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OCR for page 126
126 THE LIFE SCIENCES
HEREDITY AND EVOLUTION
When the Origin of Species was published in 1859, Darwin convinced
biologists that all living forms are related to life in the past, from which
they evolved by small changes preserved by natural selection. But the
fundamental mechanism of this process eluded him. This was provided in
the formulation of the rules of inheritance by Gregor Mendel, based on his
observations with garden peas, which led to understanding that heredity is
particulate in nature. Shortly thereafter, observations of the behavior of
chromosomes, particularly the manner in which the chromosome number
is halved during the formation of sperm and egg, made it apparent that the
chromosomes were the carriers of these particulate genetic factors, later
called "genes." In the 1920's, as a result of a large body of ingenious,
elegant experimentation with the fruit fly Drosophila melanogaster, genes
were shown to be arranged in single file on the chromosomes. By 1940,
the chromosomal mechanisms of genetic transmission were thoroughly
understood, and the concept of mutation a heritable change in a gene or
chromosome so that it produces a new effect-was well established. The
rules of mutation were well understood by 1950 that any individual
occurrence is essentially unpredictable although the average can be mea-
sured, that most mutations are harmful, and that the rate of mutation can
be increased by raising the temperature, by radiation, and by a variety of
chemicals. But the chemical nature of the gene itself and of the mutation
process was not understood. The chemical structure of DNA, and the
concept of mutation as a process involving the substitution of one of the
four bases of DNA for one of the others, or of deletion of some portion of
the DNA, or inversion of some portion of the molecule, or crossing-over by
exchange between two genes or chromosomes, was established in the last
two decades. Fundamental theory and the detailed mechanisms of genetics
now rest on rather secure grounds.
Population Genetics An Extension of Mendelism
A new field, population genetics, is addressed to more detailed understand-
ing of how mutation, selection, migration, population size, environmental
conditions, and other factors influence the distribution of individuals, the
character of populations, and the evolutionary process. To date, however,
available methods permit the study of only microevolutionary change-
changes within species rather than the study of the origin of higher cate-
gories such as genera or families. The first step was to determine the rela
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FRONTIERS OF
tionship between the proportions of genes in the population and the
proportions of the various genetic types of individuals (genotypes) that
arise by random combinations of these genes. Thus, if Pi, P.,, P3 . . . repre-
sent the proportions of alternative genes at a single chromosomal locus, the
genotype frequencies are given by appropriate terms in the quadratic ex-
pression OPT + p., + p3 ....~2.
.. . .. . ~. ,,
Many natural populations are sufficiently
large, and mating Is sumc~enny random for a number of traits, to demon-
strate that this principle applies remarkably well. It has been a powerful
tool for analyzing natural populations and determining the mode of inheri-
tance of genetic traits in populations in which experimental matings are not
possible, viz., man. One of the earliest demonstrations of the validity of the
Drinciole was the finding that the distribution of the major blood groups of
r ~ -r ~
man, A-B-O, conforms to the above rule. Because the potential number
of genotypes in the population is vastly larger than the number of genes,
a considerable simplification is achieved by considering changes in gene
frequencies rather than genotype frequencies. In any case, in a sexually
reproducing population, the genes are reasserted by the Mendelian shuffle
that occurs in each generation; the effects of such reassortment are transi-
tory because gene combinations are put together and taken apart with
each generation. Thus, the value of considering gene frequencies rather
than genotype frequencies is that the genes perpetuate themselves as intact
units, whereas the genotypes are constituted anew each generation. The
weakness of this simplification relates to the fact that individual genes are
not completely randomized in each generation. Genes close to one another
on the same chromosome often tend to be linked together in inheritance.
Accordingly, a truly sufficient mathematical theory requires extremely
complex models.
One of the earliest contributions of population genetics was to provide
understanding of the disadvantage of inbreeding. Sibling mating had long
been discouraged in human tradition, and many biologists had noted the
weakening effect of inbreeding. It was recognition of the fact that harmful
recessive genes usually produce their effects only when present in duplicate
and that the occurrence of such duplication is enormously increased by
inbreeding, as evident in the occurrence of human hereditary disorders,
that led to objections to inbreeding on scientific rather than social grounds.
Observational and experimental population genetics started with field
studies of natural populations. Although most evolutionary change is too
slow to be witnessed in a human lifetime, some examples of unusually rapid
evolution have been described. Among these is the evolution of "industrial
melanism." As smoke from factories gradually darkened tree trunks, the
light-colored forms of moths that rest on these trunks were replaced by
darker forms, a phenomenon possible only under rather intensive selection
~,
BIOLOGY 127
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128
THE LIFE SCIENCES
pressure. This pressure was demonstrated experimentally by the observa-
tion that birds selectively caught light moths from the darker tree trunks
found in industrial areas and dark moths from the lighter tree trunks found
in rural areas. A more recent and more unfortunate demonstration of the
operation of such processes is the development of insects resistant to com-
mon insecticides and of micro-organisms resistant to antibiotics. The large
numbers of individual organisms of varied genotypes and the rapid rates
of reproduction make possible rapid selection of such resistant mutants,
which then grow out and replace the original susceptible strains.
One of the greatest contributions of experimental population genetics
has been the demonstration of the large amount of hidden genetic varia-
bility, which is concealed in relatively constant natural populations.
Cytogenetics
Not long after discovery of the chromosomal basis of heredity it became
apparent that, for normal development, there must be exactly the right
number of chromosomes in the fertilized egg. Most species are diploid,
having two representatives of each chromosome in the fertilized egg and
in all the body cells derived from it. Some are polyploid having four, six,
or eight chromosomes of each type. For the diploid species in particular,
when there are too many or too few chromosomes, or even if there is an
excess or deficiency of only a part of a chromosome, the resulting animal
or plant will exhibit abnormalities and frequently cannot survive. A classic
demonstration of this phenomenon was obtained by breeding studies with
the common jimsonweed, Datura stramonium, which normally has 12
pairs of chromosomes in each cell. If an organism has three representatives
of a particular chromosome instead of two, it is said to be trisomic. Each
of the 12 possible trisomic types of jimsonweed was found to have a char-
acteristic abnormal appearance. Monosomic plants with only a single
representative of a given chromosome were also discovered, and these, too,
had characteristic abnormalities, usually considerably more severe than
the corresponding trisomics. Such data were not expected. From them
came understanding of the great importance of the correct balance among
genes on each chromosome. If an organism is to develop normally, not
only must the genes be normal, but there must be the correct numerical
balance among them. Unbalanced chromosome combinations arise because
of an accident in the process of meiosis, the reduction division that yields
egg or sperm cells containing half the normal complement of chromosomes
of somatic cells. Such accidents are not common but neither are they
exceedingly rare, and whenever they have been systematically sought they
have been found.
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FRONTIERS OF BIOLOGY
In agricultural practice trisomic and monosomic types have been of
great practical utility. They permit the determination of both the conse-
quences of a specific gene and its chromosomal location. Application of
this knowledge facilitates the transfer of useful genes e.g., those for
resistance to diseases, insects, or poor soil from one variety to another.
It was with such techniques that the gene for rust resistance was transferred
from the common weed, goat grass, into commercial wheat and, in a recent
tour de force, that a useful gene was transferred from rye to wheat. Simi-
larly, polyploidy can be exploited as in the creation of a new cereal crop,
Triticale, an octoploid with six sets of chromosomes from wheat and two
from rye.
HUMAN CYTOGENETICS
Adequate techniques for the study of human chromosomes were invented
only a dozen years ago. In fact, they are quite unsophisticated, and it is
difficult to understand the long delay in their development; even the correct
number of human chromosomes was unknown until a little more than a
decade ago. But because of the large body of material and great interest,
human cytogenetics has advanced extremely rapidly. With the new tech-
niques, a few drops of blood suffice, and knowledge of human cytology is
now comparable to that of the best-studied plants. The overriding question
was to what extent chromosome anomalies are responsible for human
disease, malformation, or early death.
The first trisomic disease, discovered in 1959, turned out to be the
already familiar "mongolism" or Down's syndrome, characterized by severe
mental retardation, a number of characteristic physical abnormalities, and
a face that appeared to Down to resemble the mongoloid peoples, a fact
that resulted in his unfortunate choice of a name for this disease. About
one infant in 700 is born with this disorder, and such patients constitute
as much as one third of the population in institutions for the most severely
retarded. A long-standing puzzle was created by the fact that mongolism
is associated with a remarkable variety of seemingly unrelated abnormali-
ties. Now that the cause is known, this is not surprising, for there must
be many genes on the responsible chromosome and any gene that produces
an abnormal result if present three times in the genome rather than the
normal two would produce this effect.
This suggested an approach to finding other chromosomal diseases, and
the study of patients with mental retardation and other superficially unre-
lated abnormalities led almost immediately to the discovery of two other
trisomic types, both new conditions previously unknown to clinical medi-
cine. But nc other examples of trisomic types have been found in several
years of subsequent study. Since the three known types all involve quite
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130
THE LIFE SCIENCES
small chromosomes, it appears likely that trisomy for the other chromo-
somes of man is simply incompatible with the development of the embryo
and fetus. Experience with experimental plants and animals indicated that
monosomv is more harmful than trisomy for the same chromosomes. In
confirmation, a study of miscarried human embryos indicated that more
than a third of spontaneous abortions are caused by tnsomy, monosomy,
and more complex chromosome anomalies.
An exception to the rule that chromosomes occur in identical pairs is
found in the sex chromosomes X and Y (Figure 30~. Moreover, these
are also the basis for the exception to the rule that monosomy is lethal
since monosomic individuals with a single X chromosome and no Y chromo-
some turned out to have the well-known but previously not understood
No rma I Fema le
lou _
|8 l~ X' f F Al I] XX
XX x~ }6 tI XA &6
7 ~ 'A 10 11 1;'
h' ~Ss se zz an sa
19
Tu rner's Synd rome
1 10~
'8 I! X' lA I' 11 x
1 2 3 4 S 6 X
X' X' ;iX Ia ah X'
.d Ah ad x! x' &.
t3 14 15 16
4x AX &A ^&
19 20 2 1 22
Normal Male
,0 ~
is ax ~8 46 §t hK 2
~ If. 3 ~ 5 it X
HA b' I] d~ h' l'
Bitt l,6 Ace. x~ no a~
13 t4 15 1~.; t7 1h,
Ix X~ 44 ^^
I) 20 2 ~ 22
Klinefelter's Syndrome
,0u
|' ~' l' dA AA X~ ~l
~2 3 4 5 6 X
HA X~ ^8 AA MA ^^
FIGURE 30 Human chromosomes of the normal female and the normal male, and
in Turner's syndrome and Klinefelter's syndrome. (From Metabolic and Endocrine
Physiology by Jay Tepperman. Copyright (I) 1968, Year Book Medical Publishers,
Inc. Used by permission. Photograph courtesy of Mary Voorhess and Lytt Gardner.)
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FRONTIERS OF BIOLOGY
Turner's syndrome (small stature, amenorrhea, absence of secondary sex
characteristics), while the trisomic XXY type has turned out to be the
known condition, Klinefelter's syndrome (apparent male with feminine stig-
mata and very small gonads). In individuals with chromosomes that have
broken and been reattached, there may be no immediate abnormality, but
such abnormal chromosomes complicate the normal process of sperm and
egg formation, markedly increasing the likelihood of unbalanced chromo-
some combinations in the next generation. This imposes a serious burden
on the prospective parents, who should be made clearly aware of the poten-
tial consequences.
Polymorphism
Naturalists have long noted that some species of animals are polymorphic,
i.e., they exist in two or more quite distinct forms such as black and
cinnamon bears or red and silver foxes in the same litters. Population
geneticists have sought to understand this process in a general way for any
gene locus. If the heterozygous individual (A,A,) is somehow selectively
advantageous in comparison with either form of homozygote (A,A, or
ALA, j, then both types of genes persist in the population in a stable equi-
librium determined by the relative fitnesses of the two homozygotes. This
has been demonstrated amply with many forms; fruit flies have been most
thoroughly studied, but polymorphisms are found throughout the animal
and plant kingdoms. Sickle cell anemia is perhaps the classical human
example. Individuals with "normal" hemoglobin are susceptible to malaria,
those with two genes for the sickle cell trait are subject to a profoundly
debilitating anemia, while the heterozygote is resistant to malaria and only
slightly incapacitated by having half his hemoglobin abnormal; hence,
the heterozygote has a selective advantage. Accordingly, both genes flourish
in African populations. As man is investigated more intensively, an increas-
ing number of polymorphisms, usually detectable only at the molecular
level, have become apparent; presumably all are maintained by the same
. .
principle.
Some Recent Accomplishments
A primary accomplishment of population genetics is the understanding it
has provided of the nature of the evolutionary process, of the value of the
sexual reproduction mechanism, and of the relation of man to all other
. . .
~v~ng organisms.
131
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THE LIFE SCIENCES
No chapter in modern biochemistry is of greater interest than the accumu-
lated demonstration of the kinship of man to other living forms. The
primary datum is the universality of the genetic code and of the operation
of the genetic apparatus. The fact that the genetic code is a constant from
bacteria to man to higher plants is the most cogent available argument
supporting the concept that all living forms derive from a single common
ancestor. At the same time, by tracing the amino acid sequences of specific
proteins with essentially identical functions, it has been possible to illustrate
how the process of mutation causes divergence from an original form. The
most thoroughly studied such protein is the electron carrier cytochrome c.
Amino acid sequences of this protein from more than 30 species are now
available, and of the 105 residues in this protein, only a quarter of the
positions remained filled by the same amino acid in all species. Strikingly,
at what is considered to be the binding site of cytochrome c to the enzyme
responsible for its oxidation, there is a run of 12 amino acids where no
substitutions have occurred in recorded history. Moreover, in a general
way, the number of differences in amino acid sequence between the cyto-
chromes c of any two species is a function of the time since the two species
separated from a common ancestral form, as indicated by the paleontologi-
cal record. Accordingly, the cytochromes c of the primates, like the
hemoglobins of the primates, are virtually identical, which is convincing
proof on the molecular level of our common origin. In contrast to the great
variability of most of the amino acids of the proteins studied to date is the
remarkable constancy of structure of a histone (a basic protein bound to
DNA in cell nuclei). Of the 115 amino acids in this molecule, only at one
position does the histone of the garden pea differ from that of the cow,
testifying to their common ancestry.
One other aspect of such studies is particularly noteworthy. As one
ascends the phylogenetic ladder, the DNA content of cells increases, as
does the number of proteins that such organisms synthesize. How did this
increase in DNA come about? The answer derives from comparative
studies of amino acid sequences of diverse proteins within a given species.
For example, it is apparent that much of the structure of the digestive
enzymes trypsin, chymotrypsin, and elastase, as well as one enzyme that
operates in the blood-clotting process, is identical. Similarly, the poly-
peptide hormones of the pituitary are very much alike, and a protein hor-
mone produced in the gastrointestinal tract closely resembles one produced
in the pancreas. Yet all of these are quite distinct proteins at the present
time. The first observation in this area was the fact that although four
different types of protein chains are involved in the structure of normal
human hemoglobins, these are essentially of equal length and show very
large areas of identity. For each such related group, one can only conclude
Representative terms from entire chapter:
amino acid
