Gregor Mendel and The Laws of Inheritance (Mendel’s Discoveries &

Principles of Heredity, The Mendelian View of the World)

Source :
[1] Emery’s Elements of Medical Genetics 16th edition
[2] Genetics : From Genes to Genomes 2021
[3] Molecular Biology of the Gene 7th Edition

I. The Puzzle of Inheritance

Gregor Mendel was the first person to combine data collection, analysis, and theory in a successful
pursuit of the true basis of heredity. For many thousands of years before that, the only genetic practice was the
selective breeding of domesticated plants and animals with desirable characteristics. This process, called
artificial selection, was of immense importance to human history. For example, by choosing plants that grew
better or were easier to cultivate as parents for the next generation, people gradually converted weedlike species
into rice, wheat, corn, and tomatoes. Similar breeding schemes developed valuable herds of sheep, pigs, and
cattle, as well as hundreds of breeds of dogs.[2]
Despite its many achievements, artificial selection was limited by its hit-or-miss nature: Parents chosen
for their desired characteristics did not always produce offspring whose qualities were more, or even equally,
favorable to those of their parents. This unpredictability was not surprising, because prior to Mendel, many
misconceptions clouded people’s thinking about heredity.[2]
Gregor Mendel’s experiments traced the results of breeding experiments (genetic crosses) between
strains of peas differing in well-defined characteristics, like seed shape (round or wrinkled), seed color (yellow
or green), pod shape (inflated or wrinkled), and stem length (long or short). His concentration on well-defined
differences was of great importance; many breeders had previously tried to follow the inheritance of more gross
qualities, like body weight, and were unable to discover any simple rules about their transmission from parents
to offspring (see Box 1-1, Mendelian Laws).[3]

A. Mendel Devised a New Experimental Approach

Two errors in interpreting the results of selective breeding were particularly misleading. The first was
the idea that one parent contributes most to an offspring’s inherited features. Nicolaas Hartsoeker, one of the
earliest microscopists, contended in 1694 that it was the male, by way of a fully formed homunculus inside
the sperm (Fig. 1.3). Another deceptive notion was the concept of blended inheritance, the idea that parental
traits become mixed and forever changed in the offspring, as when blue and yellow pigments merge to green
on a painter’s palette. The theory of blending may have grown out of a natural tendency for parents to see a
combination of their own traits in their offspring. While blending could account for children who look like a
combination of their parents, it could not explain obvious differences between biological brothers and sisters
nor the persistence of variation within extended families.[2]

In his breeding experiments, Mendel studied contrasting characters in the garden pea, using for each
experiment varieties that differed in only one characteristic.[1] What did Mendel do differently from those
who preceded him? First, he chose the garden pea (Pisum sativum) as his experimental organism (Fig. 1.4a
and b). Each pea flower has both male and female organs, which made it easy to self-fertilize or cross-
fertilize plants. In self-fertilization (or selfing), both egg and pollen come from the same plant, often from
the same flower. Peas normally self-fertilize because of the proximity of egg and pollen. To cross-fertilize
(cross) two plants, Mendel removed the male sex organs from the flowers of one plant (to prevent selfing),
and then he brushed pollen from the other plant onto the female organs of the first plant (Fig. 1.4c). Peas
offered yet another advantage. For each successive generation, Mendel could obtain large numbers of
individuals within a relatively short growing season.[2]

Second, Mendel examined the inheritance of clear-cut alternative states of particular traits—purple
versus white flower color, yellow versus green pea color. He could trace unambiguously the transmission of
such either-or traits, because no intermediate forms existed. (The opposite of these so-called discrete traits
are continuous traits, such as height and skin color in humans. Continuous traits show many intermediate
forms.)[2]
 Third, Mendel collected and perpetuated lines of peas that bred true. Matings within such pure-
breeding (or true-breeding) lines produce offspring carrying specific parental characteristics that remain
constant from generation to generation. These lines are also called inbred because they have been mated
only to each other for many generations. Plants with white flowers always produced offspring with white
flowers; plants with purple flowers produced only offspring with purple flowers. Mendel called constant but
mutually exclusive alternatives, such as purple versus white flowers or yellow versus green seeds
antagonistic pairs, and he settled on seven such pairs for his study (Fig. 1.5). In his experiments, Mendel
cross-fertilized pairs of plants to produce hybrids, offspring of genetically dissimilar parents, for each
antagonistic pair. Figure 1.5 shows the appearance of the hybrids he studied.[2]
 Fourth, Mendel made reciprocal crosses, in which he reversed the characteristics of the male and
female parents, thus controlling whether a particular characteristic was transmitted via the egg cell within the
ovule or via a sperm cell within the pollen. For example, he could use pollen from a purple flower to fertilize
the eggs of a white flower and also use pollen from a white flower to fertilize the eggs of a purple flower.
Because the progeny of these reciprocal crosses were similar, Mendel demonstrated that the two parents
contribute equally to inheritance.[2]
Fifth, Mendel worked with large numbers of plants, counted all offspring, subjected his findings to
numerical analysis, and then compared his results with predictions based on his models. He was the first
person to study inheritance in this quantitative manner. Mendel’s careful numerical analysis revealed
patterns of transmission that reflected basic laws of heredity.[2]
Finally, Mendel was a brilliant practical experimentalist. When comparing tall and short plants, for
example, he made sure that the short ones were out of the shade of the tall ones so their growth would not be
stunted. In short, Mendel purposely set up a simplified black-and-white experimental system and then
figured out how it worked. He looked at discrete traits that came in two mutually exclusive forms and asked
questions that could be answered by observation and computation.[2]

II. Mendels’ Discoveries : Genetic Analysis According to Mendel

In 1866, Gregor Mendel published in an obscure journal a paper titled “Experiments on Plant
Hybrids.” In it, Mendel describes the transmission of visible characteristics in pea plants, defines unseen
but logically deduced units (genes) that determine when and how often these traits appear, and analyzes
the behavior of genes in simple mathematical terms to reveal previously unsuspected principles of
heredity. The paper would eventually become the cornerstone of modern genetics.[2]
A. Monohybrid Crosses Reveal the Law of Segregation
For example, he noted that when strains bred for a feature such as tallness were crossed with plants
bred to be short, all of the offspring in the first filial, or F1, generation were tall. If plants in this F1
generation were interbred, this led to both tall and short plants in a ratio of 3:1 ( Fig. 1.2). Characteristics that
were manifest in the F1 hybrids were referred to as dominant, whereas those that reappeared in the F2
generation were described as being recessive. On reanalysis it has been suggested that Mendel’s results were
“too good to be true” in that the segregation ratios he derived were suspiciously closer to the value of 3:1
than the laws of statistics would predict. One possible explanation is that he may have published only those
results that best agreed with his preconceived single-gene hypothesis. Whatever the case, events have shown
that Mendel’s interpretation of his results was entirely correct.[1]
 Mendel’s proposal was that the plant characteristics being studied were each controlled by a pair of
factors, one of which was inherited from each parent. The pure-bred plants with two identical genes used in the
initial cross would now be referred to as homozygous. The hybrid F1 plants, each of which has one gene for
tallness and one for shortness, would be referred to as heterozygous. The genes responsible for these
contrasting characteristics are referred to as allelomorphs, or alleles for short.[1]
An alternative method for determining genotypes in offspring involves the construction of what is
known as a Punnett square (Fig. 1.3). This is used further in Chapter 7 (Fig. 7.1) when considering how genes
segregate in large populations, although in reality is seldom referred to nowadays.[1]
 On the basis of Mendel’s plant experiments, three main principles were established, known as the laws
of uniformity, segregation, and independent assortment.[1]

Once Mendel had isolated pure-breeding lines for several sets of characteristics, he carried out a series
of matings between individuals that differed in only one trait, such as seed color or stem length. In each cross,
one parent has one form of the trait, and the other parent has the antagonistic characteristic. Figure 1.6
illustrates one such mating. Mendel planted pure-breeding green peas and purebreeding yellow peas and allowed
them to grow into the parental (P) generation. When the plants had flowered, he brushed the stigma of green-
pea plant flowers with pollen from yellow-pea plants. He also performed the reciprocal cross, dusting yellow-
pea plant stigmas with green-pea pollen. He found that in both cases, the peas produced were all yellow.[2]
These yellow peas, progeny of the P generation, were the first filial (F1) generation. To learn whether
the green characteristic had disappeared entirely or remained intact but hidden in these F1 yellow peas, Mendel
planted them to obtain mature F1 plants that he allowed to self-fertilize. Such experiments involving hybrids for
a single trait are called monohybrid crosses. He then harvested and counted the peas of the resulting second
filial (F2) generation, progeny of the F1 generation. The progeny of one series of F1 self-fertilizations were
6022 yellow and 2001 green F2 peas, an almost perfect ratio of 3 yellow : 1 green. F1 plants derived from the
reciprocal of the original cross produced a similar 3:1 ratio of yellow to green F2 progeny.[2]

The Law of Uniformity

The law of uniformity refers to the fact that, when two homozygotes with different alleles are crossed,
all of the offspring in the F1 generation are identical and heterozygous. In other words, the characteristics do not
blend, as had been believed previously, and can reappear in later generations.[1]

The Law of Segregation

 The law of segregation refers to the observation that each person possesses two genes for a particular
characteristic, only one of which can be transmitted at any one time. Rare exceptions to this rule can occur when
two allelic genes fail to separate because of chromosome nondisjunction at the first meiotic division (p. 32).[1]

The Principle of Independent Segregation

After ascertaining that each type of parental strain bred true—that is, produced progeny with particular
qualities identical to those of the parents— Mendel performed a number of crosses between parents (P) differing
in single characteristics (such as seed shape or seed color). All the progeny (F 1 ¼ first filial generation) had the
appearance of one parent only. For example, in a cross between peas having yellow seeds and peas having green
seeds, all the progeny had yellow seeds. The trait that appears in the F 1 progeny is called dominant, whereas the
trait that does not appear in Fl is called recessive.[3]
The meaning of these results became clear when Mendel set up genetic crosses between F 1 offspring.
These crosses gave the important result that the recessive trait reappeared in approximately 25% of the F 2
progeny, whereas the dominant trait appeared in 75% of these offspring. For each of the seven traits he
followed, the ratio in F2 of dominant to recessive traits was always approximately 3:1. When these experiments
were carried to a third (F3) progeny generation, all the F2 peas with recessive traits bred true (produced progeny
with the recessive traits). Those with dominant traits fell into two groups: one third bred true (produced only
progeny with the dominant trait); the remaining two-thirds again produced mixed progeny in a 3:1 ratio of
dominant to recessive.[3]
Mendel correctly interpreted his results as follows (Fig. 1-1): the various traits are controlled by pairs
of factors (which we now call genes), one factor derived from the male parent, the other from the female. For
example, pure-breeding strains of round peas contain two versions (or alleles) of the roundness gene (RR),
whereas pure-breeding wrinkled strains have two copies of the wrinkledness (rr) allele. The round-strain
gametes each have one gene for roundness (R); the wrinkled-strain gametes each have one gene for
wrinkledness (r). In a cross between RR and rr, fertilization produces an Fl plant with both alleles (Rr). The
seeds look round because R is dominant over r. We refer to the appearance or physical structure of an individual
as its phenotype, and to its genetic composition as its genotype. Individuals with identical phenotypes may
possess different genotypes; thus, to determine the genotype of an organism, it is frequently necessary to
perform genetic crosses for several generations. The term homozygous refers to a gene pair in which both the
maternal and paternal genes are identical (e.g., RR or rr). In contrast, those gene pairs in which paternal and
maternal genes are different (e.g., Rr) are called heterozygous.[3]
One or several letters or symbols may be used to represent a particular gene. The dominant allele of the
gene may be indicated by a capital letter (R), by a superscript þ (rþ), or by a þ standing alone. In our discussions
here, we use the first convention in which the dominant allele is represented by a capital letter and the recessive
allele by the lowercase letter.[3]
It is important to notice that a given gamete contains only one of the two copies (one allele) of the
genes present in the organism it comes from (e.g., either R or r, but never both) and that the two types of
gametes are produced in equal numbers. Thus, there is a 50:50 chance that a given gamete from an F l pea will
contain a particular gene (R or r). This choice is purely random. We do not expect to find exact 3:1 ratios when
we examine a limited number of F 2 progeny. The ratio will sometimes be slightly higher and other times slightly
lower. But as we look at increasingly larger samples, we expect that the ratio of peas with the dominant trait to
peas with the recessive trait will approximate the 3:1 ratio more and more closely.[3]
The reappearance of the recessive characteristic in the F 2 generation indicates that recessive alleles are
neither modified nor lost in the Fl (Rr) generation, but that the dominant and recessive genes are independently
transmitted and so are able to segregate independently during the formation of sex cells. This principle of
independent segregation is frequently referred to as Mendel’s first law.[3]
Some Alleles Are neither Dominant nor Recessive
In the crosses reported by Mendel, one member of each gene pair was clearly dominant to the other.
Such behavior, however, is not universal. Sometimes the heterozygous phenotype is intermediate between the
two homozygous phenotypes. For example, the cross between a pure-breeding red snapdragon (Antirrhinum)
and a pure-breeding white variety gives Fl progeny of the intermediate pink color. If these Fl progeny are crossed
among themselves, the resulting F2 progeny contain red, pink, and white flowers in the proportion of 1:2:1 (Fig.
1-2). Thus, it is possible here to distinguish heterozygotes from homozygotes by their phenotype. We also see
that Mendel’s laws do not depend on whether one allele of a gene pair is dominant over the other.[3]

The Law of Independent Assortment

The law of independent assortment refers to the fact that members of different gene pairs segregate to
offspring independently of one another. In reality, this is not always true. Genes that are close together on the
same chromosome tend to be inherited together because they are “linked” (p. 90). There are a number of other
ways by which the laws of mendelian inheritance are breached (see Chapter 6), but overall, they remain
foundational to our understanding of the science.[1]
Principle of Independent Assortment
Mendel extended his breeding experiments to peas differing by more than one characteristic. As before,
he started with two strains of peas, each of which bred pure when mated with itself. One of the strains had round
yellow seeds; the other, wrinkled green seeds. Since round and yellow are dominant over wrinkled and green,
the entire Fl generation produced round yellow seeds. The Fl generation was then crossed within itself to produce
a number of F2 progeny, which were examined for seed appearance (phenotype). In addition to the two original
phenotypes (round yellow; wrinkled green), two new types (recombinants) emerged: wrinkled yellow and round
green.[3]
Again Mendel found he could interpret the results by the postulate of genes, if he assumed that each
gene pair was independently transmitted to the gamete during sex-cell formation. This interpretation is shown in
Figure 1-3. Any one gamete contains only one type of allele from each gene pair. Thus, the gametes produced
by an Fl (RrYy) will have the composition RY, Ry, rY, or ry, but never Rr, Yy, YY, or RR. Furthermore, in this
example, all four possible gametes are produced with equal frequency. There is no tendency of genes arising
from one parent to stay together. As a result, the F 2 progeny phenotypes appear in the ratio nine round yellow,
three round green, three wrinkled yellow, and one wrinkled green as depicted in the Punnett square, named after
the British mathematician who introduced it (in the lower part of Fig. 1-3). This principle of independent
assortment is frequently called Mendel’s second law.[3]

III. CHROMOSOMAL THEORY OF HEREDITY : The Chromosomal Basis of Inheritance

A principal reason for the original failure to appreciate Mendel’s discovery was the absence of
firm facts about the behavior of chromosomes during meiosis and mitosis. This knowledge was available,
however, when Mendel’s laws were confirmed in 1900 and was seized upon in 1903 by American
biologist Walter S. Sutton. In his classic paper “The Chromosomes in Heredity,” Sutton emphasized the
importance of the fact that the diploid chromosome group consists of two morphologically similar sets
and that, during meiosis, every gamete receives only one chromosome of each homologous pair. He then
used this fact to explain Mendel’s results by assuming that genes are parts of the chromosome. He
postulated that the yellow- and green-seed genes are carried on a certain pair of chromosomes and that
the round- and wrinkled-seed genes are carried on a different pair. This hypothesis immediately explains
 the experimentally observed 9:3:3:1 segregation ratios. Although Sutton’s paper did not prove the
chromosomal theory of heredity, it was immensely important, for it brought together for the first time the
independent disciplines of genetics (the study of breeding experiments) and cytology (the study of cell
structure).[3]
As interest in mendelian inheritance grew, there was much speculation as to how it actually
occurred. At that time it was also known that each cell contains a nucleus within which there are several
threadlike structures known as chromosomes, so called because of their affinity for certain stains
(chroma = color, soma=body). Chromosomes had been observed since the second half of the 19th
century after development of cytologic staining techniques. Human mitotic figures were observed from
the late 1880s, and it was in 1902 that Walter Sutton, an American medical student, and Theodour
Boveri, a German biologist, independently proposed that chromosomes could be the bearers of heredity
(Fig. 1.4). Subsequently, Thomas Hunt Morgan transformed Sutton’s chromosome theory into the theory
of the gene (1917), and Alfons Janssens observed the formation of chiasmata between homologous
chromosomes at meiosis. During the late 1920s and 1930s, Cyril Darlington helped to clarify
chromosome mechanics by the use of tulips collected on expeditions to Persia. It was during the 1920s
that the term genome entered the scientific vocabulary, being the fusion of genom (German for “gene”)
and ome from “chromosome.” [1]

When the connection between mendelian inheritance and chromosomes was first made, the normal
chromosome number in humans was thought to be 48, although various papers had come up with a range of
figures. Key to the number 48 was a paper in 1921 from Theophilus Painter, an American cytologist who had
been a student of Boveri. In fact, Painter had some preparations clearly showing 46 chromosomes, even though
he finally settled on 48. The discrepancies were probably from the poor quality of the material at that time; even
into the early 1950s cytologists were counting 48 chromosomes. It was not until 1956 that the correct number of
46 was established by Tjio and Levan, 3 years after the correct structure of DNA had been proposed. Within a
few years, it was shown that some disorders in humans could be caused by loss or gain of a whole chromosome,
as well as by an abnormality in a single gene. Chromosome disorders are discussed at length in Chapter 17.
Some chromosome aberrations, such as translocations, can run in families (p. 37), and are sometimes said to be
segregating in a mendelian fashion.[1]

IV. GENE LINKAGE AND CROSSING OVER

Mendel’s principle of independent assortment is based on the fact that genes located on different
chromosomes behave independently during meiosis. Often, however, two genes do not assort
independently because they are located on the same chromosome (linked genes; see Box 1-2, Genes Are
Linked to Chromosomes). Many examples of nonrandom assortment were found as soon as a large
number of mutant genes became available for breeding analysis. In every well-studied case, the number
of linked groups was identical to the haploid chromosome number. For example, there are four groups of
linked genes in Drosophila and four morphologically distinct chromosomes in a haploid cell.[3]
 Linkage, however, is in effect never complete. The probability that two genes on the same
chromosome will remain together during meiosis ranges from just less than 100% to nearly 50%. This
variation in linkage suggests that there must be a mechanism for exchanging genes on homologous
chromosomes. This mechanism is called crossing over. Its cytological basis was first described by
Belgian cytologist F.A. Janssens. At the start of meiosis, through the process of synapsis, the
homologous chromosomes form pairs with their long axes parallel. At this stage, each chromosome has
duplicated to form two chromatids. Thus, synapsis brings together four chromatids (a tetrad), which coil
about one another. Janssens postulated that, possibly because of tension resulting from this coiling, two
of the chromatids might sometimes break at a corresponding place on each. These events could create
four broken ends, which might rejoin crossways, so that a section of each of the two chromatids would be
joined to a section of the other (Fig. 1-4). In this manner, recombinant chromatids might be produced that
contain a segment derived from each of the original homologous chromosomes. Formal proof of
Janssens’s hypothesis that chromosomes physically interchange material during synapsis came more than
20 years later, when in 1931, Barbara McClintock and Harriet B. Creighton, working at Cornell
University with the corn plant Zea mays, devised an elegant cytological demonstration of chromosome
breakage and rejoining (Fig. 1-5).[3]
V. CHROMOSOME MAPPING
Thomas Hunt Morgan and his students, however, did not await formal cytological proof of
crossing over before exploiting the implication of Janssens’s hypothesis. They reasoned that genes
located close together on a chromosome would assort with one another much more regularly (close
linkage) than genes located far apart on a chromosome. They immediately saw this as a way to locate
(map) the relative positions of genes on chromosomes and thus to produce a genetic map. The way they
used the frequencies of the various recombinant classes is very straightforward. Consider the segregation
of three genes all located on the same chromosome. The arrangement of the genes can be determined by
means of three crosses, in each of which two genes are followed (two-factor crosses). A cross between
AB and ab yields four progeny types: the two parental genotypes (AB and ab) and two recombinant
genotypes (Ab and aB). A cross between AC and ac similarly gives two parental combinations as well as
the Ac and aC recombinants, whereas a cross between BC and bc produces the parental types and the
recombinants Bc and bC. Each cross will produce a specific ratio of parental to recombinant progeny.
Consider, for example, the fact that the first cross gives 30% recombinants, the second cross 10%, and
the third cross 25%. This tells us that genes a and c are closer together than a and b or b and c and that
the genetic distances between a and b and b and c are more similar. The gene arrangement that best fits
these data is a-c-b (Fig. 1-6).[3]

The correctness of gene order suggested by crosses of two gene factors can usually be
unambiguously confirmed by three-factor crosses. When the three genes used in the preceding example
are followed in the cross ABC abc, six recombinant genotypes are found (Fig. 1-7). They fall into three
groups of reciprocal pairs. The rarest of these groups arises from a double crossover. By looking for the
least frequent class, it is often possible to instantly confirm (or deny) a postulated arrangement. The
results in Figure 1-7 immediately confirm the order hinted at by the two-factor crosses. Only if the order
is a-c-b does the fact that the rare recombinants are AcB and aCb make sense.[3]
 The existence of multiple crossovers means that the amount of recombination between the outside
markers a and b (ab) is usually less than the sum of the recombination frequencies between a and c (ac)
and c and b (cb). To obtain a more accurate approximation of the distance between the outside markers,
we calculate the probability (ac cb) that when a crossover occurs between c and b, a crossover also
occurs between a and c, and vice versa (cb ac). This probability subtracted from the sum of the
frequencies expresses more accurately the amount of recombination. The simple formula
ab = ac + cb - 2(ac)(cb)
is applicable in all cases where the occurrence of one crossover does not affect the probability of another
crossover. Unfortunately, accurate mapping is often disturbed by interference phenomena, which can
either increase or decrease the probability of correlated crossovers.[3]

Using such reasoning, the Columbia University group headed by Morgan had by 1915 assigned
locations to more than 85 mutant genes in Drosophila (Table 1-1), placing each of them at distinct spots
on one of the four linkage groups, or chromosomes. Most importantly, all the genes on a given
chromosome were located on a line. The gene arrangement was strictly linear and never branched. The
genetic map of one of the chromosomes of Drosophila is shown in Figure 1-8. Distances between genes
on such a map are measured in map units, which are related to the frequency of recombination between
the genes. Thus, if the frequency of recombination between two genes is found to be 5%, the genes are
said to be separated by five map units. Because of the high probability of double crossovers between
widely spaced genes, such assignments of map units can be considered accurate only if recombination
between closely spaced genes is followed.[3]
 Even when two genes are at the far ends of a very long chromosome, they assort together at least
50% of the time because of multiple crossovers. The two genes will be separated if an odd number of
crossovers occurs between them, but they will end up together if an even number occurs between them.
 Thus, in the beginning of the genetic analysis of Drosophila, it was often impossible to determine
whether two genes were on different chromosomes or at the opposite ends of one long chromosome.
Only after large numbers of genes had been mapped was it possible to demonstrate convincingly that the
number of linkage groups equalled the number of cytologically visible chromosomes. In 1915, Morgan,
with his students Alfred H. Sturtevant, Hermann J. Muller, and Calvin B. Bridges, published their
definitive book The Mechanism of Mendelian Heredity, which first announced the general validity of the
chromosomal basis of heredity. We now rank this concept, along with the theories of evolution and the
cell, as a major achievement in our quest to understand the nature of the living world.[3]

VI. THE ORIGIN OF GENETIC VARIABILITY THROUGH MUTATIONS

It now became possible to understand the hereditary variation that is found throughout the
biological world and that forms the basis of the theory of evolution. Genes are normally copied exactly
during chromosome duplication. Rarely, however, changes (mutations) occur in genes to give rise to
altered forms, most—but not all—of which function less well than the wild-type alleles. This process is
necessarily rare; otherwise, many genes would be changed during every cell cycle, and offspring would
not ordinarily resemble their parents. There is, instead, a strong advantage in there being a small but
finite mutation rate; it provides a constant source of new variability, necessary to allow plants and
animals to adapt to a constantly changing physical and biological environment.[3]
Surprisingly, however, the results of the Mendelian geneticists were not avidly seized upon by the
classical biologists, then the authorities on the evolutionary relations between the various forms of life.
Doubts were raised about whether genetic changes of the type studied by Morgan and his students were
sufficient to permit the evolution of radically new structures, like wings or eyes. Instead, these biologists
believed that there must also occur more powerful “macromutations,” and that it was these events that
allowed great evolutionary advances.[3]
Gradually, however, doubts vanished, largely as a result of the efforts of the mathematical
geneticists Sewall Wright, Ronald A. Fisher, and John Burden Sanderson Haldane. They showed that,
considering the great age of Earth, the relatively low mutation rates found for Drosophila genes, together
with only mild selective advantages, would be sufficient to allow the gradual accumulation of new
favorable attributes. By the 1930s, biologists began to reevaluate their knowledge of the origin of species
and to understand the work of the mathematical geneticists. Among these new Darwinians were biologist
Julian Huxley (a grandson of Darwin’s original publicist, Thomas Huxley), geneticist Theodosius
Dobzhansky, paleontologist George Gaylord Simpson, and ornithologist Ernst Mayr. In the 1940s all
four wrote major works, each showing from his special viewpoint how Mendelianism and Darwinism
were indeed compatible.[3]

VII. EARLY SPECULATIONS ABOUT WHAT GENES ARE AND HOW THEY ACT
Almost immediately after the rediscovery of Mendel’s laws, geneticists began to speculate about
both the chemical structure of the gene and the way it acts. No real progress could be made, however,
because the chemical identity of the genetic material remained unknown. Even the realization that both
nucleic acids and proteins are present in chromosomes did not really help, since the structure of neither
was at all understood. The most fruitful speculations focused attention on the fact that genes must be, in
some sense, self-duplicating. Their structure must be exactly copied every time one chromosome
becomes two. This fact immediately raised the profound chemical question of how a complicated
molecule could be precisely copied to yield exact replicas.[3]
Some physicists also became intrigued with the gene, and when quantum mechanics burst on the
scene in the late 1920s, the possibility arose that in order to understand the gene, it would first be
necessary to master the subtleties of the most advanced theoretical physics. Such thoughts, however,
never really took root, since it was obvious that even the best physicists or theoretical chemists would not
concern themselves with a substance whose structure still awaited elucidation. There was only one fact
that they might ponder: Muller’s and L.J. Stadler’s independent 1927 discoveries that X-rays induce
mutations. Because there is a greater possibility that an X-ray will hit a larger gene than a smaller gene,
the frequency of mutations induced in a given gene by a given X-ray dose yields an estimate of the size
of this gene. But even here, so many special assumptions were required that virtually no one, not even
Muller and Stadler themselves, took the estimates very seriously.[3]
VIII. PRELIMINARY ATTEMPTS TO FIND A GENE–PROTEIN RELATIONSHIP
The most fruitful early endeavors to find a relationship between genes and proteins examined the
ways in which gene changes affect which proteins are present in the cell. At first these studies were
difficult, because no one knew anything about the proteins that were present in structures such as the eye
or the wing. It soon became clear that genes with simple metabolic functions would be easier to study
than genes affecting gross structures. One of the first useful examples came from a study of a hereditary
disease affecting amino acid metabolism. Spontaneous mutations occur in humans affecting the ability to
metabolize the amino acid phenylalanine. When individuals homozygous for the mutant trait eat food
containing phenylalanine, their inability to convert the amino acid to tyrosine causes a toxic level of
phenylpyruvic acid to build up in the bloodstream. Such diseases, examples of “inborn errors of
metabolism,” suggested to English physician Archibald E. Garrod, as early as 1909, that the wild-type
gene is responsible for the presence of a particular enzyme, and that in a homozygous mutant, the
enzyme is congenitally absent.[3]
Garrod’s general hypothesis of a gene–enzyme relationship was extended in the 1930s by work on
flower pigments by Haldane and Rose ScottMoncrieff in England, studies on the hair pigment of the
guinea pig by Wright in the United States, and research on the pigments of insect eyes by A. Kuhn in
Germany and by Boris Ephrussi and George W. Beadle, working first in France and then in California. In
all cases, the evidence revealed that a particular gene affected a particular step in the formation of the
respective pigment whose absence changed, say, the color of a fly’s eyes from red to ruby. However, the
lack of fundamental knowledge about the structures of the relevant enzymes ruled out deeper
examination of the gene–enzyme relationship, and no assurance could be given either that most genes
control the synthesis of proteins (by then it was suspected that all enzymes were proteins) or that all
proteins are under gene control.[3]
As early as 1936, it became apparent to the Mendelian geneticists that future experiments of the
sort successful in elucidating the basic features of Mendelian genetics were unlikely to yield productive
evidence about how genes act. Instead, it would be necessary to find biological objects more suitable for
chemical analysis. They were aware, moreover, that contemporary knowledge of nucleic acid and protein
chemistry was completely inadequate for a fundamental chemical attack on even the most suitable
biological systems. Fortunately, however, the limitations in chemistry did not deter them from learning
how to do genetic experiments with chemically simple molds, bacteria, and viruses. As we shall see, the
necessary chemical facts became available almost as soon as the geneticists were ready to use them.[3]