Assignment (Genetics)

Topics:
1- Pedigree Analysis
2- Environmental impact on Gene expression
3- Human Genome Project

Submitted to:

Honorable Dr. Prof. Mujahid Niaz

Submitted By:

Muhammad Pervez
MCEZ-16-15137

Zoology Department

Govt. Emerson College Multan

Introduction
A pedigree is a diagram of family relationships that uses symbols to represent
people and lines to represent genetic relationships. These diagrams make it easier
to visualize relationships within families, particularly large extended families.
Pedigrees are often used to determine the mode of inheritance (dominant,
recessive, etc.) of genetic diseases.

If more than one individual in a family is afflicted with a disease, it is a clue that
the disease may be inherited. A doctor needs to look at the family history to
determine whether the disease is indeed inherited and, if it is, to establish the
mode of inheritance. This information can then be used to predict recurrence risk
in future generations.

A basic method for determining the pattern of inheritance of any trait (which may
be a physical attribute like eye color or a serious disease like Marfan syndrome) is
to look at its occurrence in several individuals within a family, spanning as many
generations as possible. For a disease trait, a doctor has to examine existing
family members to determine who is affected and who is not. The same
information may be difficult to obtain about more distant relatives, and is often
incomplete.

In a pedigree, squares represent males and circles represent females. Horizontal

lines connecting a male and female represent mating. Vertical lines extending
downward from a couple represent their children. Subsequent generations are
therefore written underneath the parental generations and the oldest individuals
are found at the top of the pedigree.

If the purpose of a pedigree is to analyze the pattern of inheritance of a particular

trait, it is customary to shade in the symbol of all individuals that possess this
trait.

i) Generations are numbered from the top of the pedigree in uppercase.

Roman numerals, I, II, III etc.
 ii) Individuals in each generation are numbered from the left in Arab
numerals as subscripts, III1, III2, III3 etc

Modes of inheritance
Most human genes are inherited in a Mendelian manner. It is usually unaware of
the existence unless a variant form is present in the population which causes an
abnormal (or at least different) phenotype. One can follow the inheritance of the
abnormal phenotype and deduce whether the variant allele is dominant or
recessive.

Using genetic principles, the information presented in a pedigree can be analyzed

to determine whether a given physical trait is inherited or not and what the
pattern of inheritance is. In simple terms, traits can be either dominant or
recessive.

A dominant trait is passed on to a son or daughter from only one parent.

Characteristics of a dominant pedigree are:

1) Every affected individual has at least one affected parent;

2) Affected individuals who mate with unaffected individuals have a 50% chance
of transmitting the trait to each child; and

3) Two affected individuals may have unaffected children.

Recessive traits are passed on to children from both parents, although the
parents may seem perfectly "normal." Characteristics of recessive pedigrees are:

1) An individual who is affected may have parents who are not affected;

2) All the children of two affected individuals are affected; and

3) In pedigrees involving rare traits, the unaffected parents of an affected

individual may be related to each other.

Penetrance and expressivity

Penetrance is the probability that a disease will appear in an individual when a
disease-allele is present. For example, if all the individuals who have the
diseasecausing allele for a dominant disorder have the disease, the allele is said to
have 100% penetrance. If only a quarter of individuals carrying the disease-
causing allele show symptoms of the disease, the penetrance is 25%. Expressivity,
on the other hand, refers to the range of symptoms that are possible for a given
disease. For example, an inherited disease like Marfan syndrome can have either
severe or mild symptoms, making it difficult to diagnose.

Non-inherited traits
Not all diseases that occur in families are inherited. Other factors that can cause
diseases to cluster within a family are viral infections or exposure to
diseasecausing agents (for example, asbestos). The first clue that a disease is not
inherited is that it does not show a pattern of inheritance that is consistent with
genetic principles (in other words, it does not look anything like a dominant or
recessive pedigree).

Autosomal dominant
A dominant condition is transmitted in unbroken descent from each generation to
the next. Most mating will be of the form M/m x m/m, i.e. heterozygote to
homozygous recessive. Therefore, it is expected that every child of such a mating
to have a 50% chance of receiving the mutant gene and thus of being affected. A
typical pedigree might look like this:

Examples of autosomal dominant conditions include:

- Tuberous sclerosis,
- neurofibromatosis and many other cancer causing mutations such as
retinoblastoma

Autosomal recessive
A recessive trait will only manifest itself when homozygous. If it is a severe
condition it will be unlikely that homozygotes will live to reproduce and thus most
occurences of the condition will be in matings between two heterozygotes (or
carriers).

An autosomal recessive condition may be transmitted through a long line of

carriers before, by ill chance two carrier’s mate. Then there will be a ¼ chance
that any child will be affected. The pedigree will therefore often only have one
'sibship' with affected members.

a) A 'typical' autosomal recessive pedigree, and b) an autosomal pedigree

with inbreeding:

If the parents are related to each other, perhaps by being cousins, there is an
increased risk that any gene present in a child may have two alleles identical by
descent. The degree of risk that both alleles of a pair in a person are descended
from the same recent common ancestor is the degree of inbreeding of the
person.

Let us examine b) in the figure above. Considering any child of a first cousin
mating, one can trace through the pedigree the chance that the other allele is the
same by common descent.

Let us consider any child of generation IV, any gene which came from the father,
III3 had a half chance of having come from grandmother II2, a further half chance
of being also present in her sister, grandmother II4 a further half a chance of
having been passed to mother III4 and finally a half chance of being transmitted
into the same child we started from. A total risk of ½ x ½ x ½ x ½ = 1/16

Maternal and paternal alleles and their breeding

It can be thought of as either

• the chance that both maternal and paternal alleles at one locus are identical by
descent, or

• the proportion of all the individual's genes that are homozygous because of
identity by common descent, is known as the coefficient of inbreeding and is
usually given the symbol F.

Once phenotypic data is collected from several generations and the pedigree is
drawn, careful analysis will allow you to determine whether the trait is dominant
or recessive. Here are some rules to follow.

For those traits exhibiting dominant gene action:

• affected individuals have at least one affected parent • the phenotype

generally appears every generation • two unaffected parents only have
unaffected offspring

The following is the pedigree of a trait contolled by dominant gene action.

And for those traits exhibiting recessive gene action:

• unaffected parents can have affected offspring • affected progeny are both
male and female

The following is the pedigree of a trait contolled by recessive gene action.

Mitochondrial inheritance
Mitochondria are cellular organelles involved in energy production and
conversion. They have a small amount of their own mitochondrial DNA (mtDNA).
Though it is a relatively small portion of our total DNA, it is still subject to
mutation and several diseases associated with mutations in mtDNA have been
found. The inheritance patterns of mtDNA are unique. Mitochondrial DNA is
inherited maternally.

Each person inherits the mtDNA of their mother, but none of their father’s. This
is because the relatively large ovum has many copies of mitochondrial DNA but
the sperm has very few and these are lost during fertilization. Due to this unique
feature of mitochondrial DNA inheritance, there are some constraints on the
inheritance patterns of mitochondrial DNA disorders. These include:

- All children of affected males will not inherit the disease. - All children of
affected females will inherit it.

An example of this type of disease is Leber’s optic atrophy, a progressive loss of

vision in the central visual field due to degeneration of the optic nerve.

-There are relatively few human genetic diseases caused by mitochondrial

mutations but, because of their maternal transmission, they have a very
distinctive pattern of inheritance.

- A mitochondrial inheritance pedigree is that all the children of an affected

female but none of the children of an affected male will inherit the disease.

Uniparental disomy
Although it is not possible to make a viable human embryo with two complete
haploid sets of chromosomes from the same sex parent it is sometimes possible
that both copies of a single chromosome may be inherited from the same parent
(along with no copies of the corresponding chromosome from the other parent.)

Rare cases of cystic fibrosis (a common autosomal recessive disease) have

occurred in which one parent was a heterozygous carrier of the disease but the
second parent had two wild type alleles. The child had received two copies of the
mutant chromosome 7 from the carrier parent and no chromosome 7 from the
unaffected parent.
Environmental Influences on Gene Expression
Internal and external environmental factors, like gender and temperature,
influence gene expression.

Aa Aa Aa

The expression of genes in an organism can be influenced by the environment,

including the external world in which the organism is located or develops, as well
as the organism's internal world, which includes such factors as its hormones and
metabolism. One major internal environmental influence that affects gene
expression is gender, as is the case with sex-influenced and sex-limited traits.
Similarly, drugs, chemicals, temperature, and light are among the external
environmental factors that can determine which genes are turned on and off,
thereby influencing the way an organism develops and functions.

Sex-Influenced and Sex-Limited Traits

Sex-influenced traits are those that are expressed differently in the two sexes.
Such traits are autosomal, which means that the genes responsible for their
expression are not carried on the sex chromosomes. An example of a sex-
influenced trait is male-pattern baldness. The baldness allele, which causes hair
loss, is influenced by the hormones testosterone and dihydrotestosterone, but
only when levels of the two hormones are high. In general, males have much
higher levels of these hormones than females, so the baldness allele has a
stronger effect in males than in females. However, high levels of stress can lead to
expression of the gene in women. In stressful situations, women's adrenal glands
can produce testosterone and convert it into dihydrotestosterone, which can
result in hair loss.

Sex-limited traits are also autosomal. Unlike sex-influenced traits, whose

expression differs according to sex, sex-limited traits are expressed in individuals
of only one sex. An example of a sex-limited trait is lactation, or milk production.
Although the genes for producing milk are carried by both males and females,
only lactating females express these genes.

Drugs and Chemicals

The presence of drugs or chemicals in an organism's environment can also
influence gene expression in the organism. Cyclops fish are a dramatic example of
the way in which an environmental chemical can affect development. In 1907,
researcher C. R. Stockard created cyclopean fish embryos by placing fertilized
Fundulus heteroclitus eggs in 100 mL of seawater mixed with approximately 6 g of
magnesium chloride. Normally, F. heteroclitus embryos feature two eyes;
however, in this experiment, half of the eggs placed in the magnesium chloride
mixture gave rise to one-eyed embryos (Stockard, 1907).

A second example of how chemical environments affect gene expression is the

case of supplemental oxygen administration causing blindness in premature
infants (Silverman, 2004). In the 1940s, supplemental oxygen administration
became a popular practice when doctors noticed that increasing oxygen levels
converted the breathing pattern of premature infants to a "normal" rhythm.
Unfortunately, there is a causal relationship between oxygen administration and
retinopathy of prematurity (ROP), although this relationship was unknown at the
time; thus, by 1953, ROP had blinded approximately 10,000 infants worldwide.
Finally, in 1954, a randomized clinical trial identified supplemental oxygen as the
factor causing blindness. Complicating the issue is the fact that too little oxygen
results in a higher rate of brain damage and mortality in premature infants.
Unfortunately, even today, the optimal amount of oxygenation necessary to treat
premature infants while completely avoiding these complications is still not clear.
 “Yet another example of the way in which chemicals can alter gene expression
involves thalidomide, a sedative, antiemetic, and nonbarbiturate drug that was
first manufactured and marketed during the mid-1950s. While thalidomide has no
discernable effect on gene expression and development in healthy adults, it has a
profoundly detrimental effect on developing fetuses. When the drug was first
created, however, its impact on fetuses was not known. Moreover, because of its
apparent lack of toxicity in adult human volunteers, thalidomide was marketed as
the safest available sedative of its time and rapidly became popular in Europe,
Australia, Asia, and South America for countering the effects of morning sickness.
(In the United States, the drug failed to receive Food and Drug Administration
approval because its side effects included tingling hands and feet after long-term
administration, which led to concerns that the drug might be associated with
neuropathy.) Not until 1961 did Australian researcher William McBride and
German researcher Widukind Lenz independently report that thalidomide was a
teratogen, meaning that its use was associated with birth defects. Another study
associated thalidomide use with neuropathies. Sadly, the drug was withdrawn too
late to prevent severe developmental deformities in approximately 8,000 to
12,000 infants, many of whom were born with stunted limb development.
Interestingly, despite the fact that thalidomide is dangerous during embryonic
development, the drug continues to be used in certain instances yet today. For
example, it has therapeutic potential in treating leprosy, and in recent years, it has
also been used to treat cancers and enhance the effectiveness of cancer vaccines
(Bartlett et al., 2004; Fraser, 1988).”

Temperature and Light

An illustration shows two rabbits side-by-side. The rabbit at left was reared at 20
degrees Celsius. It has a white body with black ears, nose, feet, and tail. The
rabbit at right was reared at temperatures above 30 degrees Celsius. It is white
with no black coloration on its body or extremities. Both rabbits have red eyes.
Gene C controls fur pigmentation in Himalayan rabbits. Because the gene is active
when environmental temperatures are between 15 and 25°C, the rabbit reared at
20°C (left) has pigmentation on its ears, nose, and feet, where its body loses the
most heat. The rabbit reared at temperatures above 30°C (right) has no fur
pigmentation, because gene C is inactive at these higher temperatures.

In addition to drugs and chemicals, temperature and light are external

environmental factors that may influence gene expression in certain organisms.
For example, Himalayan rabbits carry the C gene, which is required for the
development of pigments in the fur, skin, and eyes, and whose expression is
regulated by temperature (Sturtevant, 1913). Specifically, the C gene is inactive
above 35°C, and it is maximally active from 15°C to 25°C. This temperature
regulation of gene expression produces rabbits with a distinctive coat coloring. In
the warm, central parts of the rabbit's body, the gene is inactive, and no pigments
are produced, causing the fur color to be white (Figure 1). Meanwhile, in the
rabbit's extremities (i.e., the ears, tip of the nose, and feet), where the
temperature is much lower than 35°C, the C gene actively produces pigment,
making these parts of the animal black.

Light can also influence gene expression, as in the case of butterfly wing
development and growth. For example, in 1917, biologist Thomas Hunt Morgan
conducted studies in which he placed Vanessa urtica and Vanessa io caterpillars
under red, green, or blue light, while other caterpillars were kept in the dark.
When the caterpillars developed into butterflies, their wings showed dramatic
differences. Exposure to red light resulted in intensely colored wings, while
exposure to green light resulted in dusky wings. Blue light and darkness led to
paler colored wings. In addition, the V. urtica butterflies reared under blue light
and V. io butterflies reared in the dark were larger than the other butterflies.

As these examples illustrate, there are many specific instances of environmental

influences on gene expression. However, it is important to keep in mind that
there is a very complex interaction between our genes and our environment that
defines our phenotype and who we are.
References :
Bartlett, J. B., et al. The evolution of thalidomide and its IMiD derivatives as
anticancer agents. Nature Reviews Cancer 4, 314–322 (2004)
doi:10.1038/nrc1323 (link to article)

Fraser, F. C. Thalidomide retrospective: What did we learn? Tetralogy 38, 201–302

(1988)

Morgan, T. H. Experimental Zoology (New York, Macmillan, 1917)

Silverman, W. A. A cautionary tale about supplemental oxygen: The albatross of

neonatal medicine. Pediatrics 113, 394–396 (2004)

Stockard, C. R. The influence of external factors, chemical and physical, on the

development of Fundulus heteroclitus. Journal of Experimental Zoology 4, 165–
201 (1907)

Sturtevant, H. The Himalayan rabbit case, with some considerations on multiple

allelomorphs. American Naturalist 47, 234–238 (1913)
 Human Genome Project (HGP)
Introduction
It is an international collaboration that successfully determined, stored, and
rendered publicly available the sequences of almost all the genetic content of the
chromosomes of the human organism, otherwise known as the human genome.
The Human Genome Project (HGP), which operated from 1990 to 2003, provided
researchers with basic information about the sequences of the three billion
chemical base pairs (i.e., adenine [A], thymine [T], guanine [G], and cytosine [C])
that make up human genomic DNA (deoxyribonucleic acid). The HGP was further
intended to improve the technologies needed to interpret and analyze genomic
sequences, to identify all the genes encoded in human DNA, and to address
the ethical, legal, and social implications that might arise from defining the entire
human genomic sequence.

Timeline Of The HGP

Prior to the HGP, the base sequences of numerous human genes had been
determined through contributions made by many individual scientists. However,
the vast majority of the human genome remained unexplored, and researchers,
having recognized the necessity and value of having at hand the basic information
of the human genomic sequence, were beginning to search for ways to uncover
this information more quickly. Because the HGP required billions of dollars that
would inevitably be taken away from traditional biomedical research, many
scientists, politicians, and ethicists became involved in vigorous debates over the
merits, risks, and relative costs of sequencing the entire human genome in one
concerted undertaking. Despite the controversy, the HGP was initiated in 1990
under the leadership of American geneticist Francis Collins, with support from the
U.S. Department of Energy and the National Institutes of Health (NIH). The effort
was soon joined by scientists from around the world. Moreover, a series of
technical advances in the sequencing process itself and in the computer hardware
and software used to track and analyze the resulting data enabled rapid progress
of the project.

Technological advance, however, was only one of the forces driving the pace of
discovery of the HGP. In 1998 a private-sector enterprise, Celera Genomics,
headed by American biochemist and former NIH scientist J. Craig Venter, began to
compete with and potentially undermine the publicly funded HGP. At the heart of
the competition was the prospect of gaining control over potential patents on the
genome sequence, which was considered a pharmaceutical treasure trove.
Although the legal and financial reasons remain unclear, the rivalry between
Celera and the NIH ended when they joined forces, thus speeding completion of
the rough draft sequence of the human genome. The completion of the rough
draft was announced in June 2000 by Collins and Venter. For the next three years,
the rough draft sequence was refined, extended, and further analyzed, and in
April 2003, coinciding with the 50th anniversary of the publication that described
the double-helical structure of DNA, written by British biophysicist Francis
Crick and American geneticist and biophysicist James D. Watson the HGP was
declared complete.

Science Behind The HGP

To appreciate the magnitude, challenge, and implications of the HGP, it is

important first to consider the foundation of science upon which it was based—
the fields of classical, molecular, and human genetics. Classical genetics is
considered to have begun in the mid-1800s with the work of Austrian botanist,
teacher, and Augustinian prelate Gregor Mendal, who defined the basic laws of
genetics in his studies of the garde pea (Pisum sativum). Mendel succeeded in
explaining that, for any given gene, offspring inherit from each parent one form,
or, of allele a gene. In addition, the allele that an offspring inherits from a parent
for one gene is independent of the allele inherited from that parent for another
gene.

 

Mendel’s basic laws of genetics were expanded upon in the early 20th century
when molecular geneticists began conducting research using model organisms
such as Drosophila melanogaster (also called the vinegar fly or Fruit fly) that
provided a more comprehensive view of the complexities of genetic transmission.
For example, molecular genetics studies demonstrated that two alleles can be
codominant (characteristics of both alleles of a gene are expressed) and that not
all traits are defined by single genes; in fact, many traits reflect the combined
influences of numerous genes. The field of molecular genetics emerged from the
realization that DNA and RNA (ribonucleic acid) constitute the genetic material in
all living things. In physical terms, a gene is a discrete stretch of nucleotides within
a DNA molecule, with each nucleotide containing an A, G, T, or C base unit. It is
the specific sequence of these bases that encodes the information contained in
the gene and that is ultimately translated into a final product, a molecule
of protein or in some cases a molecule of RNA. The protein or RNA product may
have a structural role or a regulatory role, or it may serve as an enzyme to
promote the formation or metabolism of other molecules,
including carbohydrates and lipids. All these molecules work in concert to
maintain the processes required for life.

Studies in molecular genetics led to studies in human genetics and the

consideration of the ways in which traits in humans are inherited. For example,
most traits in humans and other species result from a combination of genetic and
environmental influences. In addition, some genes, such as those encoded at
neighbouring spots on a single chromosome, tend to be inherited together, rather
than independently, whereas other genes, namely those encoded on the
mitochondrial genome, are inherited only from the mother, and yet other genes,
encoded on the Y chromosome, are passed only from fathers to sons. Using data
from the HGP, scientists have estimated that the human genome contains
anywhere from 20,000 to 25,000 genes.

Advances Based On The HGP

Advances in genetics and genomics continue to emerge. Two important advances

include the International HapMap Project and the initiation of large-scale
comparative genomics studies, both of which have been made possible by the
availability of databases of genomic sequences of humans, as well as the
availability of databases of genomic sequences of a multitude of other species.
The International HapMap Project is a collaborative effort between Japan, the
United Kingdom, Canada, China, Nigeria, and the United States in which the goal
is to identify and catalog genetic similarities and differences between individuals
representing four major human populations derived from the continents of Africa,
Europe, and Asia. The identification of genetic variations called polymorphisms
that exist in DNA sequences among populations allows researchers to define
haplotypes, markers that distinguish specific regions of DNA in the human
genome. Association studies of the prevalence of these haplotypes in control and
patient populations can be used to help identify potentially functional genetic
differences that predispose an individual toward disease or, alternatively, that
may protect an individual from disease. Similarly, linkage studies of the
inheritance of these haplotypes in families affected by a known genetic trait can
also help to pinpoint the specific gene or genes that underlie or modify that trait.
Association and linkage studies have enabled the identification of numerous
disease genes and their modifiers.

In contrast to the International HapMap Project, which compares genomic

sequences within one species, comparative genomics is the study of similarities
and differences between different species. In recent years a staggering number of
full or almost full genome sequences from different species have been
determined and deposited in public databases such as NIH’s Entrez
Genome database. By comparing these sequences, often using a software tool
called BLAST (Basic Local Alignment Search Tool), researchers are able to identify
degrees of similarity and divergence between the genes and genomes of related
or disparate species. The results of these studies have illuminated the evolution of
species and of genomes. Such studies have also helped to draw attention to
highly conserved regions of noncoding sequences of DNA that were originally
thought to be nonfunctional because they do not contain base sequences that are
translated into protein. However, some noncoding regions of DNA have been
highly conserved and may play key roles in human evolution.

Impacts Of The HGP

Impact on Medicine:
The public availability of a complete human genome sequence represented a
defining moment for both the biomedical community and for society. In the years
since completion of the HGP, the human genome database, together with other
publicly available resources such as the HapMap database, has enabled the
identification of a variety of genes that are associated with disease. This, in turn,
has enabled more objective and accurate diagnoses, in some cases even before
the onset of overt clinical symptoms. Association and linkage studies have
identified additional genetic influences that modify the development or outcome
for both rare and common diseases. The recognition that human genomes may
influence everything from disease risk to physiological response to medications
has led to the emergence of the concept of personalized medicine—the idea that
knowledge of a patient’s entire genome sequence will give health care providers
the ability to deliver the most appropriate and effective care for that patient.
Indeed, continuing advances in DNA sequencing technology promise to lower the
cost of sequencing an individual’s entire genome to that of other, relatively
inexpensive, diagnostic tests.

Impact on law and the social sciences

The HGP affects fields beyond biomedical science in ways that are
both tangible and profound. For example, human genomic sequence information,
analyzed through a system called CODIS (Combined DNA Index System), has
revolutionized the field of forensics, enabling positive identification of individuals
from extremely tiny samples of biological substances, such as saliva on the seal of
an envelope, a few hairs, or a spot of dried blood or semen. Indeed, spurred by
high rates of recidivism (the tendency of a previously convicted criminal to return
to prior criminal behaviour despite punishment or imprisonment), some
governments have even instituted the policy of banking DNA samples from all
convicted criminals in order to facilitate the identification of perpetrators of
future crimes. While politically controversial, this policy has proved highly
effective. By the same token, innocent men and women have been exonerated on
the basis of DNA evidence, sometimes decades after wrongful convictions for
crimes they did not commit.
Comparative DNA sequence analyses of samples representing distinct modern
populations of humans have revolutionized the field of anthropology. For
example, by following DNA sequence variations present on mitochondrial DNA,
which is maternally inherited, and on the Y chromosome, which is paternally
inherited, molecular anthropologists have confirmed Africa as the cradle of the
modern human species Homo Sapiens, and have identified the waves of human
migration that emerged from Africa over the last 60,000 years to populate the
other continents of the world. Databases that map DNA sequence variations that
are common in some populations but rare in others have enabled so-called
molecular genealogists to trace the continent or even subcontinent of origin of
given families or individuals. Perhaps more important than helping to trace the
roots of humans and to see the differences between populations of humans, DNA
sequence information has enabled recognition of how closely related one
population of humans is to another and how closely related humans are to the
multitude of other species that inhabit earth

References
 Big Science
 In Big Science
 eugenics
 In eugenics: The new eugenics
 evolutionary studies
 In evolution: Molecular biology and Earth sciences
 International HapMap Project
 In International HapMap Project
 philosophy of biology and ethical issues
 In biology, philosophy of: Social and ethical issues
 systems biology
 In systems biology
 In systems biology: Complexity and emergent properties
 translational medicine
 In translational medicine: Opportunities in translational medicine
 whole genome sequencing
 In whole genome sequencing: Sequencing methods: from genes to genomes

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