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Wednesday, October 17, 2018

Deduction of Chromosome Theory of Inheritance

Deduction of Chromosome Theory of Inheritance
Hertwiig working with sea urchins and some other investigators working
with other organisms, discovered that two equal-sized nuclei, one from the
sperm and the other from the egg fuse at fertilization. This is in spite of the
fact that the egg is much larger than the sperm. In other, words the difference
is in the amount of cytoplasm not the nuclear content. Based partly on this
fact and the results of crossing (mating) different types, Hertvig, and
Strasburger also in 1885 advanced the theory that the cell nucleus must
contain the hereditary materials.
Earlier in 1883, Eduoard van Beneden (1846-1910) had discovered in
Parascaris equorum (formerly Ascaris megalocephala – these names seems to
be still preferred) that the fertilized egg of this nematode contains only four
chromosomes. Furthermore, at the time of fertilization, the sperm and the egg
nuclei contain two chromosomes each. In the light of this fact one could be
more specific about the equal nuclear contribution by both the male and
female parent to the zygote. The components of the nucleus that are visibly
distributed during cell division are the chromosomes. It is therefore, quite
logical to conclude that because the parents contribute equal numbers of
chromosomes, the chromosomes must be the carriers of hereditary material.
Reasoning without the benefit of knowledge of van Beneden’s discovery,
Wilhelm Roux (1850-1924), also in 1883, in a purely hypothetical discussion
of the significance of the mitotic process strongly implied (did not say so
categorically) that the chromosomes are the bearers of hereditary materials.
Roux’s approach was teleological i.e. he started from the standpoint that there
must be a reason for the elaborate mitotic process. (For example, it is
teleological to say that we developed eyes because we needed to see). The
question in essence was “why should the division of a simple structure like
nucleus be so complicated?’
According to Roux, if one assumed that there are in the nucleus, very many
submicroscopic units which control the life processes of cell, then it would be
understandable that great care should be taken in dividing the nuclear
On the other hand, mere constriction of the cell would be sufficient for
dividing the cytoplasm. Roux reasoned that a suitable method for ensuring an
identical distribution of the very many submicroscopic units into each
daughter cell would be for each unit to be divided first, and then the sister
units would be separated. The tasks of division and separation would
however be greatly facilitated if the units were arranged like beads on a
string. There would be several such assemblies, carrying different units, in
the cell. During cell division each “string of beads” would then split
longitudinally, and the halves would move into separate daughter cells. Roux
then went on to say that because the mitotic process is so elaborate it must
serve a purpose in the organism. The purpose is the equal distribution of the
nuclear material important for the physiological and developmental processes
of the cell. We know today that Roux’s “units” are the genes, the hereditary
material, and they are carried on the chromosomes.
In formulating his theory of the Germplasm in 1885, Weismann specifically
said that the chromosomes function as the carriers of hereditary units, but the
chromosome theory was still to be clearly stated.
After the rediscovery of the Mendelian Laws in 1900, it did not take long
before the genes and the chromosomes were identified. The fact that the
observable type of transmission of chromosomes (i.e. the cytological
evidence) corresponds to the deduced type of transmission of genes (the
Mendelian Laws of inheritance) was pointed out independently by Sutton and
by Boveri in 1903. Their conclusions constitute the Chromosomes Theory of
Inheritance. The main points of the theory are:
1. That genes are located on chromosomes such that one member of a
pair of genes is on one chromosome and the other member is on a
partner chromosome, i.e. the homologous chromosome with which it
synapses in meiosis.
2. Different pairs of genes are located on different chromosomes. This is
not to say that there is only one gene on each chromosomes. Rather,
the point is that non-homologous chromosomes carry different genes.
There is more than one gene on each chromosome.
The parallels between the genetic and cytological facts which form the basis
for the theory are:
i) In diploid organisms, genes occur in pairs and so do chromosomes.
ii) Members of a gene pair separate at the time of gamete formation so
that each gamete receives only one member of the pair. The same is
true for chromosomes (cf. Anaphase-I).
iii) The members of different gene pairs recombine at random at the time
of segregation during gamete formation.
Sutton and Boveri did not have corresponding evidence for chromosomes but
they also did not have evidence to the contrary. Recall the fact that the
metaphase-I orientation of one bivalent did not influence the orientation of
another vivalent. This piece of evidence was provided later and it confirmed
the assumption that No. (iii) was also applicable to chromosomes.
The most convincing proof of the theory that genes are on chromosomes was
provided by Theodor Boveri in his experiments with the sea urchin. Boveri
worked with a species in which 2n = 36. In other words at fertilization each
gamete contributes a haploid number of chromosomes of n = 18. Normally,
only one sperm fertilizes an egg but there are rare exceptions in which more
than one sperm fertilizes the egg. This condition is called polyspermy. It is
called dispermy when only two sperm are involved. Polyspermic embryos die
early in development. We shall consider the simplest case, i.e. the dispermic
embryos. Boveri found that there was great viariability in the time of death
and also in the type of organ whose abnormal development led to death.
The sea urchin embryo can be divided into four quadrants, each of which
arose from one of the first four cleavage blastomeres cells. Boveri observed
that the four quadrants often develop differently, thus one quadrant may be
normal and the other three abnormal but in different ways and to different
degrees. This variability in development of different parts of the same
embryo was a very important observation by Boveri. How does one acccount
for it?
At fertilization in the sea urchin the sperm contributes a centriole which
divides to form the two poles i.e. the asters of the mitotic spindle which is
formed as the asters move apart. Each of the 18 chromosomes contributed by
each gamete in normal fertilization becomes duplicated and comes to lie at
the metaphase plate (equatorial plate). This is normal mitosis. The zygote
contains 36 chromosomes and two blastomeres are formed as a result of the
first cleavage. Following the second cleavage a total of four blastomeres
gives rise to cells which will form one quadrant of the embryo.
When there is dispermy, two centrioles are introduced into the egg. Each
divides giving rise to two asters. The effect of dispermy is the production of
four asters in the zygote. The four asters are arranged like the corners of a
square. When such a zygote divides, four blastomeres are formed at once in
the first division. As mentioned earlier, each blastomere gives rise to a
quadrant in the embryo.
In order to answer the question we posed earlier, we have to try to answer
another question, namely, “How do the chromosomes behave in a quadripolar
division?’ The zygote in question is made up of contributions from two
sperm and the egg. The nucleus of each of these gametes contains 18
chromosomes, therefore, there will be 54 chromosomes. This is a 3n number
of chromosomes and it is said to be a triploid number. The chromosomes are
duplicated as in normal mitosis. However, when they move on to the
equatorial plates of the spindle, they are distributed at random on the
spindles. The consequence of this random distribution is that each of the four
resulting blastomeres may contain different types of numbers of
Boveri was able to show that the abnormal development of a dispermic
embryo was the result of the erratic chromosome distribution rather than
dispermy per se. In other words, dispermy does not invariably lead to
abnormal development. Bovery analyzed his results as follows: He found that
the size of a nucleus is dependent on the number of chromosomes present in
it. Therefore, he compared the sizes of the nuclei with the degree of
developmental success (i.e. the degree of normal development) in each
quadrant of an embryo as well as with degree of developmental success in
quadrants having similar-sized nuclei in other embryo.
Table 2.1 Comparison of Development in Two Dispermic Embryos
1 + 111
2 1111 + 11
3 +
4 11 +
1111 = Highest degree of developmental success.
From Table 2.1, one can see that similar-sized nuclei may result in different
abnormalities, hence the different degrees of developmental success. Boveri
therefore concluded that the variability in development is a reflection of
qualitative rather than quantitative differences between nuclei in different
quadrants. For instance if development were dependent on nuclear size only,
quadrants I and III having similar-sized nuclei should have had similar
degrees of developmental success.
Let us now look at a hypothetical example using only four instead 18 types of
chromosomes. In this example we shall also assume that in order to have
normal development, each type of chromosome must be represented at least
once. Since n = 4, the dispermic zygote would contain 12 chromosomes.
Recall that the distribution of the chromosomes on the spindles is a random
process. The diagram below is therefore only one of many possible ways in
which the 12 chromosomes might be distributed on the four spindles. In this
arrangement, only one quadrant develops normally.
Note: 1 - 4 = Chromosome types
1 - IV = Blastomeres that will form quadrants
I & IV = Have equal-sized nuclei. Some for II and III.
Only IV is normal since all 4 types of chromosomes are present.
Since Boveri was aware that the chromosomes vary in shape and size he
concluded that there are qualitative differences between chromosomes.
Specific abnormalities would therefore, arise when particular chromosomes
were missing. This would be the case only if different chromosomes carried
different genes.
As a further test of his hypothesis about qualitative differences between
chromosomes, Boveri found the expected frequency with which any quadrant
might lack all three of any one of the 18 types of chromosomes. He found
that the expected frequency compared favourably with the observed
frequency of abnormally developing quadrants.
One of the main points of the chromosome theory is that different
chromosomes carry different genes. It is pertinent under the circumstances to
ask whether the chromosomes are stable structures or whether they
disintegrate during interphase and are reassembled during prophase. If that
were so it would also be probable that genes would “move” from one
chromosome to possibly a non-homologous chromosome. There would also
be the possibility that the genes are not normally carried on chromosomes.
The fact that chromosomes are stable structures which maintain their
integrity even during interphase, was established by Boveri using the
fertilized eggs of Parascaris equorum. In this nematode the arms of the
chromosomes are not completely retracted at the end of telophase to give a
spherical nucleus. Boveri found that at the end of telophase, the two daughter
nuclei are mirror images of each other as shown in Fig. 2.2.
Fig. 2.1: Mitotic Daughter Nuclei of P. Equorum (2n = 2)
These nuclei retain their shape until the next prophase when the
chromosomes reappear. The chromosomes reappear with their tips still in the
projectins from the nucleus. It is therefore, reasonable to conclude that the
chromosomes did not lose their identity from generation to generation.
3.2 Other Evidence in Support of the chromosome Theory
In our consideration of cell division, we found that the chromosomes in a cell
could be considered as sets, such that a diploid cell would have two sets of
chromosomes. The general terms used to describe the number of whole sets
of chromosomes is "“ploidy”. Continuing on the same theme, there are
euploid aneuploidy conditions. The term euploidy is used to describe
variations in the numbers of whole sets of chromosomes haploid = n; diploid
= 2n; traploid = 3n. These variations which involve whole sets of
chromosomes generally result in normal development. Aneuploidy on the
other hand refers to variations in the numbers of individual chromosomes.
Such variations give unbalanced sets of chromosomes.
From the discussion of Boveri’s sea urchin experiments above, it is obvious
that aneuploidy provides a lot of information in support of the theory that
genes are located on chromosomes. The same is true for the assertion that
different chromosomes carry different genes. In this section then we shall be
considering mainly evidence from aneuploid conditions.
In discussions of chromosomes one often talks of karyotype and idiogram. A
karyotype is an individual’s chromosomes complement in terms of number
and size of chromosomes as well as the location of the centromere in the
different chromosomes. The idiogram on the other hand is a diagrammatic
representation of an individual’s karyotype with the different chromosomes
arranged in order of decreasing size.
In the plant, Datura, the haploid number is 12. Occasionally unusual plants
may arise. These unusual plants contain 25 instead of the normal 24
chromosomes. These plants look different from the normal diploid plant.
Twelve different types each having 25 chromosomes can be identified in
terms of the seed capsule. It was found that each of the twelve variants
possessed a different one of the twelve types of chromosomes. In other
words, in each variant, a given chromosome was present in triplicate. This
aneuploid condition in which three instead of two of a given chromosome are
present is described as a trisomy. Thus, if the different chromosomes are
numbered 1 – 12, an individual with Trisomy – 1 (or Triplo – 1) has three of
chromosomes – 1 present. Note that as we said earlier, these trisomic plants
have only one chromosomes extra, hence the total number is 25 or 24 + 1
which can be stated as 2n + 1; with the exception of the particular
chromosome under consideration all the other chrommosomes are in pairs.
With respect to the example of Datura under consideration, the aneuplooid
effect due to Trisomy – 2 and so on. Because the effect of each trisomy is
distinguishable from all the others, it is logical to conclude that different
chromosomes carry different genes.
Normally in mitosis, the two daughter chromosomes move to opposite poles
during anaphase. Very rarely, however, mistakes do occur and both daughter
chromosomes migrate to the same pole. This situation is described as nondisjunction.
Non-disjunction can also occur in both meiosis –I and meiosis-
II. In the former case, homologous chromosomes would be involved while
the latter would be similar to mitotic non-disjunction. Non-disjunction will
give rise to aneuploid conditions.
Trisomic conditions also occur in man. One example is Trisomy – 21. This
chromosome imbalance produces a condition known as Down’s syndrome.
The term syndrome is used when a number of symptoms characterise an
ailment. This particular case was first described by Down. In man, the diploid
number is 46 but those affected with Down’s syndrome have 47
chromosomes, the extra being chromosome – 21. Amongst other symptoms,
affected individuals are mentally retarded.
Where it has been studied (e.g. U.S.A.) the occurrence of Trisomy – 21
(production of an egg with 24 chromosomes) has been found to be associated
with the age of the mother. The proof of the effect of maternal age is that in
general population, the occurrence of Trisomy – 21 is one in 600 live births.
However, when different age groups are considered separately, the frequency
for mothers about 20 years old is one in 3,000, but for mothers around 45
years, the frequency of occurrence rises to one in 40 live births. The rise in
frequency starts when the woman is about 35 years. A corresponding study
keeping the female age fairly constant but varying the father’s age does not
show any difference between age groups. The reason for the association with
the age of the mother is not known.
Non-disjunction is not the only cause of Trisomy – 21. Although it was said
earlier that every chromosome maintain its integrity (with the exception of
reciprocal exchange between homologues during crossing-over) it sometimes
happens that a portion of one chromosome is transferred to another
chromosome, usually or non-homologue. This phenomenon is known as
trans-location. Chromosome – 21 is a very small chromosome while 14 is
fairly large. In some very rare individuals the bulk of 21 has been
translocated to 14 to give a chromosome designated 14.21.
Figure 2.2: Translocations Involving Human Chromosomes 14 and 21
The translocation occurs as shown above in a diploid individual. The small
chromosome 21.14 is lost without any adverse effect and so the person has 45
chromosomes, but is normal because virtually all of 14 and 21 are combined in the
14.21 chromosome. If the egg produced carries both the 14.21 and the free 21, it
would have two doses instead of one of 21. Fertilisation by a normal sperm would
therefore, produce an individual with 46 chromosomes but with three effective doses
of chromosome – 21. Notice that the fact that particular effects are associated with
specific trisomic conditions and also, the fact that the translocated 14.21 can be
transmitted unchanged are proof that chromosomes retain their integrity.
If non-disjunction can produce a gamete containing two of one type of chromosome,
the reverse situation is also possible. There are cases known in which as organism
carries only one instead of two of a given chromosome; such individuals are said to
be monosomic for that chromosome. Monosomy – 21 is not known in man, so the
condition is assumed to be non-viable. The same is true for monosomy – 14. These
cases illustrate the point that in some organisms, unlike the sea urchin studied by
Boveri, the mere presence of some genes is not a sufficient condition for normal
development, rather the genes must be present in a balanced dose. In Drosophila
melanogaster, a fruit fly, the haplo – IV (monosomy – IV) condition survives
although the fines have reduced viability and fertility. Some other aneuploid
conditions are:
Tetrasomy = 2n + 2 i..e. two extra of a given chromosome.
Double Trisomy = 2n + 1 + 1 i.e. one extra of each of two different chromosomes.
Nullisomy = 2n – 2 i.e. a given chromosome has both members absent.
The significance of chromosomes as well as dosage of chromosomes with respect to
characteristics exhibited by organisms extends to sex determination as we shall see
later. It is sufficient to mention one extreme example here, namely, the honey –bee
in which male are haploid while females are diploid.
When an organism has more than two whole sets of chromosomes i.e. 3n or more
such as individual is described as being polyploid. The 3n individual is a triploid
individual; tetraploid = 4n and pentaploid = 5n. Polyploidy is rather common in
plants but it is rare and often easily recognizable because with certain limits they are
larger than their diploid counterparts.
Rather than try to summarize the examples considered, it is sufficient to say that the
chromosome theory of inheritance states that the genes are an integral part of the
chromosomes. The basis for this generalization is the fact that particular deviations
from say the normal diploid chromosome number, whether euploid or aneuploid
have specific detectable effects. These specific effects are an indication that
chromosomes carry genes and more specifically that different chromosomes carry
different groups of genes.
We have learnt that genes are borne on chromosomes, and occur in pairs in diploid
organisms. The gene pairs separate at the time of gamete formation so that each
gamete receives only one member of the pair. Pairing is restored when members of
different gene pairs recombine at random. The randomness of recombination is the
basis of genetics.

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