lndividuals belonging to the same species differ with respect to a multitude

of inherited characteristics. Population genetics is largely concerned with

under- standing the nature and source of these inherited differences, with
predicting the changes in the relative frequencies of the different types in
a population, and with determining the conditions when equilibrium between
the forces affecting their frequencies is reached. The theory underlying these
predictions is effectively the quantitative theory of evolution.
Following the rediscovery of Mendelism at the tum of the century, the
mathematical theory of evolution based on Mendelian genetics was
developed, mostly by R. A. Fisher, J. B. S. Haldane, and Sewall Wright.
Much further theoretical work has been based on the foundations laid down
by these three great scientists. Experimental population geneticists-starting
with S. S. Chetverikov, who, working with Drosophila, was the first to identify large sources of genetic
variability in natural populations, and contnuing with the classic work of
Theodosius Dobzhansky, E. B. Ford, and others-have provided basic
observations on natural and artificial populations that test evolutionary
theories and predictions. Although studies of experimental population
genetics are necessarily restricted to short periods of time and usually to
limited geographic areas, such micro- evolutionary studies have,
nevertheless, helped greatly in understanding the gen eral phenomena of
evolution on a larger time scale (namely, macroevolution). Data from
evolutionary comparisons on a molecular level are adding important new
information to challenge the validity of our evolutionary theories.
Since the pioneering work of W. Weinberg it has been clear that the analysis of
human genetic data must rely heavily on concepts of population genetics.
Because it is not possible to carry out controlled experimental breeding
with humans, the study of inheritance depends on observations of those
matings that happen to take place in the human population. Human
population genetics is needed, therefore, to predict the frequencies with which
possible types of matings will be found.
Medica! genetics, the study of inherited diseases, depends on a knowledge
of
human population genetics. This dependence has been emphasized by our
growing awareness that individual reactions to drugs and other agents, and
also susceptibility to sorne chronic diseases, may often be, at least in part,
genetically controlled.
Severa! disciplines, including public health, require more knowledge of
the range of individual variation and how environmental and genetic factors
deter- mine it. For example, no longer can we ignore the need for different
educational responses to individual differences. Sociologists cannot afford to
ignore the sources of differences when studying interactions between
individuals. Physical anthropologists are becoming increasingly aware of the
need to provide a theoretical background for their observations. Psychologists
must take into account genetic differences in their studies of human behavior.
Last, but by no means least, it is important that the demographer, whose aim
is the prediction of the future course of population changes, also realize the

need to take account of population genetic principies and, especially, of the

family as the unit of information in making demographic predictions.
So far no comprehensive treatment of the genetics of human populations
emphasizes the interpretation of data in relation to the theoretical models.
This book is an attempt to fill the need for such a treatment. We have
included sorne original work, which we were led to in the course of writing this
book ; for example, we looked into the effects of ascertainment biases on the
estimation of mutation rates, the treatment of the hemoglobin ACS
polymorphism including the effects of migration, a new method for calculating
effective population size taking into account age structure, estimates of the
selective effects of the association between ABO and duodenal ulcer, sorne of
the treatment of the effects of selection on quantitative characters, and sorne
of the results on molecular evolution.
For those readers with a more extensive knowledge of mathematics, we have
included, in worked examples at the end of the chapters, more extensive
mathematical treatment of sorne of the problems. We have also felt it
appropriate to include an introductory first chapter that summarizes basic
concepts of genetics in a form that is meant to be little more than an
annotated glossary of terms and concepts most important for an
understanding of human population genetics. In the same vein we have
included in an appendix a brief summary of sorne basic concepts of statistics;
this also should be considered as little more than an annotated list of
definitions and formulas.
We have not attempted to be comprehensive in our review of genetic
differences, though we have tried to present at least a brief description of
ali those which we use for the sake of illustration. The most important source
of information on genetic differences in humans is the catalogue
published by V. A. McKusick, Mendelian Inheritance in Man. We have
provided at the end of individual chapters bibliographies of general
references relevant to the chapters and have collected ali the references cited
together at the end of the book.
Many of our colleagues were helpful to us in the course of writing this book.
In particular, we would like to express our gratitude to E. Anderson, M.
Feldman, D. Kennedy, l. Gottesman, l. M. Lerner (deceased), R. Lewontin, and
C. Stem for making many constructive comments and criticisms on the
typescript. Margaret Muller transformed our crude sketches into clear and
attractive illustrations, the late Jackie Dale typed what turned out to be a very
long manuscript, while Judy Kidd helped with the proofs and index, and our
wives were patient throughout our ordeal.
This book had its origin in courses given mostly at Stanford by the two authors.
The manuscript was finished in the summer of 1969, and few additions or
modifications were made after that date.

Introduction

Severa! advances have been made in human population genetics since our
book was completed in 1969. though most of the fundamentals of the
subject as we presented it then have not changed. Here we shall highlight
briefly sorne of the majo relevant developments and give appropriate
references so readers can pursue these topics further.
At the time our book was first published there were major developments
in
techniques for distinguishing different chromosomes by patterns of
banding; these have revolutionized human chromosome studies. Each
chromosome has its own highly characteristic banding pattern and can
be easily distinguished from ali the others. Furthermore. the banding
patterns are sufficiently detailed that translocations, invcrsions. and
deletions frequently can be defined precisely with respect to their position
on the chromosome in relation to these banding pauerns. Two major
techniques are used: First, Caspersson and colleagues developed techniques
dependent on fluorescent intensity staining differences ; second, a number of
laboratories throughout the world simultaneously developed techniques for
simple staining with Giemsa under mild conditions of incubation. As a
result of these developments. there has been much more research on the
incidence and effects of a large variety of human chromosome changes and
even documentation of polymorphisms for small inversions around the
centromere. For an elementary account of these developments, see
Genetics. Evolution and Man by Bodmer and Cavalli-Sforza, 1976, especially
Chapters 4 and 8; whereas detailed original reports can be found in journals,
such as Cell and Cytogenetic, and also in Population Cytogenetic: Studies in
Humans, edited by E. B. Hook and l. H. Porter (Academic Press, New York,
1977).
Another major advance in human genetics has been the development of
somatic cell genetics through cell fusion techniques; this advance has
extraordinarily in- creased our knowledge of the human gene linkage map.
Well over a hundred genes are now mapped, many of them down to the
level of specific chromosome bands, and all chromosomes have at least one
gene assigned to them. An elementary account of these developments can
be found in Chapter 5 of Genetics, Evolution and Man, while up-to-date
accounts are published periodically in Proceedings of the Human Gene
Linkage Workshops of which Volume 3 was published in l 977, edited by
McKusick et al. Birth Defects Original Article Series, the National Foundation,
Vol. XII, No. 7, 1976. Enzyme polymorphisms have been detected and, of
course, associated studies of heterozygosity levels have advanced. A new
edition of the book Human Biochemical Genetics by H. Harris was published
in 1975 by North-Holland, and is a valuable general reference.
We have furthered our understanding of the HLA system. There are now three
loci-HLA-A, B, and C-with approximately twenty alleles at the HLA-A and B
loci, and seven at the HLA-C locus, each determining serological
specificities detected on most tissues. In addition, there is a fourth locus,
HLA-D, first deter- mined by mixed lymphocyte culture reactions and
recently correlated with serological determinants identified specifically on B
lymphocytes. Three international histocompatibility workshops have been

given since the publication of our book, namely, Histocompatibility Testing

1972, edited by Dausset and Colombani; Histocompatibility Testing 1975,
edited by Kissmeyer-Nielsen; and Histocompatibility 1977, edited by W. F.
Bodmer et al. (all published by Munksgaard, Copen- hagen). These
workshops describe in detail further advances in the HLA field: In 1972
they gave the world-wide distributions of HLA gene frequencies; in 1975 they
established the HLA-C locus and, by mixed lymphocyte culture typing, the
HLA-D locus; and in 1977 they defined clearly the serological specificities
associated with the HLA-D locus and made major associations of HLA with
disease.
The relationship of HLA with disease has been a rapidly expanding field
of research and is well reviewed in the book HLA and Disease, edited by
Dausset and Svejgaard, published in 1977 by Munksgaard, Copenhagen. Now
many diseases, especially some of the autoimmune and chronic diseases,
including rheumatoid arthritis, show striking HLA associations. In some
instances we can probably explain these by the presence of immune
response genes in the HLA region and linkage disequilibrium between
them and the genes controlling the detected antigens. Linkage
disequilibrium is now clearly a key phenomenon for the HLA system and
helps explain many HLA and disease associations. Persistence of linkage
disequilibrium can be surmised for some combinations of alleles of the HLA
region loci and provides suggestive evidence for the action of natural selection
on this system. The chemistry of the gene products is well developed, and it
is clear that those of the HLA-A, B, and C loci are closely homologous and
probably represent the products of duplicate genes, whereas the product of
the HLA-D locus is quite different. In addition, now we know that three
components of the complement system are coded by genes in the HLA
region.
Very recently our understanding of gene organization at the molecular level
has expanded through the application of the now famous recombinant
DNA technique. Many surprises are in store, including even genes that
overlap or their protein products that are made from noncontiguous DNA
segments, perhaps in different combinations. The clustering of duplicated
genes with perhaps quite complex patterns of control of expression may
represent a major feature of the genetic organization of higher organisms.
The estimation of fitness in populations with overlapping generations has been
the subject of extensive research by Charlesworth (Theoretical Population
Biology, 1 :352-70, 1970; 3:377-95, 1972; and 6:108-33, 1974). To B. and D.
Charles- worth we also owe the English translation, with some additions (in
particular on demographic aspects) of the excellent book by A. Jacquard, The
Genetic Structure of Populations (Springer-Verlag, Berlin, Heidelberg, and New
York, 1974). After an introduction to the standard statistical properties of
Mendelian populations, this book gives the theory of the genetic
relationships between individuals of a population, following closely the elegant
approaches started by G. Malecot and further developed by French scholars.
There follows an exposition of the theories of mutation and selection and a
chapter on migration (by D. Courgeau). Also included is an analysis of
genetic distances and an exposition of principal components analysis. The

book is almost entirely theoretical but <loes contain a few examples and a
chapter at the end on selected human applications.
Considerable discussion of quantitative inheritance and continuous variation
has been stimulated mostly by the problems of individual, race, and social
class differences in IQ. Interpretations of existing data have ranged widely. L. J.
Kamin, in The Science and Politics of IQ (Erlsbaum, Hillsdale, N .J., 1977), has
challenged the contention that the available data prove the existence of a
genetic component of IQ. Among the several inconsistencies and flaws in
the data analyzed by Kamin were those concerning the contributions of
the late Sir Cyril Burt. Later developments of this story have made
headlines in the newspapers. At the opposite end of the spectrum, A. R.
Jensen (Genetics and Education, Methuen, London, 1972; and Educability
and Group Differences, Harper & Row, New York,
1973) has maintained a staunch hereditarian position. In spite of minor flaws
in the analysis, C. Jencks et al. tine quality, Basic Books, New York, 1972;
gave what is perhaps the most balanced account of the inheritance of IQ.
(See also Race Differences in Intelligence, Loehlin, Lindzey and Spuhler, W.
H. Freeman, San Francisco, 1975). Jencks and coworkers used path
coefficients, a method developed by S. Wright in the l 920s; it became
popular in sociology and econometrics but had few applications in genetics.
D. C. Rao and colleagues have also applied path analysis extensively to data
on IQ and other continuous variates (American Journal of Human Genetics,
26:331-59, 1974; 26:767-72, 1974;
27:509-20, 1975; 28:228-42, 1976; Behaviour Genetics, 7:147-59, 1977).
Different fitting techniques and slightly different models have been used by L.
J. Eaves and others (for a summary see J. Royal, Stat. Soc. Series, A General,
140 :324-55,
1977).
lt would be impossible to review here these and many other contributions from
other sources. In general the heterogeneity of the available data and the
assumptions implicit in the models used for fitting make the results of the
analyses un- convincing. Among the problems is the complexity of
expectations of cultural transmission, theoretical models and probes for
which were initiated by one of us in collaboration with M. Feldman
(Theoretical Population Biology, 4 :42-55,
1973; 9:238-59, 1976; 11 :161-81, 1977; American Journal of Human
Genetics,
25:618-37, 1973; Annals of Human Biology, 2:215-26, 1975; Proceedings of
the N.A.S., 73:1689-92, 1976; Genetics, 1978, in press). Sorne discussion of
current ideas and controversies can be found in a symposium on genetic
epidemiology held at the University of Hawaii in 1977 (now in press). This
symposium will also contain information on recent developments in the
techniques of segregation analysis and in the now developing art of pedigree
analysis.
One area that was dealt with only briefly in our book has subsequently become
notorious under the name of "sociobiology," and in particular through the book

of that title by E. O. Wilson. In Chapter 10 we discuss natural selection and the

sex ratio, and the evolution of sexual dimorphism, both key topics in
discussions of group and kin selection. We do not, however, discuss the
important work of Hamilton on the theory of kin selection (see especially
Journal of Theoretical Biology, 7:1-52, 1964; Journal of Theoretical Biology,
12:12-45, 1966; Science,
156:477-88, 1967; Nature, 228:1218-20, 1970; also Reviews of Ecology
and
Systematics, 3: 193-232, 1972) and several further developments, including
models for the interaction of biological and cultural evolution (Cavalli-Sforza
and M. Feldman, as mentioned above).
Molecular evolution, human evolution and racial differentiation were the subject of three chapters in our book Genetics, Evolution and Man, which
contains a more up-to-date account of these topics than the present book.
With respect to the study of evolution, one development worth mentioning is
a novel method for the analysis of evolutionary trees (A. Piazza et al., Tissue
Antigens, 5 :445-63,
1975; and L. Cavalli-Sforza and A. Piazza, Theoretical Population Biology,
8:127-65, 1975).
Problems at the interface of genetics and medicine, as well as of genetics and
society, dealt with rather briefly in the last chapter of the present book, were
the focus of two long chapters in Genetics, Evolution and Man.

1
The Basic Concepts of Genetics
Darwin formulated his theory of evolution by natural selection without
knowledge of Mendelian genetics. The most widely held theory of
inheritance in Dar- win 's time was the blending theory, according to which
the heritable potentialities of the parents were simply mixed, or blended, like
liquids in the offspring. Once blended, the parental attributes could never
again be separated. Darwin realized that such a theory would rapidly
eliminate the heritable variation that was an essential ingredient of his
theory, unless there was a very high rate of spontaneous production of new
variability. As a result he sought, unsuccessfully, to find a more suitable theory
of inheritance than the blending theory. He never, apparently, carne in contact
with Mendel's great work. Had he been aware of it and recognized its
importance, he right have changed, even further, the course of modern
biology.
Those scientists who rediscovered Mendelism at the turn of the century did
not at first realize that it was entirely compatible with Darwin's theory of
evolution by natural selection. It remained for R. A. Fisher, J. B. S. Haldane,
and Sewall Wright to show how many of the phenomena of evolution could
be readily explained in terms of Mendelian inheritance. An understanding of

the theory of inheritance is a prerequisite for the study of population genetics,

and thus for the study of the genetics of human populations.
2

The Basic Concepts o/ Genetics

Almost all our readers will have had, at one time or another, some instruction
in Mendelism and the concepts of modern biology; some may welcome a
review of these fundamental subjects. Knowledge of the concepts of
molecular biology has developed over the last 10-20 years, and only recently
have they been introduced into high school and college courses.
Appreciation of these concepts can help greatly in understanding basic
genetics. The following short introduction to basic genetics with reference to
molecular biology is intended to serve as a refresher and also as a compact
guide or annotated glossary to the genetics needed for the study of the
human population genetics.

The real subject of this book starts in the second chapter, to which readers
not wishinq to review the general concepts of genetics can proceed directly,
1.1

Cells, DNA, and Protein

THE NUMBER AND VARIETY OF CELLS THAT FORM ONE HUMAN INDIVIDUAL
A man can, theoretically, be resolved into his constituent cells which
number about 1014 (one hundred thousand billion) in an adult individual.
Many of these cells can be cultured in vitro. All of them have a number of
common features. They all have an outer envelope whose contents, the
cytoplasm, include various organelles, which are common to most cell types.
Every cell potentially able to reproduce has a nucleus, that is, a spherical body
usually centrally located with a membrane around it, containing the material
chemically known as deoxyribonucleic acid (DNA) organized in bodies
known as the chromosomes. In other respects, the shape, size, internal!
structure, composition, and function of various cell types may differ
greatly. Almost all cells are highly differentiated and have specific
functions. In spite of their differences, almost all cells of an organism contain
the same amount and type of DNA.
STRUCTURE AND FUNCTION OF DNA
lt is known from experiments in microorganisms, the essentials of which have
a/so been shown to be true for higher organisms, that DNA contains the
information needed to make new cells essential/y identical to their parents.
DNA also contains the information for producing the various specific types of
cells and for making sure the right ones are available at the right time. Thus
every cell contains all of the same information but uses only a fraction of it to
develop its specific activities.
1.1 Ceils, DNA, and Protein

The amount of DNA per human cell is of the order of 6 x 10-12 grams. This is
a very small quantity, but the information contained is nevertheless enormous
and sufficient for the purpose of directing the synthesis of a human
individual. DNA molecules constitute one class of large molecules, A molecule
of DNA is usually a very long double strand. Each strand is made of a series
of elements attached one to the other in a linear sequence. These elements
are called nucleotides, of which there are four types. They are distinguished
by the presence of the substances adenine (whose symbol is A), guanine (G),
thymine (T), and cytosine (C). The two strands carry substantially the same
information in complementary forms and are strictly paired along their length.
Structural reasons restrict which nucleotides can be opposite each other in the
complementary strands. The rules of complementarity are that if in one strand
there is an A at a given position, in the other strand there can only be a T at
that position, and vice versa; and that if in one strand there is G at a given
position, there can only be C in the other, and vice versa. These rules make
the total quantity of G equal to that of C, and that of A equal to that of T. The
nucleotide pairs AT, TA, GC, and CG are generally the only allowable
combinations in double-stranded DNA. We may consider, as an example,

a sample of a strand of DNA

containingjust nine nucleotides: ATTAGACAA
its complementary strand: TAATCTGTT
the double strand formed by their pairing: ATTA G A CA A

1 1 1 1 1 1 1 1 1
TAATCTGTT

Though DNA is almost always in the double-stranded form, it sometimes

occurs as a single strand. The double-stranded form has different physical
properties from those of unpaired single strands. A double strand is extremely
thin, having a diameter of 2 millimicrons (2 x 10-9 meters or 2 nanometers)
and can be almost endlessly long. A nucleotide pair occupies 0.34
millimicrons of the length of a double strand. The DNA in a single human
cell comprises some six billion nucleotide pairs. lt is present mainly in the
chromosomes. We know little about the fine structure of a human
chromosome but it is possible that its DNA is simply a very long unbroken
thread. For the longest chromosome, this thread completely un- coiled would
be 6 centimeters long, that is about 500,000 times the average diameter of a
cell. A nucleus that contains ali the 46 chromosomes present in each human
cell, is only about ten-thousandths of a millimeter in diameter and therefore it
is clear that DNA, in spite of a certain rigidity due to its double strandedness,
must usually be folded many, many times within the chromosomes.
4

The Basic Concepts of Genetics

PROTE!NS, THEIR STRUCTURE A D FUNCTION

The cytoplasm and the nucleus contain other important chemical constituents,
many of which belong to another class of large molecules, the proteins.

Proteins are made of folded filaments called polypeptides. Sorne protein

molecules consist of a single filament, others are made of two or more
identical or different ones. Sorne proteins also have other substances
associated with them. A polypeptide is a linear series of equally spaced
elements called amino acids. There are twenty main types of amino acids,
whose individual names are given at the bottom of Table 1.1. Each amino
acid is made of one short common element that has one end with acidic
properties, and another with alkaline properties. In addition, the element has a
differentiating side group. Amino acids attach to one another to form polypeptide chains, an acidic end uniting with the alkaline end of another amino
acid, and so on.
Polypeptides found in the human body can be formed by as few as a dozen
oras
many as a few hundred amino acids. The number, types, and sequences
of the amino acids in a polypeptide chain determine its properties. A
polypeptide tends to assume a given shape by folding in a threedimensional way determined by the physicochemical properties of its
constituent amino acids. The shapes of protein molecules differ widely. The
number of different protein molecules in existence is enormous, probably in
the hundreds of thousands for an organism like man. Sorne are very abundant
in certain tissues. Thus, for example, there is about one kilogram of the
protein hemoglobin in the blood, and several! kilograms of the muscle protein
actomyosin in the adult human body. One kilogram of hemoglobin is
roughly ten billion billion molecules. At the other extreme, some proteins
(for example regulatory proteins) are represented by a few molecules found
in relatively few cells of the body.

As a consequence of their different physicochemical properties and shape,

every protein has a different function, Perhaps the most common-type of
protein activity is that of an enzyme.

Enzymes are proteins capable of increasing enormously the rate of, that is
catalyzing, some special reaction. For example, the attachment of
phosphoric acid to glucose, which is the first step in the utilization of this
sugar, can be facilitated by a particular enzyrne, which is called a kinase.
Other enzymes mediate later steps in the utilization of glucose. 1 n general
there is a specific enzyme for each step of each of the many biochemical

processes that go on in the body. The reactions catalyzed by enzymes

might also occur in their absence, but at reaction rates so slow as to be
practically meaningless. Enzymes are thus responsible for the metabolism
of ali small molecules, namely the degradative reactions that free the
chemical energy contained in various compounds and make it available for
other processes, and the synthetic reactions needed to transform molecules
available in the environment into those necessary for growth and
reproduction of cells. There are man y thousands of different enzymes in a
cell, each with some specific metabolic function.

Other protein functions involve transfer or storage of a variety of chemical

sub- stances.

Hemoglobin and myoglobin take up, store, transport, and release oxygen;
ferredoxin has a similar function with iron; haptoglobin binds hemoglobin, and
so on. Sorne proteins have mechanical functions such as the role of collagen
in connective tissue or that of elastin in elastic fibers. Still others have special
protective functions. For example, there is a Large class, probably numbering
at least several thousands, of slightly different proteins, the gamma globulins,
which have the property of binding with specific foreign substances, antigens,
and serve to protect the body against them and to facilitate their capture
and elimination. Antigens can, for instance, be substances present on the
surface of bacteria or other parasites. Gamma globulins thus participate in a
major way in the body's defense against infections.

1.2

The Synthesis of Proteins and the Genetic Code

Proteins cannot reproduce themes/ves. The information .for making a given

protein is coded in a DNA nucleotide sequence.

A given sequence of nucleotides in DNA, starting from a given point, is

converted into a unique corresponding sequence of amino acids according to
rules that are summarized by a simple dictionary called the genetic code
(see Table 1.1). Three adjacent nucleotides in a DNA strand correspond to
one amino acid, which is thus determined by a word of three letters, a triplet,
in the DNA code. These letter triplets are "read" in sequence and converted
by the machinery of protein syn- thesis into the corresponding amino acids.
The letters are the four possible nucleo- tides, A, G, C, and T, corresponding
to adenine, guanine, cytosine, and thymine. There are thus 4 x 4 x 4 = 64
possible different triplets, 61 of which actually deter- mine amino acids. There
are, however, only twenty major amino acids, and it is found

that there are from one to six triplets, coding for each of these. The
remaining three triplets out of the 64 determine termination of the
polypeptide chain.
The genetic code given in Table l.l is that of the bacterium Escherichia coli.
lt
B though there is no
a
b from that
A of man,
probably differs very Iittle,
if at all,
direct evidence for this. We have a unique perspective from which to view the
unity of life when we consider the closeTyr
similarities,
even
identities, of
Cys
b
Phe
Ser
many of the basic
phenomena
common
toend
all living
chain organisms.
end
A
Leu
Ser
chain
a

6
TABLE
b

1.1

Leu

Ser

chain end

Try

Leu
Leu

Pro
Pro

His
Gin

Arg
Arg

Leu

Pro2nd letter Gin

Arg

b
A
B

lle
lle

Thr
Thr

Asn
Lys

Ser
Arg

Met

Thr

Lys

Arg

Val
Val
Val

Ala
Ala
Ala

Asp
Glu
Glu

Gly
Gly
Gly

b
A
B

The Genetic Code

...

..."'

...
]

'.E....

Note: Each amino acid is coded by a triplet ofthree bases, as shown in

the table, which is a compact way of setting out the sixty-four possible
triplets.
The four bases are denoted by the letters a, b, A, and B. In DNA the
four bases are:

a= Adenine
b= Guanine

A= Thymine
B = Cytosine

In messenger-RNA they are:

a= Uracil
b= Cytosine

A= Adenine
B = Guanine

The twenty amino acids are identified as follows:

Ala
Arg
Asn
Asp
Cys
Glu
Gin
Gly
His
lle
Leu

Alanine (A)
Arginine (R)
Asparagine (N)
Aspartic acid (D)
Cysteine (C)
Glutamic acid (E)
G!utamine (Q)
Glycine (G)
Histidine (H)
Isoleucine (1)
Leucine (L)

Lysine (K)
Lys
Methionine (M)
Met
Phe
Phenylalanine (F)
Pro
Proline (P)
Ser
Serine (S)
Thr
Threonine (T)
Try
Tryptophan (W)
Tyr
Tyrosine (Y)
Val
Valine (V)
Chain End.

For example the triplet bAB stands for Gin= Glutamine. This implies
that Guanine-Thyrnine-Cytosine codes for glutamine in DNA and
Cytosine-Adenine-Guanine codes for glutamine in RNA. The letters
in parentheses are a shorthand single-letter code often used for the amino
acids.

Source: Based on Crick, 1966.

1 .2

The Synthesis of Proteins and the Genetic Code

. Protein synthesis has been reproduced in the test tube and been shown to
depend on three kinds of ribonuc/eic acids (RNA).

Ribonucleic acids are similar to DNA. They differ mainly in the sugar
component of the nucleotide, ribose, which is analogous to the deoxyribose in
DNA; in the fact that T (thymine) is replaced by U (uracil), which has the
same pairing properties (U pairs with A); and in that they may occur as
relatively short single strands. There are three forms of RNA.

Messenger RNA (m-RNA). DNA does not act directly, but through an
intermediary form of ribonucleic acid called messenger RNA. Messenger RNA is
formed by the action of an enzyme, RNA polyrnerase, which copies the
sequence from one strand of DNA and forms an RNA strand of the
complementary sequence. Only one of the two DNA strands is generally
active as a "template" for m-RNA synthesis, the other DNA strand remaining
uncopied. The m-RNA sequence is identical to that in the uncopied strand of
DNA except that T is replaced by U. Messenger RNA remains single stranded.
One molecule or strand can generally be used for the manufacture of a large
number of protein molecules, each with the amino acid sequence
corresponding to the m-RNA 's nucleotide sequence. The number of
nucleotides in an m-RNA strand is three times the number of amino acids in
the polypeptide chain copied from it plus three nucleotides to indicate the

termination of the chain, and possibly, another triplet for its initiation. The
mechanism for chain initiation is still not entirely clear.

Transfer RNA (t-RNA).

Before amino acids are joined to forma polypeptide
chain, they must be " activated" by the attachment of a special phosphoric
acid group. They are then attached to another type of RNA called transfer RNA.
There are as many varieties of t-RNA molecules as there are triplets that can
determine amino acids in the code. The attachment of an amino acid to
its corresponding t-RNA is directed by a specific enzyme. The t-RNA carries at
one end the activated amino acid and ata special position has a triplet of
nucleotides complementary to the triplet code for its amino acid. This latter
triplet, which is part of the m-RNA, is often called a codon and that on the tRNA the anticodon. The principle of pairing complementarity is used for the
recognition by the t-RNA of its appropriate triplet on the m-RNA.

Ribosomal RNA (r-RNA). Alignment of the t-RNA and the m-RNA and the
progression of polypeptide synthesis along the m-RNA, which is "read" from
beginning to end, is mediated by special particles, the ribosomes. These are
present in the cell in large numbers. A ribosome is made from a third form of
ribonucleic acid called ribosomal RNA (whose structure is not yet well
determined) together with a large number of protein molecules, twenty or
more, whose detailed function is also not yet clear.

The Basic Concepts of Genetics

Figure l.! gives a schematic representation of the whole process of protein

syn- thesis. The amounts of ali the basic materials, including enzymes, that
are needed for the process are carefully controlled by the cell in relation to
its environment.
The first step of protein synthesis, the transfer of information from DNA to mRNA through the synthesis of m-RNA on the DNA template, is called
transcription; the second step, the synthesis of proteins from m-RNA, is
called translation.

FIGURE 1.1

The pe cha in bcmg syruhesized

A scheme of protein synthesis.

Sorne mechanisms of regulation of protein synthesis act during transcription.

Regulation of protein synthesis allows for adaptation to the living

environment. Only when a certain substance, for example, a sugar, is present
in the environment is it worthwhile for a cell to develop the enzymes needed
to utilize the substance (enzyme induction). At other times, when a certain end
product of a reaction chain, necessary for growth (for example, sorne amino
acid), is present in the environment, cells can cease making it and the
enzymes necessary for its synthesis (enzyme repression). Mechanisms have
so developed that most proteins are made only when

1.2

The Synthesis o/ Proteins and the Genetic Code

they are useful. Some such mechanisms have been shown to operate in
microrganisms during transcription, that is, by stopping the production of the
specific m-RNA when the proteins coded by it are not needed. The information
about the presence or absence of the chemical substances in the environment
is conveyed to the DNA by other specific "regulatory" proteins coded for by
other DNA segments, as is shown diagrammatically in Figure 1.2.

FIGURE 1.2
Enzyme induction, a phenomenon investigated in bacteria, may help the
understanding of the regulation of protein synthesis in higher organisms,
which is largely unknown. A: The substance i, utilized in the reaction chain
promoted by enzymes e1, e2, e3 is absent. The regulatory protein r
produced by the regulator gene R, in that absence of i,
combines with an end (O) of the DNA region that produces enzymes e1. e2,
e3 and inhibits formation of the m-RNA required for their synthesis.

Therefore genes E,, E2, E3 making these enzyrnes are inactivc and the
enzymes are not formed. B: Substance i is present and combines specially
with r, which is now unable to combine with the region O. Messenger RNA
from E,, E2, E3, and the corresponding enzymes
e., e2. e3 are produced.

Other mechanisms of regulation have been described. Those of the cells of

higher organisms are largely unknown, but are believed to be similar in some
respects to those operating in microorganisms. Undoubtedly, the regulation of
protein synthesis must be at the basis of differentiation, which is the
development of different
1O

The Basic Concepts o/ Genetics

cells and tissues. Evidence from various sources shows that various proteins
are formed, and correspondingly, that various portions of the DNA are
active in different tissues and cells at different times during development.

1.3

Duplication of DNA and Cell Reproduction

DNA has a central role in the life process in both supplying the information for
the synthesis of proteins and the basis for duplicating this information.

In the presence of nucleotide precursors and an enzyme, DNA-polymerase,

an identical copy of the DNA molecule can be formed by the production of
strands complementary to those in the original" template" DNA. If the process
takes place in the presence of just one strand, then only the complementary
strand is produced. When, however, a double strand is copied, two double
strands are formed, as out-lined below.
The nucleotides used for synthesis and the newly synthesized strands are
marked with asterisks. lt is clear that the two new double strands are each
formed of one old strand and one completely new complementary strand.
Two new cells can thus be formed from an old one, and each will have exactly
the same information for building the basic cellular materials.

It is clearly essential that each daughter cell receives a complete complement

of DNA. This is assured in higher organisms, such as man, by a mechanism
called mitosis.

The DNA is contained in the nucleus of a cell in parcels consisting of long

filaments wrapped in a protein matrix. The parcels are called chromosomes
and a human cell has 46.

In a cell that is not actively reproducing, the chromosomes are probably

uncoiled and indistinguishable under a light microscope. When a cell is
preparing for reproduction, the chromosomes undergo coiling and structural
reorganization, as a con- sequence of which each becomes much shorter and
thicker. lt is then visible under the light microscope. The name
chromosome, meaning "colored body," comes from its staining properties.
Each human chromosome has a characteristic shape and size, generally
similar in every cell and individual, although it is not always possible to
distinguish, morphologically, each of the chromosomes in a given cell.

Mitosis, the process of cell reproduction, assures an equal distribution of

chromosomes to each daughter cell.

In the preparation for cell division, each individual chromosome has its DNA
split internally into two separable threads called chromatids, each presumably
constituted from one of the two new DNA double strands. The division is,
however, not initially apparent and a human cell starting mitosis still has just
46 visible chromosomes. Then follows a complex process of preparation within
the cell for the precise division of each chromosome into two equal parts. Each
daughter cell must receive one copy of each chromosome, and thus a
complete set of the 46 chromosomes. A specific part of the chromosome that
contains visibly less DNA, the centromere, is attached to the double thread of
DNA contained in each chromo- some at this stage. The centromere splits in
two with each of the resulting new centromeres attached to a different one of
the two chromatids.

Prophase: the cell al the beginning of mitosis. The chromosomes are

represented as oval structures with the centromeres indicated as dots. The
DNA in the chromosome occupies half of the total volume and is highly folded.
lt
duplicates before mitosis. The chromosomes can only be visualized
individually during mitosis, when they are highly contracted.

Metaphase: the new cell poles are shown on the left and on the right. The
nuclear membrane has dissolved; the centromeres, attached to the equator of
the spindle defining the major axis of cell division, have not divided, but the
rest of each chromosome has.

Anaphase: migration toward the poles. Each half has followed the
centromeres. which are migrating to the opposite poles.

Telophase: separation. Two new cells identical to the original one have been
formed.

FIGURE 1.3
Mitosis in a cell of a hypothetical organism that has one pair of identical
chromosomes and one pair whose members are different.
12

The Basic Concepts o/ Genetics

At this stage a spindle has formed in the cytoplasm that extends along the
major axis of division and defines the two poles of the cell. The nuclear
membrane has disappeared so that the chromosomes can move freely through
the cytoplasm. They attach by their centromere to the central or equatorial
region of the spindle. Each chromosome is separated visibly into two moieties.

One of the two centromeres of each dividing chromosome moves to one pole
and the other to the other pole. This assures that the daughter chromosomes
separate in a balanced way to form the two daughter cells (Figure 1.3).

The chromosome set is double in diploid organisms.

Man's 46 chromosomes are made up of 22 pairs, each of which comprises two

members that are alike and an additional pair, the sex chromosomes, whose
members are alike in females but quite dissimilar in males. This scheme is the
consequence of sexual reproduction, which depends on the fusion of two
cells, the gametes (a male gamete, or sperm, and a female gamete, or egg),
to form a new individual. Each gamete carries 23 chromosomes, one member
of each pair. When
the two gametes unite by the process known as fertilization (Figure 1.4), the
nucleus

of the sperm and that of the egg fuse to form a single nucleus that has 46
chromosomes. The new cell is called a zygote, and its multiplication gives rise
to all the cells of the new organism. An organism whose cells contain pairs
of chromosomes formed in this way is called diploid. Gametes are haploid:
that is, they have one set of chromosomes instead of two.
Both a man and a woman have 46 paired chromosomes (see Figure 1.5), with
one pair in the female being different from the corresponding pair in the male,
as aired y mentioned. Ali the other 22 pairs are made of two members that
are like each other in shape and size. There are, however, practical! limitations
to recognition of chromosomes dueto the fact that, at least in man, some pairs
are so similar to others that it is usually impossible to tell them apart. In
practice, one can easily

The Basic Concepts of Genetics

recognize in man the seven groups indicated in the figure by letters A-G,
using the relative position of the centro mere and possible other peculiarities
as distinguishing features. The pair that differs between males and females

is responsible for the sex of the individual, and the members of this pair
are called the sex chromosomes The sex chromosomes present in the
female, conventionally called X chrornosomes, are intermediate in size among
the human chrornosomes, while in the male there is one X and one
differentiated sex chromosome responsible for maleness, the Y
chromosome, which is one of the smallest of the human set. Chromosome
arrange- ments, such as those shown in Figure 1.5, are called karyotypes.

1.4

The Formation of Gametes: Meiosis, or Reduction

The human zygote and almost all the cells of an adult that are derived from it
have 46 chromosomes. There must, therefore, be a process that reduces
their number to 23 during gamete formation in order that the union of two
gametes will produce a new individual with 46 chromosomes. This special
process, called reduction, or meiosis, is a successive pair of modified mitoses.
lt assures the formation of gametes each of which contains one member only
of each pair of chromosomes. One chromosome from each pair must be
included in each garnet because each pair of chromosomes has a unique
DNA sequence and those special set of functions. The complete set of
instructions is necessary for the formation of new cells and organisms that
are like their precursors.
The meiosis represented in Figure 1.6 is that of the same hypothetical
organism used in Figure 1.3; the organism has one pair whose members are
identical and one whose members are different, which could be the sex
chromosomes. At the begin- ning of the first meiotic division, DNA double
strands divide, but centromeres do not. This is followed by separation of the
members of each homologous pair. The phenomenon that assures an equal
distribution of the members of each pair, one to each daughter cell is
pairing between homologues. Pairing serves as a guide for the centromere of
one member of the pair to move to one pole, and that of the other
member to the other pole. lt is presumably based on similarity or identity in
nucleotide sequence. J n pairs whose members are not identical, such as the X
and Y at least a part of the two chromosomes must be similar, or homologous,
enough to assure pairing.
Jf pairing did not take place, the regular distribution to the two poles, and
hence
to the daughter cells would not be assured. The two members of one pair
might migrate to the same pole, giving rise to unbalanced gametes, one of
which would contain both members of the pair, and the other none. This

event, called nondisjunction, happens very rarely. It tends to happen more

often for the sex chromosomes probably because of their more limited
pairing capacity and also because of the small size of the Y chromosome.