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Classical Papers in Genetics CS374 Fall 2004 Lecture 10, 10/28/04

Lecturer: Olga Russakovsky Scribe: Stephen Guo

Classical Papers in Genetics


Based on the following papers:
1. Sulton, W. S. The Chromosomes in Heredity, 1903
2. Demerec, M. What is a Gene? 1933
3. Crick, Francis. Central Dogma of Molecular Biology, 1970.

1 Motivation

This lecture was different from the others presented in the course, in that it did not involve applications of
computer science to biology. The 45-minute lecture outlined several classical survey papers in genetics.
The first half of the lecture surveyed the results of the 1903 paper, “The Chromosomes in Heredity,” which
described all that was known about chromosomes in the early 20th century. The second half of the lecture
partially surveyed the results of the 1933 paper, “What is a Gene?,” which highlighted all of the
information known about the gene at the time. Due to time constraints, the “Central Dogma of Molecular
Biology,” was only briefly described at the end of the lecture.

The lecturer chose to highlight the interesting results of each paper, and present the experiments and
methodology used to infer those results. A prerequisite for this lecture is some knowledge of high school
genetics and molecular biology.

2 The Chromosomes in Heredity [1903]


The most ancient theory of heredity began with Aristotle, who believed that cells from different organs of
the mother and father came together to form the cells of the child. Example: he believed that if a man
scarred his hand, his child would have a scarred hand as well. Although his theory was quite flawed,
Aristotle’s theory was much more accurate than the most of the theories formed two thousand years after
his time. In 17th century Europe, some biologists called “spermists” believed that life was stored in the
sperm cell and was incubated in the egg. Others called “ovulists” believed that life was stored in the egg
and enriched by the sperm. After much argument, biologists came up with a blending theory, that children
cells were formed from a mix of mother and father cells.

2.1 Background: Mendel’s experiments

The correct study of heredity originated with Mendel’s crossbreeding experiments of garden pea plants.
Starting out with one pure yellow pea plant and one pure green pea plant, after the first round of breeding,
he observed four yellow pea plants (assume that yellow is dominant). Next he crossbred two of the first
generation yellow plants, and observed that there were three yellow and one green plants in the second
generation.

From these results, he came to the conclusion that “while in the organism maternal and paternal
potentialities are present in the field of each character, the germ cells in respect to each character are pure.”
In other words, he concluded that the color gene had two alleles, one dominant yellow and one recessive
green. Parents only passed on one of their alleles to their children. These assumptions explained the
observed 3:1 phenotypic ratio in the second generation, and let him conclude there was a 1:2:1 genotypic
ratio. Mendel’s experiments were landmark because they disproved the “blending theory” of heredity
popular at the time. Deviations from Mendel’s theory correspond to deviations in chromosome processes.

2.2 Cell organization and division


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Classical Papers in Genetics CS374 Fall 2004 Lecture 10, 10/28/04
Lecturer: Olga Russakovsky Scribe: Stephen Guo

After Mendel announced his theory of heredity, other biologists began to wonder whether these
symmetrical phenotypic ratios existed in some form within the chromosome itself. In the words of
Bateson, they began “suspecting that this fact must correspond with some symmetrical figure of
distribution of the gametes in the cell division by which they are produced.”

Now, what was known about cell organization and division in 1933? During the time, the chromosome
formation cycle was assumed to be as follows:

Prophase - two equivalent chromosome series (maternal and paternal)

B
A C
C
B

Metaphase - (synapsis) union of pairs of the homologues

A B B C C

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Classical Papers in Genetics CS374 Fall 2004 Lecture 10, 10/28/04
Lecturer: Olga Russakovsky Scribe: Stephen Guo

Meiosis II - first postsynaptic division equational, so no differentiation

B B C C

A A B B C C

Meiosis I - (reducing division) separation of homologous chromosomes

A
B
C B C

B A B
A C
C

Cells divide – Throughout the cell cycle, chromosomes retain their individuality.

Note that our modern day view of the cycle is vastly different from what was presented above. The process
above is missing numerous stages, and Meiosis I should occur before Meiosis II.

2.3 Which chromosomes?

Now about the application of heredity to the cell cycle, biologists wondered whether maternal and paternal
chromosomes separated to opposite poles of the cell?

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Classical Papers in Genetics CS374 Fall 2004 Lecture 10, 10/28/04
Lecturer: Olga Russakovsky Scribe: Stephen Guo

A
B
If separation did occur then:
A C B C
1 - No crossbreeding can produce more variety than first
cross
versus

B A B
A C
C

Consider AB x AB -> ABAB parent cell -> ½ AB and ½ AB germ cells


Then crossbreeding yields germ cells:

AB AB
½ AB
AB AB ½ AB

½ AB AB
AB ½ AB

2 - There can be at most 4 different combinations in offspring of a single pair

Consider AB x CD -> ¼ AC, ¼ AD , ¼ BC, ¼ BD

A B C D

AB CD

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Classical Papers in Genetics CS374 Fall 2004 Lecture 10, 10/28/04
Lecturer: Olga Russakovsky Scribe: Stephen Guo

3 - Can receive traits from only one grandparent each from the paternal and maternal lines.

Demonstrated in the above diagram.

Since all of the three properties above were observed to have counterexamples, biologists concluded that
separation did not occur.

Another question biologists had was about whether germ cells received their chromosomes only from the
mother or only from the father, or if germ cells received a combination of chromosomes from mother and
father?

Example for 2 pairs of chromosomes:

Assuming that children can take chromosomes from only mother or only father, there are only 2 possible
germ cells: ABCD ABCD

Assuming that children chromosomes can be a combination from mother and father, there are 24 possible
germ cells: ABCD, ABCD, ABCD, ABCD, ABCD, ABCD, ABCD, ABCD, ABCD, ABCD, ABCD, ABCD, ABCD, ABCD,
ABCD, ABCD

From the large diversity observed in children germ cells, biologists acknowledged the latter theory,
concluding that germ cells can simultaneously take on a combination of chromosomes from mother and
father.

At the time, it was known that there were at least 16 human chromosomes, ie 8 homologous pairs of
chromosomes. Therefore, there were 28 possible combinations of germ cells and (28)2 = 65536 possible
children for two unrelated individuals. This calculation agreed with scientific observations about the size
of diversity possible.

2.4 Roles of chromosomes

Further studies conducted upon the grasshopper Brachystola confirmed Mendel’s first law (segregation of
characters) in the cell cycle, ie concepts of “dominant,” “recessive,” “homozygous,” and “heterozygous.”
Additional studies on germ-cell division observed purity of units, independent transmission of one trait
from each parent to child, and a double basis for each germ cell character. These properties were all noted
by Mendel in his heredity study.

In addition to “bringing the chromosome theory into final relation with the known fact of heredity,”
biologists also studied the fundamental role of chromosomes. Studies of the time were conducted upon
chromosome-lacking larvae to understand the functions of specific chromosomes. This was not discussed
in great detail because it was not the main purpose of the paper.

2.5 Alleles and dominance

Returning to the topic of germ cell division and heredity, biologists also observed relationships between
allelomorphs, unit characters, and chromosomes. Biologists at the time had two main questions about
alleles:

1 - Is the whole chromosome one allele, or are alleles only part of the chromosome?

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Classical Papers in Genetics CS374 Fall 2004 Lecture 10, 10/28/04
Lecturer: Olga Russakovsky Scribe: Stephen Guo

Due to the amount of variety observed between generations, biologists concluded that it was impossible for
a chromosome to be limited to carrying only one allele. By the pigeonhole principle, some chromosomes
must carry multiple alleles to explain the quantity of diversity.

2 – Is a chromosome entirely dominant, or can some parts be dominant and other parts recessive?
The latter theory was confirmed by observations that in the same chromosome, sometimes both traits were
dominant over the homologue, while other times only one was dominant.

Example that demonstrates (part dominant-recessive) theory:

Key: A = green color of seed


a = brown color of seed
B = big leaves
b = small leaves

If Chromosome 1 is AB and Chromosome 2 is ab, there will be observed correlation between the traits of
the offspring (green-big, brown-small).

However, if Chromosome 1 is Ab and Chromosome 2 is aB, observed correlation will be opposite from
above.

3 What is a Gene? [1933]

After studying chromosomes, the logical next step is to study the gene.
At the time of the paper, it was known that a gene was:
-a minute organic particle
-capable of reproduction
-located in a chromosome
-responsible for the transmission of a hereditary characteristic

The goal of the paper was to expand the definition of the gene, and summarize all knowledge known about
genes.

3.1 Gene definition analyzed

Size: the first question biologists had about the gene was its size. Early studies estimated size by
determining the volume of a chromosome, approximating the number of genes in the chromosome, and
dividing the two numbers to get the volume of a gene. Using this method, proposed upper limits from
various biologists on the size were 10, 20, 50, 60, 70 millimicrons (size of a few organic molecules). As is
apparent from the large range of upper bounds, this method was not particularly accurate.

Biologists understood the limitations of the previous estimates as well. They had some direct evidence that
a gene was smaller than their estimates, because chromosomes were not visible inside nuclei until division.

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Classical Papers in Genetics CS374 Fall 2004 Lecture 10, 10/28/04
Lecturer: Olga Russakovsky Scribe: Stephen Guo

Separate studies using X-rays observed that genes reacted to being hit
by photoelectrons. Using this more refined X-ray technique, biologists
estimated the size of a gene as a single organic molecule. Height
Capacity of reproduction: at the time, biologists knew little about gene
reproduction. Their only notable observation was based on the study of
unstable genes: new genes tended to form next to old genes, rather than
old genes splitting up in two.
Hair color
Transmission of hereditary characteristics: biologists understood that
the overall hereditary process depended upon the presence of all genes.

Location of genes: It was observed that genes were present on a


chromosome in linear order, with each gene appearing in a permanent
locus on the chromosome. Changes in the order of genes on a
Finger length
chromosome corresponded to genetic abnormalities. Also, it was found
that genetic distance between genes did not correspond to the actual
physical separation distance.

3.2 Stability of the gene Nail shape


Another area of gene studies is how genes are mutated. It was observed
that genes change naturally from one allele to another, with very low
probability. The use of X-rays and radiation increased this mutation
rate. Different genes had different mutation rates, genes with high
mutation rate were labeled as “unstable” genes. The mutation rate of Eye color
genes in general was observed to be a continuous series, ie plotting the
mutation rates of all genes roughly forms a line. Regarding the
different mutation rates of different genes, biologists observed that gene mutation rates were correlated
with what tissues the genes were located in, as well as the stage of development of the cell. Example
mutation rates are in the table below:

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Classical Papers in Genetics CS374 Fall 2004 Lecture 10, 10/28/04
Lecturer: Olga Russakovsky Scribe: Stephen Guo

Experiment demonstrating correlation between gene mutation and stage of development: The flower
Delphinium ajacis has two unstable genes that affect the color of the flowers, corresponding to rose and
lavender. Both of these genes eventually change to the color purple. It was observed that the number of
purple spots on a flower was directly related to the number of gene mutations. And the size of the spots on
the flower indicated the stage of ontogeny in which the stage occurred. Additionally, this flower only
existed in two forms: lavender with small spots and rose with varying size spots. From these facts, the
conclusion was that the lavender gene was unstable late in the cell development process, while the rose
gene was equally unstable at all stages of development.

Regarding the different types of gene mutations, it was observed that given a germ cell and somatic ell
with equal mutation probability, the germ cell was more stable. In general, unstable genes mutated with
higher frequency than stable genes. Biologists also noted that unstable genes were more likely to mutate in
tissues that were more easily observable.

3.3 Role of genes

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Classical Papers in Genetics CS374 Fall 2004 Lecture 10, 10/28/04
Lecturer: Olga Russakovsky Scribe: Stephen Guo

The most important observation about genes was discussed at the end of the paper: “any radical change
eliminates the gene from the gene complex, and the elimination of a single gene usually is lethal.”

From this observation, the author derived the crux of the paper: the primary function of the gene is not the
one by which we recognize it (determination of phenotypes), but the regulation of life processes of the cell.

4 Central Dogma of Molecular Biology [1970]


The Central Dogma of Molecular Biology can be summarized with one picture. Black arrows indicate
known routes of information transfer. Dotted lines indicate unlikely information transfer routes (occur in
only a limited number of cells). Arrows not present indicate information routes postulated to not exist.

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