why should inversion heterozygores be heterotie? Some inversions may cause
position effects favorable in heterozygous condition. But for a maiority of them the answer lies
probably elsewhere. Heterozygosis for an inversion causes suppression of the recombination
in a chromosome, or a part of the chromosome,
which contains the inversion. Suppose that the
chromosomes differing by the inversion carry the
genes NtB1C~DL and D2C~B~A~ respectively, and
that the heterozygote A1B~CtD~/D2C2B2A2 is
heterotie. The inversion preserves, then, the
gene complexes A1B1CxD1 and D~C2B2A2 from
being broken up by recombination. Inversion
polymorphs are supergene polymorphs.
It will suffice here to mention a single experiment (Dobzhansky and Pavlovsky 1958), in
which a dissolution of heterosis was obtained by
breaking up the supergenes normally bound together by an inversion. Two geographic populations of Drosophila pautistorum from the eastern
slope of the Peruvian Andes are both polymorphic
for a certain inversion. Experimental populations in laboratory population cages were made
separately from population samples from the two
localities. The potymorphism was conserved for a
series of generations; it is evidently balanced
owing to hybrid vigor in the heterozygotes. Experimental populations were then made, using as
the foundation stocks hybrids between strains
coming from the two geographic localities. This
25
time, the inversion heterozygotes became rare,
and within a year from the start of the experiment were close to elimination. How shall we
interpret these results? Suppose that one geographic population has chromosomes A1B1C1D1
and D~C2B2A~, and that the heterozygotes
AtB1C~D1/D~C2B~A2 are heterotic; the other population has
chromosomes AaBaCaDa and
D~C~B~A4, and the heterozygotes AaBaCaDs/
D4C4B4A4 are also heterotie. When the populations are crossed, the genotypes AIBICIDI/
AaBaC3Da and D2C2B~A~/D4C4B4A4 will be formed
among the hybrids. Crossing over is not suppressed in these genotypes, and recombination
of the constituent parts of the supergenes yields
chromosomes which produce no hybrid vigor in
heterozygotes.
The formation of supergenes guarded by the
inversions may be visualized as follows. Disregarding the possible position effects, an inversion may arise in a chromosome carrying the
alleles AxB~, which happen to interact favorably
with the combination ByA~ which is reasonably
common in the same population. Balanced polymorphism is established owing to the heterosis in
the heterozygote AxB=/ByAy. The supergenes are
built up further by addition, either by mutation or
by recombination, of further gene differences, such
that A~B~C~D~/DyCyByAy
has a net adaptive
advantage (Haldane 1957).
The assumption that the inversion happens to
arise in a chromosome with a heterotic complex
of polygenes makes no undue demands on chance.
We have seen above that recombination of genes
present in "normal" chromosomes in a Mendelian
population may generate an amazing amount of
genetic variance. New polygene complexes are,
then, constantly formed and broken down, and
some of them are heterotic in combination with
other complexes present in the gene pool of the
same population. Chromosomal inversions also
arise from time to time; most of them confer no
advantage on their possessors, because they do
not contain a polygene complex of any particular
merit in heterozygotes. Such inversions are lost, or
remain rare and local. Only a minority of the
inversions persist and spread. After all, the 50
inversions in Drosophila willistoni, which is the
record number thus far for any species, are doubtless a small fraction of the total assortment of
inversion which arose in the species, at different
times and places, in its evolution.
The properties of supergenes merit more attention than they have received. The simplest
form of gene interaction is, unquestionably,
additivity of gene effects. But it should be kept
in mind that epistatic and other interactions are
by no means unknown. Reference has been made
above to the experiments of Spassky, Spiess,
Levene, and the writer on the release of the
genetic variance by recombination in three species
of Drosophila. Crossing over between chromosomes giving normally viable homozygotes, yields
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DOBZHANSKY
recombination chromosomes, the average viability
of which in homozygous condition, is decidedly
below that of the parental chromosomes. Moreover, a chromosome A may give only normally
viable recombinants with B, and B with C, while
A and C may give many lethal or scmilethal recombinants. In short, a substantial part of the
variance released by recombination between
"normal" chomosomes is due to epistatic
interactions between the polygenes which they
contain.
Levitan (1958) found an even more unexpected
kind of interaction in Drosophila robusta. Suppose
that a population is polymorphic for two inversions in the same chromosome, A1-A2 and
BI-B2. The double heterozygotes may, evidently,
be of two kinds: A1B1/A2B2 and A1B2/A2B1 (i.e.,
the inverted sequences in the same chromosome
or in the opposite chromosomes). One would
suppose that these two kinds of heterozygotes
should be exactly alike, hut Levitan finds that
they are sometimes different. At first sight, this
appears to be like a case of position effect, with
the "cis" and "trans" combinations being different. But if so, it is a very special case; the inversions A and B are, in Levitan's material, far
apart in the chromosome, and the two chromosomal configurations, A1B1/A~B2 and A1B2/
A2BI, are cytologically indistinguishable. Perhaps
one should refer to the phenomenon discovered
by Levitan as "organization effect"; it consists
in allelic variants of different genes interacting
differently when they lie in the same chromosome
and in homologous chromosomes.
Perhaps some of you will find the following
suggestion not too audacious or far-fetched. In
determining the fitness of their carriers, the
chromosomes, or certain sections of them, may
act, especially in higher organisms, not as mechanical aggregations of independently functioning genes, but as supergenes. A gone combination which a chromosome or chromosome section
may carry, should, as far as its effects on fitness
are concerned, be considered as a supergene
allele of classical genetics. A population, the gone
pool of which contains a great variety of gene
patterns in its ehromosomes, carries in effect a
very large number of allelie variants of a relatively small number of supergenes. The formation by recombination of ever-new gene patterns
in the chromosomes amounts to emergence of
new altelie variants of the supergenes. Supergenes are, then, units of integration of hereditary
materials, which are greater than genes (eistrons),
and equal to or smaller than chromosomes.
SUMMARY
Both the ontogenetic and the phylogenetic
development of living organisms is epigenetic.
Neither organs, nor body parts, nor characters,
nor biochemical constituents of the adult organism are preformed in the gametes. The heredity
is coded in the gametes by means of the "genetic
alphabet" consisting of only four "letters", which
are the four kinds of nucleotide pairs of the deoxyribose nucleic acids. Evolution may be viewed
as a result of these "letters" combining into new
"words". The genetic code has become perfected
in the course of organic evolution. The genes,
which may be compared with "words" in the
genetic message, have probably become better
integrated when gene recombination and sexual
reproduction became firmly established. The
prevalence of polygenic (isoallelic) mutations and
of heterotic heterozygotes created the need for
further integration of the genes into supergenes.
The supergenes in a chromosome may perhaps
be treated as being in some ways similar to multiple alleles.
ACKNOWLEDGEMENTS
The author is deeply grateful to several colleagues, particularly to Betty Moore, J. A. Moore,
M. Demerec, R. Lewontin, George Streisinger, and
Monroe Strickberger, for most valuable suggestions and criticisms which have helped to eliminate several errors. Needless to say, the author
alone is responsible for the errors which still
remain in the article.
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27
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DISCUSSION
EMERSON: Instead of an example of a "homologous" organ (eye), with strong selection pressure
resulting in nearly complete genetic change during
phylogeny, does not the long retention of vestigial
organs with weak selection pressure depend upon
molecular identity of portions of the genetic complex with many other pleiotropic effects?
DOBZHANSKY: Let us keep in mind that genes do
not determine "organs" or "traits" or "characters"; they determine the development pattern of the organism, of which traits or characters
are manifestations. Vestigial organs need not be
determined by vestigial genes. They are rather
by-products of developmental processes which
bring about the appearance of vestigial as well
as of non-vestigial organs and characters. The
retention in the phylogeny of vestigial traits is,
accordingly, no different from that of fully functional ones. Neither means necessarily that a
certain gene, or genes, has remained unchanged.
The same developmental pattern may be brought
about in ancestral and in descendant forms, as
well as in different contemporaneous forms, by
different genetic systems. Suppose we find a
vestigial organ, such as the vermiform appendix,
retained in the phylogeny long after it has presumably lost its function. One asks the question:
W h y has this organ not disappeared? One m a y
as well ask this: W h a t advantage would the
organism get from so modifying its development
that the vestigial organ will be gone but the
rest of the development will remain unchanged?
If there existed a one-to-one relation between a
gene and a trait (as classical geneticists liked to
assume), then a vestigial organ would make a
gene unnecessary and it would disappear. But
the situation is really different: evolution does
not consist of independent changes of organs or
traits; what changes is the genetic system and the
developmental system which rests on it.
APPENDIX
The work of Chetverikov (S. S. Tsehetwerikoff),
entitled "Concerning certain aspects of the evolutionary process from the standpoint of modern
genetics", was published in the Zhurnal Experimentalnoi Biologii, Vol. 2, pp. 1-54, in 1926. The
translation printed below covers parts of
Chetverikov's Chapter II, "Mutation under the
conditions of free crossing" (parts of pages 1522 of the original), and the "Conclusions" (parts
of pages 48-51). The places in which some paragraphs of the original are omitted in the translation are marked by . . . . The obsolete word
"genovariation" employed by Chetverikov has
been translated as "mutation". His use of the
expression "free crossing" is however rather wider
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28
DOBZHANSKY
t h a n w h a t is u s u a l l y m e a n t b y " r a n d o m m a t i n g " ,
and it has been preserved in the translation.
MUTATION UNDER THE CONDITIONS
OF FREE CROSSING
. . . . Free crossing is the normal condition found in a
great m a j o r i t y of n a t u r a l species of animals as well as of
plants, a n d the i m p o r t a n c e of this factor in evolution
m u s t be appreciated. Indeed, w h a t an i m p o r t a n t role
was ascribed to this factor b y the greatest evolutionists
can be seen from the fact t h a t D a r w i n considered till
t h e end of his life, t h a t the most i m p o r t a n t objection
against his theory was raised n o t b y a n y of the great
biologists, b u t by an engineer, Jenkins, who in 1867
showed b y a simple calculation t h a t , as a result of free
crossing, a n y accidentally arising genetic v a r i a n t will
very soon be dissolved in a mass of normal individuals.
Free crossing has a dissolving, swamping according to
Darwin, effect on a n y newly arising single genetic variant, even a strongly m a r k e d one.
These considerations p r o m p t e d Darwin, in the successive revisions of his theory, to deviate more and more
from the m o d e r n genetic views on the role of single
changes, m u t a t i o n s (sports, according to D a r w i n ' s
terminology), in the process of the development of t h e
living world, a n d forced him to ascribe greater and
greater roles to the small b u t widespread individual
v a r i a t i o n s , now referred to as " f l u c t u a t i o n s " . As we
shall see below, the considerations which have so m u c h
impressed Darwin do n o t appear valid according to the
modern conceptions of the role of crossing. I t is, nevertheless, i m p o r t a n t to point out t h a t they have deflected
D a r w i n ' s t h i n k i n g from his earlier and more valid ideas
towards acceptance of views akin to the m o d e r n neoLamarckism . . . .
Among all the works referred to above, the greatest
i n t e r e s t and i m p o r t a n c e for us are the studies of K.
Pearson a n d G. H. H a r d y . T h e l a t t e r a u t h o r has, in a
s h o r t paper only two pages long, established a most imp o r t a n t law, governing t h e equilibrium s t a t e u n d e r the
conditions of Mendelian i n h e r i t a n c e a n d of free crossing.
I t m a y be referred to as the law of equilibrium with free
crossing, or H a r d y ' s law. This law can be s t a t e d as follows : T h e relative frequencies of homozygous ( d o m i n a n t
as well as recessive), and of heterozygous individuals,
with free crossing and in the absence of any selection,
remain c o n s t a n t if the p r o d u c t of the frequencies of the
homozygotes ( d o m i n a n t s times recessives) equals t h e
square of the half-frequency of the heterozygotes.
To express this law in a genetic formula, the composition of the population if represented as p A A 42qAa -4- ran, where p, 2q, a n d r are the frequencies of
the respective homozygotes a n d heterozygotes. T h e
equilibrium condition u n d e r conditions of free crossing
is t h e n :
pr = q~
A conclusion of great i m p o r t a n c e to us follows from
this law: since for any values of p a n d r there is always
a value of 2q such t h a t pr =q~, therefore a population
u n d e r free crossing m a y be at equilibrium with any
frequencies of the d o m i n a n t and recessive forms. In a
free-crossing population m a y be preserved from gene r a t i o n to generation not only t h e classical Mendelian
r a t i o 1:2:1 (phenotypically 3:1), b u t the frequency of
either homozygote (the d o m i n a n t or the recessive one)
m a y equal, or be greater t h a n , t h a t of the other, and
yet, t h e p o p u l a t i o n will remain a t equilibrium, provided
only t h a t the basic condition pr =q2 is satisfied.
Closely connected with the law s t a t e d above stands
a n o t h e r i m p o r t a n t law, h a v i n g to do with the equilibrium s t a t e in a free-crossing population, which m a y
be called t h e law of stabilizing crossing. I t was established b y K. Pearson in 1904, b u t remained unnoticed
because of its a b s t r a c t form inaccessible to a great maj o r i t y of biologists who received it initially. This law
was again d e m o n s t r a t e d b y H a r d y in the article re-
ferred to (1908), a n d s u b s e q u e n t l y s t a t e d again in
different m a t h e m a t i c a l a n d biological formulations
(Jennings 1916, W e n t w o r t h a n d Remick 1916, Tietze
1923). This second law of free crossing, which we shall
refer to as t h e law of stabilizing crossing or P e a r s o n ' s
law, m a y be s t a t e d briefly as follows: In a population
with a n y initial frequencies of homozygous or heterozygous p a r e n t a l forms, the equilibrium condition is
a t t a i n e d after a single generation of free crossing. T h e r e fore, no m a t t e r how m u c h an external factor m a y modify
the equilibrium in a free-crossing population, t h e first
generation of free crossing establishes in the p o p u l a t i o n
a new equilibrium, which will t h e n be m a i n t a i n e d u n t i l
again d i s t u r b e d by some external force.
Using genetic formulae again, we m a y s t a t e t h e above
thus : Given a free-crossing p o p u l a t i o n
x A A A- 2yAa + zaa,
in which t h e equilibrium condition has been so disturbed that
xz ~= y2,
t h e n the very first generation of stabilizing crossing
will lead to the relation
xl 2 A A + 2XLZlAa -4- zl~aa,
such t h a t
xl2zl 2 = (XlZl) 2
a n d t h e population wilt be a t a stable equilibrium (according to H a r d y ' s law).
T h u s , in the very m e c h a n i s m of free crossing t h e r e is
c o n t a i n e d an a r r a n g e m e n t which stabilizes the frequencies of t h e components of this population. Any
a l t e r a t i o n of these frequencies is possible only because
of some external influence, a n d remains possible only as
long as t h a t external influence is acting.
Among these external influences, we shall consider
in the present article only two: selection in the b r o a d e s t
sense of this word, a n d the appearance of genotypic
changes, m u t a t i o n s . We shall take up the m u t a t i o n s
first.
In the foregoing paper, I tried to show t h a t t h e r e is
no reason to deny t h a t new m u t a t i o n s arise c o n t i n u o u s l y
in n a t u r e . T h e d a t a concerning the best s t u d i e d Drosophila show t h a t the n u m b e r of m u t a t i o n s k n o w n is
growing w i t h o u t limit; some m u t a t i o n s h a v e arisen
repeatedly and more or less f r e q u e n t l y (e.g., white,
N o t c h , etc.), while in other cases the same gene changes
in various ways, giving rise to a series o[ alleles (e.g.,
t h e same gene white, also T r u n c a t e , d u m p y , etc.). However, a m a j o r i t y of m u t a n t s have arisen only once, a n d
the n u m b e r of possible kinds a n d v a r i a n t s of m u t a n t s
seems thus far to be unlimited.
What, then, is the fate of these single m u t a n t s , these
" s p o r t s " according to D a r w i n ' s terminology? Are t h e y
really disappearing w i t h o u t trace, dissolved in a sea of
normal individuals, h a v i n g no influence on the fate of
t h e species a n d on its evolution?
Let us consider first the appearance in n a t u r e of a
recessive homozygous m u t a n t , aa. W h a t shall be t h e
fate of this gene? T h e appearance of t h e m u t a n t dist u r b s the equilibrium s t a t e of t h e free-crossing population. If t h e m u t a n t is not destroyed by n a t u r a l selection
because of its defective v i a b i l i t y or poor adaptedness,
it will m a t e with a normal form, A A . F r o m t h e law of
stabilizing crossing we deduce t h a t in the next generation the equilibrium is reestablished, and the recessived
gene passes in a hetero~ygous condition, Aa.
Assuming t h a t a pair of p a r e n t s aa x A a will, in a
numerically c o n s t a n t population, produce a progeny of
two, t h e p o p u l a t i o n will contain two p h e n o t y p i e a l l y
normal individuals heterozygous for a pair of alleles,
Aa. This equilibrium s t a t e of t h e populations, or of the
species, will t h e n continue u n c h a n g e d generation a f t e r
generation.
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E V O L U T I O N OF G E N E S A N D G E N E S I N E V O L U T I O N
29
A simple reckoning shows t h a t the p r o b a b i l i t y of
such two heterozygous individuals meeting t o g e t h e r is
equal to u n i t y , divided b y the n u m b e r of individuals in
t h e p o p u l a t i o n minus one. Assuming, t h e n , t h a t the
p o p u l a t i o n c o n s i s t s of N + 1 individuals, the p r o b a b i l i t y
of the meeting of t h e heterozygotes is:
where m , which is the n u m b e r of the concealed m u t a n t s ,
m a y e v i d e n t l y grow w i t h o u t limit. I t is evident t h a t as
t h e n u m b e r m increases, this p r o b a b i l i t y m a y become
very large, a n d the species will manifest here one and
t h e r e a n o t h e r of the m u t a n t s which it c o n t a i n s . . . . .
p = 1/N
Let us summarize:
1. The process of m u t a t i o n is going on in n a t u r e as it
does in the l a b o r a t o r y and among domesticated animals
a n d c u l t i v a t e d plants. Observing it in n a t u r e is, however, difficult because of several reasons.
2. Most m u t a n t s are less viable t h a n the normal
forms. This is, however, not a general rule, since there
are some m u t a n t s the v i a b i l i t y of which is not reduced.
3. A freely-crossing species p o p u l a t i o n is a stable
system which includes a m e c h a n i s m which stabilizes t h e
frequencies of the c o m p o n e n t pairs of alleles (the laws
of H a r d y a n d of Pearson).
4. E v e r y m u t a t i o n which arises is absorbed b y the
species in a heterozygous condition, and, provided t h a t
selection is absent, remains indefinitely conserving its
frequency.
5. New m u t a n t s arise year a f t e r year, generation a f t e r
generation. T h e y are either like the m u t a n t s which arose
previously or new ones. The m u t a n t s are absorbed into
the species population, which conserves its external
uniformity. T h e heterozygosity for m u t a n t s gradually
s a t u r a t e s the species, combining a n d spreading as random (in so far as t h e separate genes are not linked),
and e v e n t u a l l y " i n f e c t s " most individuals.
6. When a large enough n u m b e r of m u t a n t s have
arisen, and this depends upon the " a g e " of the species,
almost all individuals will be " i n f e c t e d " by different
recessive and heterozygous m u t a n t s .
7. A l t h o u g h the p r o b a b i l i t y of m a n i f e s t a t i o n of a n y
given m u t a n t is extremely low, the probabilities are
additive, a n d c o n s e q u e n t l y the p r o b a b i l i t y of manifestation of some m u t a n t s is proportional to the n u m b e r of
the m u t a n t s absorbed by t h e species. When enough of
t h e m are absorbed, t h e y will become manifested more
a n d more often, the species becoming u n s t a b l e a n d
"old".
8. T h e most favorable conditions for m a n i f e s t a t i o n
of the genotypic v a r i a t i o n are found in large species
s u b d i v i d e d in m a n y medium-sized isolated colonies
(island forms of land snails).
9. Isolation i n t e r a c t i n g with the continuous m u t a tion process is the basic factor bringing a b o u t the i n t r a specific, a n d consequently also the inter-specific, differentiation. The isolation is mostly spatial, b u t sometimes
it is temporal, or else e n v i r o n m e n t a l (ecological).
10. N a t u r a l selection is an a n t a g o n i s t of the free
crossing. It is a dynamic factor.
11. T h e t a b l e of N o r t o n shows t h a t a n y e v o l u t i o n a r y
process caused by selection, either with d o m i n a n t or
w i t h recessive v a r i a n t s , always leads to complete replacement of the less well a d a p t e d b y the b e t t e r a d a p t e d
form. I t shows also t h a t selection utilizes and e v e n t u a l l y
fixes every i m p r o v e m e n t , no m a t t e r how small.
12. A d a p t i v e evolution w i t h o u t isolation leads to a
t r a n s f o r m a t i o n of the species (Waagen's m u t a t i o n s ) ,
b u t can never split t h e species in two and thus lead to
speciation.
13. D i s c o n t i n u a t i o n of selection leads to f o r m a t i o n
of stable polymorphic species.
14. Selection, like free crossing, leads to accumulation in the p o p u l a t i o n of recessive, and less viable, genes
in heterozygous condition.
15. T h e great p r e d o m i n a n c e in some of the forms
studied of the recessive, compared to d o m i n a n t , mut a n t s is a c c o u n t e d for by this a c c u m u l a t i o n u n d e r nat u r a l conditions of recessive r a t h e r t h a n d o m i n a n t
genes, b r o u g h t a b o u t b y the specific action of b o t h t h e
free crossing a n d selection.
16. W i t h respect to newly arising m u t a t i o n s , t h e role
of selection and of the free crossing differs greatly from
t h e above. T h e free crossing conduces to differentiation
This means t h a t one such meeting is liable to occur
in N consecutive series of meetings (generations). To
illustrate b y a concrete example: let us assume t h a t in
the whole n o r t h e r n E u r a s i a are living 1,000,000 + 1 grey
crows. Suppose t h a t t h e r e appears among t h e m one
homozygous recessive albino m u t a n t . If the m u t a n t is
not lost a n d m a t e s with a normal individual, the popul a t i o n in the next generation, a n d in generation after
generation, will c o n t a i n two individuals, normal in appearance b u t heterozygous for the albinism. T h e probability of t h e two heterozygotes meeting and m a t i n g
(assuming ideal r a n d o m mating) is 1 / N = 1/1,000,000.
T h e chance t h a t a white, homozygous, individual will
appear is only one among 1,000,000 consecutive matings.
I n practice this is negligible, and therefore the albino
m u t a n t is concealed, " a b s o r b e d " , b y the free crossing.
And yet, the fate of the m u t a n t will be quite different from w h a t was imagined b y old evolutionists. T h e
m u t a n t does not perish, is not dissolved in the mass of
normal individuals. I t will continue to exist in heterozygous condition generation after generation, being concealed from view, b u t representing a certain genotype.
T h e above considerations p e r m i t us to see more
clearly and more profoundly the g.enetic s t r u c t u r e of a
freely-crossing population, a specms. Is a species population genotypically uniform? And assuming some
heterogeneity, how to explain the constancy, the "monot y p i s m " , which is so characteristic of n a t u r a l , wild,
species, c o n t r a s t i n g with domestic breeds? . . . .
Assume a freely-crossing population of N + 1 individuals. T h e p r o b a b i l i t y of a new appearance, owing
to a m a t i n g of heterozygous individuals, of a previously
arisen m u t a n t , a a , is, as we have seen 1 / N , which is,
with large N's, negligibly small. B u t imagine t h a t in
some population t h e r e has arisen a n o t h e r single m u t a n t ,
bb, which has also passed in a heterozygous state. The
p r o b a b i l i t y of a reappearance of this m u t a n t will also
be 1 / N , a n d the same will be for a t h i r d m u t a n t , ce, for
a fourth, dd, a fifth, ee, etc.
All these m u t a n t s arising among normal representatives of the species, pass into the heterozygous state,
a n d are t h u s concealed, absorbed into the species, existing in it as isolated individuals. T h e species acts like a
sponge, absorbing heterozygous m u t a n t s , a n d yet remaining p h e n o t y p i c a l l y uniform. T h a t this conception
of the genotypic s t r u c t u r e of the species is realistic, is
confirmed b y the as yet unfinished analysis of n a t u r a l
populations of species of D r o s o p h i l a u n d e r t a k e n b y the
L a b o r a t o r y of Genetics of the I n s t i t u t e of E x p e r i m e n t a l
Biology last sulnmer (1925).
T h e p r o b a b i l i t y , 1 / N , of the meeting of two like
heterozygotes is so small in more or less large species as
to be practically negligible. B u t w i t h repeated origin of
the m u t a n t , the p r o b a b i l i t y of m a n i f e s t a t i o n of some of
t h e m will be growing more and more, according to the
law of s u m m a t i o n of i n d e p e n d e n t probabilities. Thus,
with two concealed m u t a n t s , the p r o b a b i l i t y of a m a n ifestation will be almost twice as great:
p = 2/N
-
1 / N ~,
and with t h r e e m u t a n t s will be 3 / N - ( 3 / N 2 - 1/NS).
In general, with m m u t a n t s concealed in a population,
t h e p r o b a b i l i t y , p, of t h e m a n i f e s t a t i o n of a n y one of
t h e m t h r o u g h r e c o m b i n a t i o n with a free crossing will be:
p=l--
CONCLUSIONS
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30
DOBZHANSKY
of forms, while selection, destroying the harmful mutants, purges the species of excessive variability, and
generally tends towards a uniformity of the species.
17. There is no reason to deny the possibility of unadaptive evolution. In many cases one may suppose that
the existing adaptive differences of closely related forms
were not the reasons of the divergence of the latter, but,
on the contrary, the specific character of these adaptive
traits is a consequence of an earlier separation of these
forms. The more ancient the separation, the greater will
be the number of adaptive traits in which the forms
will differ.
18. The concept of pleiotropic action of genes, introduced by Morgan, is very important for understanding the action of selection. This concept leads us to
the idea of the genotypic milieu, which acts from the in-
side on the manifestation of every gene in its character.
An individual is indivisible not only in its soma but also
in the manifestation of every gene it has.
19. The concept of the pleiotropic action of genes
helps to clarify some difficult and confused problems in
genetics--intensifiers, modifiers, and the invariably
polymeric nature of quantitative traits.
20. The selection selects not only a gene which determines the character under selection, but it affects
the whole genotype (the genotypic milieu), leads to an
intensification of the trait selected, and in this participates actively in the evolutionary process.
21. The concept of pleiotropic action of genes gives a
new theoretical basis of the phenomena of relative
variability and of genotypie correlation of traits.
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Evolution of Genes and Genes in Evolution
Theodosius Dobzhansky
Cold Spring Harb Symp Quant Biol 1959 24: 15-30
Access the most recent version at doi:10.1101/SQB.1959.024.01.004
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