Afaq Ahmad’s Classical Genetics Notes

Mendel's Genetics
For thousands of years farmers and herders have been
selectively breeding their plants and animals to produce more
useful hybrids . It was somewhat of a hit or miss process
since the actual mechanisms governing inheritance were
unknown. Knowledge of these genetic mechanisms finally
came as a result of careful laboratory breeding experiments
carried out over the last century and a half.
Hybridized domesticated horses
By the 1890's, the invention of better microscopes allowed biologists to
discover the basic facts of cell division and sexual reproduction. The focus
of genetics research then shifted to understanding what really
happens in the transmission of hereditary traits from parents to children.
A number of hypotheses were suggested to explain heredity, but Gregor
Mendel , a little known Central European monk, was the only one who
got it more or less right. His ideas had been published in 1866 but largely
went unrecognized until 1900, which was long after his death. His early
adult life was spent in relative obscurity doing basic genetics research and
Gregor Mendel
teaching high school mathematics, physics, and Greek in Brno (now in the
1822-1884 Czech Republic). In his later years, he became the abbot of his monastery
and put aside his scientific work.

While Mendel's research was with plants, the basic underlying

principles of heredity that he discovered also apply to people
and other animals because the mechanisms of heredity are
essentially the same for all complex life forms.

Through the selective cross-breeding of common pea plants (Pisum Common edible peas
sativum) over many generations, Mendel discovered that certain traits show up in offspring
without any blending of parent characteristics. For instance, the pea flowers are either purple
or white--intermediate colors do not appear in the offspring of cross-pollinatedpea plants.
Mendel observed seven traits that are easily recognized and apparently only occur in one of
two forms:

1. flower color is purple or white 5. seed color is yellow or green

2. flower position is axil or terminal 6. pod shape is inflated or constricted
3. stem length is long or short 7. pod color is yellow or green

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 4. seed shape is round or wrinkled

This observation that these traits do not show up in offspring plants with intermediate forms
was critically important because the leading theory in biology at the time was that inherited
traits blend from generation to generation. Most of the leading scientists in the 19th century
accepted this "blending theory." Charles Darwin proposed another equally wrong theory
known as "pangenesis" . This held that hereditary "particles" in our bodies are affected by
the things we do during our lifetime. These modified particles were thought to migrate via
blood to the reproductive cells and subsequently could be inherited by the next generation.
This was essentially a variation of Lamarck's incorrect idea of the "inheritance of acquired
characteristics."

Mendel picked common garden pea plants for the focus of his research because they can be
grown easily in large numbers and their reproduction can be manipulated. Pea plants have
both male and female reproductive organs. As a result, they can either self-pollinate
themselves or cross-pollinate with another plant. In his experiments, Mendel was able to
selectively cross-pollinate purebred plants with particular traits and observe the outcome
over many generations. This was the basis for his conclusions about the nature of genetic
inheritance.

Reproductive
structures of
flowers

In cross-pollinating plants that either produce yellow or green pea seeds exclusively, Mendel
found that the first offspring generation (f1) always has yellow seeds. However, the following
generation (f2) consistently has a 3:1 ratio of yellow to green.

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This 3:1 ratio occurs in later generations as well. Mendel realized that this underlying
regularity was the key to understanding the basic mechanisms of inheritance.

He came to three important conclusions from these experimental results:

1. that the inheritance of each trait is determined by "units" or

"factors" that are passed on to descendents unchanged (these
units are now called genes )
2. that an individual inherits one such unit from each parent for each
trait
3. that a trait may not show up in an individual but can still be passed
on to the next generation.

It is important to realize that, in this experiment, the starting parent plants

were homozygous for pea seed color. That is to say, they each had two identical forms
(or alleles ) of the gene for this trait--2 yellows or 2 greens. The plants in the f1 generation
were allheterozygous . In other words, they each had inherited two different alleles--one
from each parent plant. It becomes clearer when we look at the actual genetic makeup,
or genotype , of the pea plants instead of only the phenotype , or observable physical
characteristics.

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Note that each of the f1 generation plants (shown above) inherited a Y allele from one parent
and a G allele from the other. When the f1 plants breed, each has an equal chance of passing
on either Y or G alleles to each offspring.

With all of the seven pea plant traits that Mendel examined, one form appeared dominant over
the other, which is to say it masked the presence of the other allele. For example, when the
genotype for pea seed color is YG (heterozygous), the phenotype is yellow. However, the
dominant yellow allele does not alter the recessive green one in any way. Both alleles can be
passed on to the next generation unchanged.

Mendel's observations from these experiments can be summarized in two principles:

1. the principle of segregation

2. the principle of independent assortment

According to the principle of segregation, for any particular trait, the pair of alleles of each
parent separate and only one allele passes from each parent on to an offspring. Which allele in
a parent's pair of alleles is inherited is a matter of chance. We now know that this segregation
of alleles occurs during the process of sex cell formation (i.e., meiosis ).

Segregation of alleles in the production of sex cells

According to the principle of independent assortment, different pairs of alleles are passed to
offspring independently of each other. The result is that new combinations of genes present in
neither parent are possible. For example, a pea plant's inheritance of the ability to produce
purple flowers instead of white ones does not make it more likely that it will also inherit the
ability to produce yellow pea seeds in contrast to green ones. Likewise, the principle of
independent assortment explains why the human inheritance of a particular eye color does not
increase or decrease the likelihood of having 6 fingers on each hand. Today, we know this is
due to the fact that the genes for independently assorted traits are located on
different chromosomes .

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These two principles of inheritance, along with the understanding of unit inheritance and
dominance, were the beginnings of our modern science of genetics. However, Mendel did not
realize that there are exceptions to these rules. Some of these exceptions will be explored in
the third section of this tutorial and in the Synthetic Theory of Evolution tutorial.

By focusing on Mendel as the father of genetics, modern biology often forgets that
his experimental results also disproved Lamarck's theory of the inheritance of
acquired characteristics described in the Early Theories of Evolution tutorial. Mendel
rarely gets credit for this because his work remained essentially unknown until long
after Lamarck's ideas were widely rejected as being improbable.

NOTE: Some biologists refer to Mendel's "principles" as "laws".

NOTE: One of the reasons that Mendel carried out his breeding experiments with pea plants
was that he could observe inheritance patterns in up to two generations a year. Geneticists
today usually carry out their breeding experiments with species that reproduce much more
rapidly so that the amount of time and money required is significantly reduced. Fruit flies and
bacteria are commonly used for this purpose now. Fruit flies reproduce in about 2 weeks from
birth, while bacteria, such as E. coli found in our digestive systems, reproduce in only 3-5 hours.

Probability of Inheritance
The value of studying genetics is in understanding how we can predict the likelihood of
inheriting particular traits. This can help plant and animal breeders in developing varieties that
have more desirable qualities. It can also help people explain and predict patterns of
inheritance in family lines.

One of the easiest ways to calculate the mathematical probability of inheriting a specific trait
was invented by an early 20th century English geneticist named Reginald Punnett . His
technique employs what we now call a Punnett square. This is a simple graphical way of
discovering all of the potential combinations of genotypes that can occur in children, given the
genotypes of their parents. It also shows us the odds of each of the offspring genotypes
occurring.

Setting up and using a Punnett square is quite simple once you understand how it works. You
begin by drawing a grid of perpendicular lines:

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Next, you put the genotype of one parent across the top and that of the other parent down the
left side. For example, if parent pea plant genotypes were YY and GG respectively, the setup
would be:

Note that only one letter goes in each box for the parents. It does not matter which parent is
on the side or the top of the Punnett square.

Next, all you have to do is fill in the boxes by copying the row and column-head letters across or
down into the empty squares. This gives us the predicted frequency of all of the potential
genotypes among the offspring each time reproduction occurs.

In this example, 100% of the offspring will likely be heterozygous (YG). Since the Y (yellow)
allele is dominant over the G (green) allele for pea plants, 100% of the YG offspring will have a
yellow phenotype, as Mendel observed in his breeding experiments.

In another example (shown below), if the parent plants both have heterozygous (YG)
genotypes, there will be 25% YY, 50% YG, and 25% GG offspring on average. These percentages
are determined based on the fact that each of the 4 offspring boxes in a Punnett square is 25%

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(1 out of 4). As to phenotypes, 75% will be Y and only 25% will be G. These will be the odds
every time a new offspring is conceived by parents with YG genotypes.

An offspring's genotype is the result of the combination of genes in the sex cells or gametes
(sperm and ova) that came together in its conception. One sex cell came from each parent. Sex
cells normally only have one copy of the gene for each trait (e.g., one copy of the Y or G form of
the gene in the example above). Each of the two Punnett square boxes in which the parent
genes for a trait are placed (across the top or on the left side) actually represents one of the
two possible genotypes for a parent sex cell. Which of the two parental copies of a gene is
inherited depends on which sex cell is inherited--it is a matter of chance. By placing each of the
two copies in its own box has the effect of giving it a 50% chance of being inherited.

If you are not yet clear about how to make a Punnett Square and interpret its result, take the
time to try to figure it out before going on.

Are Punnett Squares Just Academic Games?

Why is it important for you to know about Punnett squares? The answer is that they can be
used as predictive tools when considering having children. Let us assume, for instance, that
both you and your mate are carriers for a particularly unpleasant genetically inherited disease
such as cystic fibrosis . Of course, you are worried about whether your children will be
healthy and normal. For this example, let us define "A" as being the dominant normal allele
and "a" as the recessive abnormal one that is responsible for cystic fibrosis. As carriers, you
and your mate are both heterozygous (Aa). This disease only afflicts those who are
homozygous recessive (aa). The Punnett square below makes it clear that at each birth, there
will be a 25% chance of you having a normal homozygous (AA) child, a 50% chance of a healthy
heterozygous (Aa) carrier child like you and your mate, and a 25% chance of a homozygous
recessive (aa) child who probably will eventually die from this condition.

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 If both parents are carriers of the recessive
allele for a disorder, all of their children will
face the following odds of inheriting it:
25% chance of having the recessive disorder
50% chance of being a healthy carrier
25% chance of being healthy and not have
the recessive allele at all

If a carrier (Aa) for such a recessive disease mates with someone who has it (aa), the likelihood
of their children also inheriting the condition is far greater (as shown below). On average, half
of the children will be heterozygous (Aa) and, therefore, carriers. The remaining half will inherit
2 recessive alleles (aa) and develop the disease.

If one parent is a carrier and the other has a

recessive disorder, their children will have the
following odds of inheriting it:
50% chance of being a healthy carrier
50% chance having the recessive disorder

It is likely that every one of us is a carrier for a large number of recessive alleles. Some of these
alleles can cause life-threatening defects if they are inherited from both parents. In addition to
cystic fibrosis, albinism, and beta-thalassemia are recessive disorders.

Some disorders are caused by dominant alleles for genes. Inheriting just one copy of
such a dominant allele will cause the disorder. This is the case with Huntington
disease, achondroplastic dwarfism, and polydactyly. People who are heterozygous
(Aa) are not healthy carriers. They have the disorder just like homozygous dominant
(AA) individuals.

If only one parent has a single copy of a

dominant allele for a dominant disorder,
their children will have a 50% chance of
inheriting the disorder and 50% chance
of being entirely normal.

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Punnett squares are standard tools used by genetic counselors. Theoretically, the likelihood of
inheriting many traits, including useful ones, can be predicted using them. It is also possible to
construct squares for more than one trait at a time. However, some traits are not inherited
with the simple mathematical probability suggested here. We will explore some of these
exceptions in the next section of the tutorial.

Exceptions to Simple Inheritance

Since Mendel's time, our knowledge of the mechanisms of genetic inheritance has grown
immensely. For instance, it is now understood that inheriting one allele can, at times, increase
the chance of inheriting another or can affect how and when a trait is expressed in an
individual's phenotype. Likewise, there are degrees of dominance and recessiveness with some
traits. The simple rules of Mendelian inheritance do not apply in these and other exceptions.
They are said to have non-Mendelian inheritance patterns.

Polygenic Traits
Some traits are determined by the combined effect of more than one pair
of genes. These are referred to as polygenic , or continuous, traits. An
example of this is human stature. The combined size of all of the body
parts from head to foot determines the height of an individual. There is
an additive effect. The sizes of all of these body parts are, in turn,
determined by numerous genes. Human skin, hair, and eye color are also
polygenic traits because they are influenced by more than one allele at Polygenic traits:
stature, body shape,
different loci. The result is the perception of continuous gradation in the hair and skin color
expression of these traits.

NOTE: whether an individual achieves his or her genetically programmed height is

significantly affected by thyroid gland hormones and human growth hormones (HGH)
produced in the pituitary gland . A deficiency in the amount of these hormones
during childhood and puberty can result in stunted growth. Too much of them can
cause excessive growth resulting in exceptional height. Differences in diet and other
environmental factors during the crucial growth years can also be important in
determining stature and other complex traits. Usually, about 10% of an individual's
height is due to the environment.

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 Intermediate Expression
Apparent blending can occur in the phenotype when there is incomplete dominance resulting in
an intermediate expression of a trait in heterozygous individuals. For instance, in primroses,
snapdragons, and four-o'clocks, red or white flowers are homozygous while pink ones are
heterozygous. The pink flowers result because the single "red" allele is unable to code for the
production of enough red pigment to make the petals dark red.

Another example of an intermediate expression may be the pitch of human male voices. The
lowest and highest pitches apparently are found in men who are homozygous for this trait (AA
and aa), while the intermediate range baritones are heterozygous (Aa). The child-killer disease
known as Tay-Sachs is also characterized by incomplete dominance. Heterozygous
individuals are genetically programmed to produce only 40-60% of the normal amount of an
enzyme that prevents the disease.

Fortunately for Mendel, the pea plant traits that he studied were controlled by genes that do
not exhibit an intermediate expression in the phenotype. Otherwise, he probably would not
have discovered the basic rules of genetic inheritance.

Codominance
For some traits, two alleles can be codominant. That is to say, both are expressed in
heterozygous individuals. An example of this is people who have an AB blood type for the ABO
blood system. When they are tested, these individuals actually have the characteristics of both
type A and type B blood. Their phenotype is not intermediate between the two.

Type AB blood testing as both A and B

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 Multiple-allele Series
The ABO blood type system is also an example of a trait that is controlled by more than just a
single pair of alleles. In other words, it is due to a multiple-allele series. In this case, there are
three alleles (A, B, and O), but each individual only inherits two of them (one from each parent).

Some traits are controlled by far more alleles. For instance, the human HLA system, which is
responsible for identifying and rejecting foreign tissue in our bodies, can have at least
30,000,000 different genotypes. It is the HLA system which causes the rejection of organ
transplants. The more we learn about human genetics the more it becomes clear that multiple-
allele series are very common. In fact, it now appears that they are more common than simple
two allele ones.

Modifying and Regulator Genes

There are two classes of genes that can have an effect on how other genes function. They are
called modifying genes and regulator genes.

Modifying genes alter how certain other genes are expressed in the phenotype. For instance,
there is a dominant cataract gene which will produce varying degrees of vision impairment
depending on the presence of a specific allele for a companion modifying gene. However,
cataracts also can be promoted by diabetes and common environmental factors such as
excessive ultraviolet radiation, and alcoholism. Nearly half of all people in North America over
65 years of age eventually develop them.

Regulator genes can either initiate or block the expression of other genes. They control the
production of a variety of chemicals in plants and animals. For instance, the time of production
of specific proteins that will be new structural parts of our bodies can be controlled by such
regulator genes. Shortly after conception, regulator genes work as master switches
orchestrating the timely development of our body parts. They are also responsible for changes
that occur in our bodies as we grow older. In other words, they control the maturation and
aging processes. Regulator genes that are involved in subdividing an embryo into what will
become the major body parts of an individual are also referred to as homeotic

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, homeobox , or Hox genes. They are responsible for setting generalized cells on the
path to become a head, torso, arms, legs, etc.

Gene Control--video clip from Teachers' Can We Slow Aging--video clip from Nova
Domain ScienceNow
View in: QuickTime or Windows Media Player about a regulator gene that controls the aging process
(length = 2 mins 58 secs) (length = 11 mins 30 secs)

Incomplete Penetrance
Some genes are incompletely penetrant. That is to say, their effect does not normally occur
unless certain environmental factors are present. For example, you may inherit the genes that
are responsible for type 2 diabetes but never get the disease unless you become greatly
overweight, persistently stressed psychologically, or do not get enough sleep on a regular basis.
Similarly, the genes that cause the chronic autoimmune disease, multiple sclerosis , may be
triggered by the Epstein-Barr virus and possibly other specific environmental stresses. New
research suggests that abundant exposure to the sun in childhood can provide some protection
from developing MS. Subsequently, people who grow up in tropical and subtropical regions of
the world have significantly lower rates of MS as adults.

Sex Related Genetic effects

There are three categories of genes that may have different effects depending on an
individual's gender. These are referred to as:

1. sex-limited genes
2. sex-controlled genes

Human gender differences in facial hair

3. genome imprinting

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Sex-limited genes are ones that are inherited by both men and women but are normally only
expressed in the phenotype of one of them. The heavy male beard is an example. While
women have facial hair it is most often very fine and comparatively sparse.

In contrast, sex-controlled genes are expressed in both sexes but differently. An example of
this is gout , a disease that causes painfully inflamed joints. If the gene is present, men are
nearly eight times more likely than women to have severe symptoms.

Some genes are known to have a different effect depending on the gender of the parent from
whom they are inherited. This phenomenon is referred to as genome imprinting or genetic
imprinting. Apparently, diabetes , psoriasis , and some rare genetically inherited
diseases, such as a form of mental retardation known asAngelman syndrome , can follow
this inheritance pattern. Recent research by Catherine Dulac of Harvard University points to
genetic imprinting as being an important factor in causing male and female brains to develop
somewhat differently. She suggests that this is due to the fact that some of the genes inherited
from the opposite sex parent are likely to be turned off following conception.

Pleiotropy
A single gene may be responsible for a variety of traits. This is called pleiotropy . The
complex of symptoms that are collectively referred to as sickle-cell trait , or sickle-cell
anemia, is an example. A single gene results in irregularly shaped red blood cells that painfully
block blood vessels, cause poor overall physical development, as well as related heart, lung,
kidney, and eye problems. Another pleiotropic trait is albinism . The gene for this trait not
only results in a deficiency of skin, hair, and eye pigmentation but also causes defects in vision.

Stuttering Alleles
Lastly, it is now known that some genetically inherited diseases have more severe symptoms
each succeeding generation due to segments of the defective genes being doubled in their
transmission to children (as illustrated below). These are referred to as stuttering alleles or
unstable alleles. Examples of this phenomenon are Huntington's disease, fragile-X syndrome,
and the myotonic form of muscular dystrophy .

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 Unstable allele doubling each generation

Mendel believed that all units of inheritance are passed on to offspring unchanged. Unstable
alleles are an important exception to this rule.

Environmental Influences
The phenotype of an individual is not only the result of inheriting a particular set of parental
genes. The specific environmental characteristics of the uterus in which a fertilized egg is
implanted and the health of the mother can have major impacts on the phenotype of the future
child. For instance, oxygen deprivation or inappropriate hormone levels can cause lifelong,
devastating effects. Likewise, accidents, poor nutrition, and other environmental influences
throughout life can alter an individual's phenotype for many traits.

Geneticists study identical or monozygotic twins to determine which traits are inherited
and which ones were acquired following conception. Since monozygotic twins come from the
same zygote, they are essentially identical in their genetic makeup. If there are any differences
in their phenotypes, the environment is virtually always responsible. Such differences show up
in basic capabilities such as handedness, which had been assumed to be entirely genetically
determined. In rare instances, one monozygotic twin will be clearly right-handed while the
other will be left-handed. This suggests that there may be both genetic and environmental
influences in the development of this trait.

Summary
Researchers have identified more than 5,000 genetically inherited human diseases and
abnormalities. As we learn more about the inheritance patterns for these traits, it is becoming
clear that at least some of the twelve exceptions to the simple Mendelian rules of inheritance
described here are, in fact, relatively common. It would not be surprising if other "exceptions"
were discovered in the future. However, it is important to keep in mind that there are at least
18,000 human traits controlled by genes that follow the basic Mendelian rules of inheritance.

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NEWS: Susan Lolle et al. reported in the March 2005 issue of Nature that they have
discovered a plant species that can overwrite the genetic makeup inherited from
parents. These cress plants seem to be able to revert back to the DNA sequences of
their grandparents including genetic information that was lost in the intervening
generation. The researchers suggest that since the DNA sequences were not present
in the parents that there may be a "template-directed process that makes use of an
ancestral RNA-sequence cache." The implication is that this is a form of inheritance
that does not follow the basic tenets of classical genetics. ("Genome-wide Non-
Mendelian Inheritance of Extra-genomic Information in Arabidopsis", Nature, Vol.
434, No 7032, March 24, 2005)

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