A FIRST LOOK INTO GENETIC MUTATIONS 1

A First Look into Genetic Mutations

Sophia Kuhn

Independent Research

Magnet Honors English 10

Mrs. Graves

June 2, 2018
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Genetics are the basis for life. Studying genetics has allowed scientists to have a better

understanding of biological life. This topic is prevalent to all life, not just to scientists working in

the field. The study of genetic mutations, specifically, has allowed for those with genetic

disorders to live a more comfortable life. With current understandings about genetic mutations,

scientists and researchers are working towards treating genetic disorders. Cancer is just one

example of a disease that manifests from a genetic mutation. For several decades, scientists have

been dedicating time to understanding how cancer works and how it can be treated. Without a

basic understanding or knowledge of genetic mutations, we wouldn’t have the cancer treatments

used today (e.g., radiation and chemotherapy.) Genetic mutations are responsible for genetic

variation, an important mechanism in evolution. They also explain the origins of genetic

disorders and their symptoms.

What I Knew Before Research

Before my initial research, I knew the basics of genetics and gene mutations (I had

learned most of the basic information in my molecular biology class.) I knew that disorders such

as sickle cell anemia, cystic fibrosis (CF), and color-blindness are the result of genetic mutations.

Genetic mutations are mistakes in an organic structure called DNA, deoxyribonucleic acid. DNA

contains the information to synthesizing proteins that are essential in the building of different

structures found in the body. In a genetic mutation, a part of the DNA strand is sequenced

incorrectly which in turn causes the production of dysfunctional proteins. Aside from other,

mainly random, facts about genetics and gene mutations, my comparatively limited knowledge

fueled my interest it this large field of research.

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There were several things that I wanted to answer through this research. This included the

different types of genetic mutations, different types of genetic disorders, the technology used to

study genes, and the current methods used to treat genetic disorders. I also wanted to connect the

topic to the world today through reviewing genetic counseling and the Human Genome Project.

With my research, I wanted to answer my big question: ​What are genetic mutations, how are

they formed, and what are their leading effects? ​Through this research, I studied the cause of

genetic mutations and their leading effects.

My Research Journey

When I first began to dive into the topic of genetic mutations, I decided to start with

videos rather than articles. I was able to find a playlist of videos discussing the basics of genetic

mutations on Khan Academy. While the visual aids were helpful, the videos didn’t provide

enough explanation for the concepts discussed. Immediately after watching a few videos, I

searched for articles that discussed the basics of genetic mutations. Two sites that were

especially helpful were Learn.Genetics and the NIH (National Institutes of Health) website. With

these sites, and several others, I was able to obtain a better understanding of what genetic

mutations are, including the different categories in which they are organized.

After finishing the first part of my research, I was ready to start researching human

genetic disorders. I decided to start with Waardenburg Syndrome. I began my research with the

NIH website that thoroughly described the disorder, its causes, and its effects. One problem I ran

into when researching this disorder was finding which type of mutation is linked with this

disorder. Several sites gave which genes are mutated, but never explained what type of mutation

occurs on those genes. After awhile of searching through several sites, I decided to just simply
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list the genes that were mutated. I then went on to study Huntington's disease (HD.) I started with

the NIH website and then branched out onto other helpful and secure websites such as the NCBI

(National Center for Biotechnology Information) website. After completing my research of HD, I

decided to research one more disorder called cystic fibrosis (CF.) As I did with the other two

disorders, I first read through articles on the NIH website and then branched off into other

databases and medical websites. I was able to find several websites that were created by

organizations specialized in CF. I was both amazed and overwhelmed to see the almost endless

amount of information about each disorder.

After using the internet for some time, I used the ​Gale Encyclopedia of Genetic

Disorders​, a massive, 2-volume paper encyclopedia of gene linked disorders,​ ​for fact-checking

and research. During this time in my research, I had reached out to an expert I was interesting in

interviewing. Unfortunately, I got a negative response explaining that the clinic’s tight schedule

would make it difficult to conduct an interview. However, I was sent contact information to a

genetic lab in Maryland. Of course, it would have been a little difficult to do considering that

Maryland is almost five hours away from Virginia Beach. Although I was disappointed to

receive a negative response, as it would be an exciting experience and open connections with

other experts in this field, I was content knowing that I was at least able to reach out and get a

response. I decided to focus on the academic side to my research and continue using online and

offline resources.

At this point in my research, I had answered my major questions: ​What are the different

types of genetic mutations, different types of genetic disorders, the technology used to study

genes, and the current methods used to treat genetic disorders?​ I wanted to connect my topic
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globally by applying it to the field of genetic counseling as well as the Human Genome Project.

When researching genetic counseling, I found the NSGC (National Society of Genetic

Counselors) website to be particularly helpful. It provided me with both concrete explanations of

the field along with personal accounts about the field from certified genetic counselors.

For my last post I decided to look into the Human Genome Project. I thought this would

be a good way to end my research by applying the information to an international project

concerning genes. I went straight to Google and typed "What was the Human Genome Project?"

While I had heard my biology teacher mention this project, I wanted to understand more about

its goals and findings. I went to the NIH website under the National Human Genome Research

Institute, along with a few other websites, and found a plethora of information concerning the

international project and its discoveries.

After researching the Human Genome Project, I had accumulated quite a bit or research

and was ready to write the research paper. The research journey, although long, was rewarding

and has opened several new doors in the field of genetics and medicine. With this research, I

hope to continue my interest in genetics into my coming years of my academic career in high

school.

The Results of My Long Research Journey

The study of genetic mutations is a very large topic. It took many hours of research to

find a concrete answer to the question, ​What are genetic mutations, how are they formed, and

what are their leading effects? ​While I was able to thoroughly answer this question, it is rather

hard to summarize the answer in one sentence due to the topic’s largeness. Genetic mutations are

a set of different mistakes within DNA, an organic molecule where the information for protein
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synthesis is contained. Therefore, if a genetic mutation is present, the resulting protein made will

be different and possibly dysfunctional. If a dysfunctional protein is continuously synthesized,

the function of the whole organism will be affected. These types of genetic mutations cause

genetic disorders. While not all genetic mutations affect an organism negatively, they can, in

some cases, become life-threatening. The study of genetic disorders led to the growing field of

genetic counseling in which trained professionals work with individuals managing genetic

disorders. There are over 6,000 genetic disorders that have been studied, and the list is growing.

Some of the genetic disorders studied today were discovered through the Human Genome

Project. This project was created with the goal of mapping out the entire human genome. The

Human Genome Project lead to many advancements in the field of genetics and greatly

contributed to the study genetic mutations. Overall, the central idea of my research is that genetic

mutations are mistakes within DNA that are responsible for genetic disorders.

Before I am able to discuss genetic mutations, I must explain the mechanism behind

genetics: DNA. DNA, or deoxyribonucleic acid, is a double stranded organic molecular structure

made up of a sequence of nucleotides. Encoded within the long DNA strand, lies the recipe for

proteins. Proteins are large organic molecules essential to the structure and function of different

body tissues, such as muscles. For proteins to be synthesized, the instructions for building a

protein found in DNA must be translated into information that the cell can use to synthesize the

protein. DNA is found in the nucleus of a cell, and it is rather large. Its large size prevents it from

leaving the nucleus, therefore it must use another molecule to transfer its information to outside

of the nucleus where proteins are synthesized. RNA, an organic molecule similar to DNA, acts as

the medium between DNA and proteins. They take the information encoded in DNA and make it
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usable for the cell in protein synthesis. The Central Dogma of molecular biology describes this

transfer of information from DNA to RNA to a protein. For this transfer of information to occur,

two steps are needed: transcription and translation. However, before transcription and translation

occurs, DNA is copied in a process called replication.

DNA replication is the process in which a preexistent (parental) DNA stand is used to

make a complementary DNA strand. DNA is a long sequence of nucleotides; a DNA nucleotide

is made of a phosphate, a deoxyribose (missing an oxygen atom) sugar, and a nitrogenous base.

The DNA nitrogen bases, which are nitrogen-containing organic molecules that have chemical

properties of bases, are thymine, guanine, adenine, and cytosine. The complementary base-pair

rule states that adenine must bond with thymine and cytosine must bond with guanine. As

mentioned, DNA is double stranded. Therefore, there are two separate DNA strands that are

connected by hydrogen bonds between the corresponding nitrogenous bases. The complementary

base-pair rule is applied in DNA replication to synthesize a new DNA strand that is

complementary to the parental DNA strand. In replication, DNA nucleotides will be placed in a

certain order; the order is dependent on the sequence of nucleotides in the parental strand. The

nitrogen bases on the parental strand are used to correctly place a new DNA nucleotide based on

the complementary base-pair rule. If a nitrogen is incorrectly placed, a mutation occurs. The

information coded in the replicated DNA, strand along with the mutation, will be used in

transcription and translation, and affect the resulting proteins synthesized.

The next step in the transfer of information is called transcription; the information

encoded on a DNA strand is used to synthesize an RNA, ribonucleic acid, strand. RNA is also

made up of a sequence of nucleotides. However, the nitrogenous base thymine that is found in
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DNA is replaced by uracil in RNA. Furthermore, the deoxyribose sugar is replaced with ribose

sugar that contains the oxygen atom absent in deoxyribose. Once transcription is complete, the

RNA strand is used to build a protein in a process called translation. During translation, the

information encoded in RNA, read in the form of codons, a set of three consecutive nucleotides,

is used to build a sequence of corresponding amino acids. Amino acids are the building blocks

that make up proteins. There are 20 different amino acids categorized into 5 groups based on

their properties. The order of amino acids in an amino acid sequence determines the function of

the protein. Therefore, if a mistake occurs in the replication of DNA, and the faulty instructions

are used, the function of the resulting protein synthesized is altered.

When understanding genetic mutations and their effects on organisms, it is crucial to

know how information for producing proteins is transferred through different molecular

structures in a cell. Proteins determine how a certain mechanism in the cell will function, and, on

a larger scale, how the organism will function and appear as a whole. Therefore, if a certain

protein is synthesized incorrectly, its phenotypic output will be different than what is expected.

That is why it is crucial that no mistakes are made in DNA replication. If a mistake, or mutation,

does occur, it can lead to genetic disorders such as Waardenburg syndrome, Huntington's

disease, and cystic fibrosis (all of which will be discussed later in this paper.)

The section of a DNA strand that is read in transcription is called a gene. Genes are

responsible for the synthesis of proteins. Depending on which genes are used, the protein

synthesized will most often have a direct effect on an organism’s phenotype. The phenotype is a

physical expression of an organism's genotype, or genetic makeup. When an egg is fertilized and

forms a zygote, the first cell of an embryo, the genetic material from the female and male is
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"combined." This means that the genetic information of both the female and male will be present

in the offspring. However, which gene is expressed depends on which gene is dominant.

Different versions of the same gene are called alleles. In a pair of alleles, there can be two

dominant, two recessive, or one dominant and one recessive genes. In simple genetics, a

recessive trait will only be expressed if there are two recessive alleles present. If a dominant trait

is present, it will be expressed. Knowing whether or not a genetic mutation will affect an

individual is dependent on these properties of genetics.

Genetic mutations are permanent alterations in DNA sequences that make up a gene. The

size of a genetic mutation can range from a mistake in single base-pair to a set of several codons.

It is important to understand that genetic mutations do not only cause diseases and disorders.

They are also responsible for genetic variation, an important factor in the evolution of humans

and other species. Aside from the mutations that result in genetic disorders, genetic variation can

come from mutations that good or neutral.​1 ​A polymorphism is a common genetic mutation that

is considered "normal.”. For example, variation in eye color, a polymorphism, is the result of

genetic mutations. Throughout the history of biological life, genetic mutations have been the

basis for genetic variation, a mechanism that leads to evolution. However, as we know, genetic

mutations can also negatively impact an organism.

There are thousands of types of genetic mutations that have been studied in humans.

Therefore, it is only natural that we would categorize them into different groups. Genetic

mutations can first be placed into two major categories based on when they occur: hereditary and

somatic. Hereditary mutations occur in the formation of gametes (sperm and egg)​ ​in meiosis

before fertilization. When the sperm and egg cell unite of two individuals, the resulting offspring
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will receive DNA from both the father and mother. If either gamete has mutated DNA, the

mutation will be inherited in every cell of the offspring. Hereditary mutations, as the name

suggests, are inherited through each generation. Therefore, those who have a hereditary mutation

will have offspring that inherit the mutated gene. On the other hand, somatic mutations do not

occur in the formation of gametes and are not inherited through each generation. These

mutations develop within the individual after fertilization of the egg or after birth, and they only

affect a partial number of cells in the offspring. These mutations can be caused by environmental

factors (such as exposure to UV rays) or if an error is made during DNA replication in cell

division as a baby is developing in the womb. While these mutations last for the duration of an

individual's life span, it cannot be inherited by his or her offspring.​1,2

In addition to categorizing mutations by when they occur, they are also classified by ​how

they occur. ​The two major types of genetic mutations are point and frameshift mutations. ​Point

mutations are caused by the substitution of a single DNA strand. ​This category is separated into

three subcategories: nonsense mutations, missense mutations, and silent mutations. Frameshift

mutations occur when the reading frame of DNA strand is "shifted," therefore the sequence of

codons is changed. This type of mutation can be the result of a deletion, insertion, duplication, or

repeat expansion mutation.​3

As mentioned, point mutations are subcategorized into three grou​ps: ​nonse​nse mutations,

missense mutations, and silent mutations. ​Nonsense mutations occur when the substituted

nucleotide changes a codon that codes for an amino acid to code for a stop codon. ​A stop codon,

or termination codon, is a trinucleotide sequence that signals for the termination of protein

synthesis. ​Therefore, the synthesis of the protein will be stopped, and an incomplete protein will
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be made. ​On the other hand, missense mutations result in an amino acid change. In this mutation,

the substitution of a nucleotide will result in the coding for a different amino acid​ and therefore

change the overall sequencing of amino acids in a protein. ​Lastly, silent mutations occur when

the substitution of a nucleotide doesn't affect the production of the protein synthesized. Different

nucleotide sequences in codons can code for the same amino acid, therefore it is possible that a

point mutation in a DNA sequence doesn't change the amino acid created.​4,5

Frameshift mutations can be the result of a deletion, insertion, duplication, or repeat

expansion mutation. When an extra nucleotide, or set of nucleotides, is/are added to a sequence

of nucleotides, it is called an insertion. On the other hand, if a nucleotide or set of nucleotides are

removed from a sequence, it is called a deletion. Insertions and deletions ​may​ cause a frameshift

mutation. When one or two nucleotides and inserted or deleted, the frame of sequence of codons

will be shifted. However, if a whole codon or set of codons are added or deleted, the reading

frame is not shifted. While it will affect the resulting sequence of amino acids, it is not

considered a frameshift mutation. This is also true when studying duplication and repeat

expansion. Duplication is a type of mutation in which a piece of a DNA sequence is abnormally

repeated one or more times. Repeat expansion mutations occur when a short DNA sequence is

consecutively​ repeated in a DNA sequence. In duplication and repeat expansion, the reading

frame in a DNA molecule will not be shifted if a whole codon is repeated. Therefore, frameshift

mutations only occur if the reading frame of a DNA molecule is moved. If it is moved, the whole

sequence of amino acids synthesized will be altered.​5

When comparing point and frameshift mutations, frameshift will have the most effect on

the resulting protein. Point mutations will only change one amino acid at a time in an amino acid
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sequence. On the other hand, frameshift causes the whole reading frame of a DNA strand to be

skewed. Therefore, the sequence of the amino acids is changed completely, preceding from the

point of the mutation.

An example in which these terms can be applied is when studying sickle cell disease, or

SCD. SCD occurs when hemoglobin, a protein in human blood, is mutated to a less active form

called hemoglobin S. This results in a crescent-shaped red blood cell. The change in hemoglobin

is caused by a glutamate residue being converted to a valine residue. This mutation is a missense

mutation in which only one nitrogenous base is affected and results in the creation of a different

amino acid.​6

Understanding these different classifications is crucial in evaluating what disorder(s) a

patient has and possible treatments. From a researcher's standpoint, it is incredible to think that a

single shift in genetic code can lead to a debilitating disorder or disease, such as cancer. There

are several thousand types of genetic disorders that have been studied so far in genetics. This

paper will focus on three different disorders: Waardenburg syndrome, Huntington’s disease, and

cystic fibrosis.

Waardenburg Syndrome is a genetic disorder characterized by hearing loss and abnormal

pigmentation in the skin, hair, and eyes. Symptoms can vary for each patient affected by this

syndrome. The most common features include congenital (originating from birth) hearing loss;

premature graying of the hair or the presence of a white forelock; pale blue eyes, heterochromia

iris (different colored eyes), pale blue eyes, or different coloration in one eye.​7 ​There are four

subtypes of Waardenburg Syndrome: Type I, Type II, Type III, and Type IV. They are each

distinguished by different symptoms.​8

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Type I and Type II are similar because they share some features. However, Type I is

more often characterized by widely spaced eyes, while Type II is more often associated with

hearing loss. Type I and Type II are the most common types of Waardenburg syndrome. Type

III, or Klein Waardenburg syndrome, is characterized by upper limb anomalies as well as hearing

loss and abnormal pigmentation as listed before. Type IV, or Waardenburg-Shah syndrome, has

symptoms of both Waardenburg syndrome and Hirschsprung disease. Hirschsprung disease is an

intestinal disorder that causes blockage of the intestine. Therefore, patients with Type IV

Waardenburg syndrome will have abnormal bowel function. Unlike Type I and Type II, it is rare

to see many Type III and Type IV cases of Waardenburg syndrome.

Diagnosis of Waardenburg syndrome involves observing the presence of the symptoms

mentioned. Type I, the most common form of this syndrome, is diagnosed when either two

major, or one major and two minor, criteria are met. Major criteria includes congenital hearing

loss, abnormal iris or hair pigmentation, and lateral displacement of the eyes. Minor criteria

include white patches of skin (leukoderma), monobrow (synophrys), high or wide nasal bridge,

and incomplete development of the nostrils (hypoplasia.) Diagnosis for each subtype, however,

is slightly different due to the different symptoms associated with each type. For example, for the

diagnosis of type IV Waardenburg syndrome to be valid, the patient must display major and

minor criteria along with having Hirschsprung disease.​9

Waardenburg syndrome is caused by mutations on the EDN3, EDNRB, MITF, PAX3,

SNA12, and SOX10 genes. These genes are used in the formation of several cells, including the

melanocyte cells. These cells are responsible for producing the pigment melanin, found in hair,

eyes, and skin. Melanin also plays an important role in hearing. Therefore, if there is a mutation
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in one of these genes, the resulting phenotype will be abnormal pigmentation in the hair, eyes, or

skin along with hearing loss. Type I and Type III are caused by mutations of the PAX3 gene.

Mutations on the MITF and SNA12 gene can result in Type II Waardenburg syndrome.

Mutations on the EDN3, EDNRB, and SOX10 gene can result in Type IV. Aside from its

importance in the development of melanocyte cells, EDN3, EDNRB, and SOX10 are responsible

for the formation of nerve cells found in the intestine. Therefore, mutations in these genes can

cause intestinal problems diagnosed as Hirschsprung disease.​8

When researching, it was unclear as to which type of mutations occurred on which genes.

It appears that several types of mutations (e.g. deletion and substitution) are involved in the

development of Waardenburg syndrome. This disorder is rarely seen as a somatic mutation; it is

most often inherited from the parents. Waardenburg syndrome is commonly found as an

autosomal (a chromosome not responsible for determining sex) dominant inheritance pattern.

Therefore, if one allele has the mutation, the offspring will express the syndrome. There are

some cases, particularly in Type II and IV, when there is an autosomal recessive pattern of

inheritance. Therefore, both alleles must have the mutation for the offspring to develop the

syndrome.

In Waardenburg syndrome, the severity of hearing loss can vary for each affected person.

There are three major cases of hearing loss studied with Waardenburg syndrome: those that have

normal hearing loss, those that have progressive hearing loss that can result in moderate to

profound hearing loss, and those that have severe hearing loss early on in life. Early severe

hearing loss is most commonly found in the autosomal recessive inheritance patterns, while
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progressive hearing loss is commonly found in cases that are autosomal dominant. However,

both these cases are congenital, meaning that the hearing loss is present from birth.

About one in 40,000 people are affected by this syndrome and accounts for 2 to 5 percent

of all congenital hearing loss cases. 8​​ While this syndrome cannot be "treated," patients can be

given hearing aids to help with hearing loss. If a patient has severe to profound hearing loss with

poor word recognition, they can be given a cochlear implant.

Waardenburg syndrome is one of many genetic disorders that causes hearing loss. It was

interesting to see the direct connection between proteins and the function of systems in the body.

The importance of the function of proteins is made obvious through this genetic disorder. This

concept is also strongly represented in Huntington’s disease where the mutation of a single gene

leads to mental degeneration.

Huntington's disease (HD) is a genetic disorder in which nerve cells within the brain

begin to deteriorate. This break down of nerve cells causes involuntary movements, called

chorea, loss of cognition, and emotional issues. While the whole brain is involved in this

disorder, the basal ganglia, found at the base of the brain, is most affected by this disorder. The

basal ganglia is responsible for motor control along with motor learning, emotions, and executive

function.​10 ​This disorder most often occurs as an adult-onset disease, however there are cases in

which it begins during adolescence called Juvenile Huntington’s disease (JHD.) Those affected

by adult-onset Huntington's will see the appearance of the disorder between the ages of 30 and

50. The "appearance" of Huntington's is marked by chorea, loss of the ability to reason or

comprehend, and emotional issues such as depression and irritability. Chorea will worsen with

the disorder and can hinder a patient's ability to walk, talk, or swallow. In those affected by the
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adult-onset form, the disease will progress for about 15 to 20 years until the patient dies from

heart failure, pneumonia, or other complications due to their weakened state. JHD has similar

symptoms as the adult-onset form. Additional symptoms include clumsiness, frequent falling,

slurred speech, and drooling. Unlike the adult-onset form, JHD progresses faster leaving the

estimated lifetime, after the first appearance of symptoms, to be between 10 and 15 years.

This disorder is caused by a mutation on the HTT gene, known for playing an important

role in the function of neurons. On this gene lies a CAG trinucleotide repeat where the sequence

of cytosine, adenine, and guanine is repeated several times in a row. In a normal HTT allele,

there would be 26 or fewer repeats; on a HD-causing allele, there are over 36 CAG repeats. The

severity of the disorder is dependent on the number of CAG repeats on the HTT gene. There is a

possibility that those with 36 to 39 CAG repeats will not develop symptoms; however, those with

over 40 will always develop the disorder. Adult-onset HD is usually caused by the HTT gene

having between 40 and 50 CAG repeats, while those with JHD will have more than 60 repeats.

Individuals that have HTT alleles with 27 to 35 CAG repeats can be described as having

intermediate HD alleles. Intermediate means that while the individual is not at risk for

developing the disorder, future offspring will have a risk of developing the disorder. This is due

to the idea of "anticipation." Like Waardenburg syndrome, HD is an autosomal dominant trait,

meaning that one can develop the disorder if they have one mutated HD allele. As a mutated HD

allele is passed through offspring, the number of CAG repeats tends to increase, making the

CAG trinucleotide larger. Therefore, those who don't have the disorder but have an altered HTT

allele can have offspring that develop the disorder. This is the phenomenon called "anticipation."
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In this case, through each generation, the age of onset will decrease as the manifestation will

increase from mild to moderate to severe.

The reason why the alteration of the HTT gene results in HD has to do with the size of

the protein synthesized from HTT. HTT codes for a protein called huntingtin, hence the name of

the disorder. As the number of CAG repeats increases on the HTT gene, the length of the

huntingtin protein increases. The elongated protein is broken into smaller, toxic segments that

accumulate in neurons. The accumulation of these fragments disrupt the function of the neural

cells and causes the affected neurons to die. The death of these cells leads to the symptoms seen

in this disorder.​11

Huntington’s Disease can be separated into three stages based on its progression. In early

stage HD, the patient will experience subtle changes in their coordination such as chorea.

Cognition begins to deteriorate as their ability to think through problems worsens. Depression

and irritability is also observed and can be treated using medication. In this stage, their ability to

work and function declines, but they are not completely dependent on others. The intermediate

stage is seen with the worsening of the symptoms in the early stage as the disorder becomes

more of an issue for the patient. Medication in this stage is often used to treat chorea. Speaking

and swallowing become an issue, and the patient may require a speech pathologists. In the late

stage, the patient is completely dependent on others. As swallowing becomes a serious issue, the

concern for choking increases. Chorea can become severe or altogether stop affecting the patient.

Patients in the late stage will no longer have the ability to walk or speak, however they generally

are able to comprehend others. When a patient with HD dies, it is usually caused by
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complications such as choking, pneumonia, or heart failure, rather than a direct cause from the

disease itself.​12

A positive family history for HD, clinical symptoms, and detection of 36 or more CAG

repeats is evidence for Huntington's disease. Genetic tests are used to determine whether an

individual will develop the disorder, and prenatal tests are used to determine whether the

individual's offspring will have or has the disease. While HD can affect all races and ethnic

groups, it is more commonly seen in individuals of European descent. HD is less common

among those of non-European descent, such as Japanese, Chinese, and African. There is an

estimated 3 to 7 per 100,000 people of European descent to have HD.​11

I found this disorder particularly interesting because the genetic mutation not only caused

physical deterioration but mental degeneration as well. This disorder is life-threatening, but its

physical effects are not as serious when compared to other genetic disorders such as cystic

fibrosis (CF). CF is a genetic disorder that can become severely life-threatening if not treated

properly.

CF is an inherited genetic disorder in which thick sticky mucus accumulates in different

pathways, causing severe damage to different organs. The most common effects of CF are

damage to the respiratory system and chronic digestive problems. Mucus is a vital slippery

substance secreted in several different glands in the body. It is used as a lubricant and protects

the linings of airways, the digestive and respiratory systems, and several different organs.

However, in CF, mucus becomes abnormally thick and sticky, and has the potential to block

several pathways. This genetic disorder has a major impact on the repository system. The

abnormal mucus will block airways causing respiratory problems and increase the potential for
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bacterial infection. Overtime, these issues can lead to permanent lung damage and the formation

of cysts (scar tissue) and fibrosis within lung tissue. In addition to respiratory problems, CF often

damages the digestive system. In newborns, mucus can block the pathway of the intestine, called

meconium ileus. In addition, mucus can accumulate in the pancreas. The pancreas is responsible

for producing insulin, a hormone that regulates the amount of sugar in an individual's blood

stream. It also produces several enzymes used in digestive processes. The mucus will block ducts

in the pancreas, reducing the amount of insulin produced and preventing the release of digestive

enzymes. Problems in digestion can cause a variety of symptoms such as diarrhea, poor growth,

malnutrition, constipation, and weight loss. In addition, due to the shortage of insulin, diabetes

linked with CF can develop, called cystic fibrosis-related diabetes mellitus (CFRDM.)

While these symptoms are commonly seen in those affected by CF, its features and

severity can vary for each affected individual. Some may have a severe form of CF from birth

while others may have a few symptoms early in life that progressively worsen into adulthood.

Fortunately, those affected by CF today have a higher chance of living longer compared to those

of previous decades due to technological and research advancements. For example, with

improved screenings and treatments, those diagnosed with CF can live as long as 50 years.

CF is caused by a mutation on the CFTR gene. The CFTR gene is responsible for the

synthesis of a protein called cystic fibrosis transmembrane conductance regulator. This protein

acts as a channel across the membrane (outer casing) of a cell that produces mucus, saliva, tears,

sweat, and digestive enzymes. This channel transports negatively charged chloride ions in and

out of the cell. Chloride is found in sodium chloride, a salt contained in sweat. However, more

importantly, chloride helps to control the movement of water in tissues. This is crucial in the
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production of free flowing mucus that can lubricate and protect various pathways. In addition,

the CFTR gene regulates other channels. It can regulate a channel that transports positively

charged sodium ions across the cell membrane that are necessary for the function of organs such

as the lungs and pancreas. Mutations of the CFTR gene will inhibit the gene’s ability to

synthesize functional cystic fibrosis transmembrane conductance regulator proteins.​13

Over 1,000 mutations have been identified on the CFTR gene in those with CF. The

majority of these mutations are missense mutation in which a single base pair is substituted in for

another. Therefore, there will be a change in one amino acid in the sequence of a protein. A

small portion of DNA in the CFTR gene can also be deleted in CF. The most common mutation

on the CFTR gene is called delta F508. This mutation is a deletion of a codon on the CFTR gene

that codes for phenylalanine. This mutation occurs in about 70 percent of all CF patients. The

abnormal protein channel is broken down shortly after it is synthesized, therefore it never is able

to reach the cell membrane. Therefore, the regulation of water movement in and out of a cell will

be abnormal, and abnormal mucus will be produced.

CF is an autosomal recessive inherited disorder, meaning that both alleles of a

chromosome must have CF-causing mutations for the individual to develop the disorder. Those

that have one mutated gene, called carriers, will not develop CF. As a carrier, he or she has the

potential to pass the genetic mutation to his or her offspring. Around one in 31 Americans are

carriers of this genetic disorder.​14 ​An estimated 1 in every 2,500 to 3,500 white newborns have

CF; it is most common in white Americans. One in about every 17,000 African Americans and

one in every 31,000 Asian Americans will have CF.​15

A FIRST LOOK INTO GENETIC MUTATIONS
21
Diagnosis of CF must include a sweat chloride test, genetic or carrier test, and a clinical

evaluation. Most children are screened as newborns and diagnosed by the age of two; however,

there are some cases where an individual is not diagnosed until their adult years. If this occurs, a

doctor will order a sweat test and genetic test to make a full diagnosis. There are various methods

and medicines that are used to regulate the symptoms of CF. Patients with CF follow a

specialized nutrition and fitness plan to stay healthy. There are also different methods to clear the

build up of mucus called airway clearance techniques (ACTs.) In addition, there are different

medicines used to help clear accumulation of mucus, reduce inflammation, and treat lung

infection. A patient with CF might use the following mucus thinners: hypertonic saline or

dornase alfa (Pulmozyme®.) Various treatments have been developed to target the defective

cystic fibrosis transmembrane conductance regulator to manage the symptoms of CF. These

treatments include ivacaftor (Kalydeco®), lumacaftor/ovacaftor (Orkambi®), and

tezacaftor/ovacaftor (Symdeko™.)​16

Studying Waardenburg Syndrome, HD, and CF has helped to clarify the role of genetic

mutations in the development of various clinical syndromes and disorders. Current technology

has provided the research community with the tools to develop various treatments for managing

the clinical manifestations of these syndromes and disorders. In addition to medicines and

technology, genetic counselors provide crucial information to those with genetic disorders and

their families.

Genetic counseling is a career in the field of genetics in which a certified individual

evaluates an individual’s risk of inheriting a certain genetic disorder. Genetic counselors meet

with patients and their families to educate them on a genetic disorder. They will evaluate a
A FIRST LOOK INTO GENETIC MUTATIONS
22
patient's genetic history to determine whether a disorder was inherited and whether there is a risk

of passing the disorder onto their offspring. Due to the growing prevalence of genetics, the

demand for experts in this career is growing rather rapidly. This career is especially interesting

because it combines medical lab work and patient interactions. A student interested in becoming

a genetic counselor must have completed a master's degree through a genetic counseling

program. This involves research, clinical training, and rigorous coursework. Candidates are

required to to pass an examination to be board certified. A growing number of states are also

requiring a license.

A genetic counselor can work in a variety of settings such as hospitals, laboratories, and

offices. Those working in hospitals and clinics can consult patients in several areas: prenatal,

pediatric, adult, and cancer. The prenatal area applies to those who are pregnant, or thinking of

becoming pregnant, and want to determine the risk of their child inheriting a genetic disorder.

Pediatric genetic counseling focuses on genetic disorders in children. The adult area applies to

people who want to assess their genetic makeup and history, especially when there is a family

history of an adult-onset genetic disorder such as Huntington's disease. A cancer setting is meant

for those who want to understand whether or not they inherited an increased risk for developing

cancer. While research in these areas is substantial, the work of a genetic counselor is not

confined to these four settings; there are several other settings including neurology.

Genetic counselors are also a source for emotional support when a family is managing a

genetic disorder. They provide guidance when a family is making important decisions such as

deciding to have a child who has a risk for developing a disorder. While they are unable to make
A FIRST LOOK INTO GENETIC MUTATIONS
23
the final decision, they can provide help, taking in consideration the emotional needs of the

individual or family, to guide a patient towards the best choice.

Genetic counseling is a rewarding career evidenced by the rapid growth in the number of

genetic counselors which has grown by 85 percent since 2005.​17 ​During my research journey, I

have become more interested in this specific field as it combines both lab work and first hand

work with patients. It is a medical prevention career which are, in my opinion, one of the most

rewarding types of careers in medicine.​17

In the lab work of genetic counselors and geneticists, there are several different tests that

can be used to collect data about the genes of a patient. This data is used for diagnosis of a

genetic disorder as well as assessing family history of disorder. There are several different types

of genetic tests which include newborn screening, diagnostic testing, carrier testing, prenatal

testing, preimplantation testing, predictive and presymptomatic testing, and forensic testing.

Newborn screening is used to study an infant's genetic makeup immediately after birth to

identify any disorders. In the United States, all states test for phenylketonuria (a genetic disorder

that can result in cognitive disabilities) and hypothyroidism (a disorder in the thyroid gland.)

These testing are very helpful in preventing a disorder from manifesting itself in an individual.

Diagnostic testing is used to identify a specific genetic or chromosomal condition in an

individual. This type of testing is most often used to confirm diagnosis of a disorder when partial

diagnosis has been made by observing symptoms. Diagnostic testing can be used at any point in

time of an individual's life from before birth to death. However, there are genes and genetic

conditions that are not yet able to be studied using diagnostic testing. A carrier testing is used to

determine whether or not an individual has an allele that causes a genetic disorder when two of
A FIRST LOOK INTO GENETIC MUTATIONS
24
the alleles are present. This is most common among individuals who have a family or ethnic

history of a certain genetic disorder. It is also helpful for determining a couple's risk of passing

on a genetic disorder to their offspring. Prenatal testing is used to observe changes in a fetus's

genes and/or chromosomes. It is helpful for determining whether a child will develop a certain

disorder. It is offered to parents and pregnant women to help them make decisions about

pregnancy or make future plans for a child. Preimplantation testing, or preimplantation genetic

diagnosis, is a technique used to reduce the risk of a child developing a genetic disorder. Genetic

changes are observed in fetuses produced by assisted reproductive methods such as in-vitro

fertilization. In-vitro fertilization involves fertilizing eggs outside of the uterus with sperm

outside of the body. Several eggs will be fertilized at once, and the embryos that have no

apparent development of harmful genetic mutations are placed in a woman's uterus with the hope

that at least one of the eggs will develop. Predictive and presymptomatic testing is used to find

the presence of disorder-causing genetic mutations in an individual after birth. Predictive testing

is specifically used to identify any gene mutations that increases and individual's risk for

developing a certain disorder such as cancer. Presymptomatic testing is used to evaluate whether

or not an individual will develop a disorder before there are noticeable symptoms. These tests are

very helpful to an individual who wants to make future life plans based off of whether he or she

will develop a genetic disorder. Lastly, forensic testing is a genetic test specifically used for legal

purposes. Unlike the tests mentioned, forensic testing is not used to identify genetic disorders. In

crime scenes, it can be used to identify victims or suspects and make biological connections

between people based on DNA found at a crime scene.​18 ​This is where genetic tests become

beneficial for a large range of people and not specifically to an individual or a family.
A FIRST LOOK INTO GENETIC MUTATIONS
25
With these different testing modalities, there are several techniques and technologies used

to study the presence of genetic mutations and disorders. Different techniques include

polymerase chain reaction, gene probes, and microchips. Polymerase chain reaction (PCR) is a

technique used to study genes by producing several copies of a certain gene. This is achieved by

inducing DNA replication. Therefore, there will be several copies of DNA that can be more

easily studied by geneticists. Genetic probes are used to locate certain genes. These “probes”

take the form of a marked DNA strand through either a radioactive ion or fluorescent dye. DNA

strands have high affinities for each other and will bind to those that match according to the

complementary base-pair rule. Therefore, scientists are able to use high power microscopic

techniques to determine the location of a gene. This technique is very useful because it can detect

genetic disorders before and after birth. Lastly, microchips are a new technology used to identify

genetic mutations. It is incredibly powerful because it can identify thousands of genetic

mutations in a single test.​19

Genetic tests are not only important to scientists, but also to patients and their families.

They provide families with information that could change the course of their lives for better or

worse. In addition, it gives families time to consider different options for handling a genetic

disorder. The field of genetics is applicable to virtually everyone. It is important for both the

physician scientist who is trying to treat disorders and diseases, such as cancer, and those coping

with a genetic disorder. The Human Genome Project (HGP) was a step towards a better

understanding of our genes and how they work.

The Human Genome Project was an international project with the goal of determining the

DNA sequencing of the entire human genome. It officially began on October 1, 1990 and ended
A FIRST LOOK INTO GENETIC MUTATIONS
26
in April 2003, surpassing their original goals. About 99% of all genes in the human genome were

mapped.​20​ They were also able to study the genomes of other organisms and develop new

technology for gene mapping. Surprisingly, the project was finished two and a half years early

and under budget. The HGP has been compared to the mission that sent the first humans to the

moon, which conveys the magnitude of this large research project. Contributors to this project

included the National Human Genome Research Institute of the NIH, the U.S. Department of

Energy (DOE), and several laboratories and universities in the United States, and international

partners in France, Germany, the United Kingdom, China, and Japan.​21 ​ This project has helped

scientists understand the basic components for “building a person.” In addition, it has lead to

several advancements in the fields of medicine, biotechnology, and the life sciences. It is rather

perplexing to think that scientists were nearly able to map the entire human genome. This was a

crucial project in the field of medicine and genetics because of the various applications related to

genetic mutations..​22

The review of this topic has answered the “big question”: ​What are genetic mutations,

how are they formed, and what are their leading effects? ​Genetic mutations are mistakes within

DNA that are responsible for both genetic disorders and variation. The field of genetics,

specifically, the study genetic mutations, is incredibly large and is still growing today. While the

genetic database is filled with pages of information concerning mutations and genetic mutations,

there are still many areas that have not been completely uncovered.

What’s Next?

This was a long research journey, obvious through extensive paper. I did enjoy reading

through several different articles and flipping through the pages of the massive ​Gale
A FIRST LOOK INTO GENETIC MUTATIONS
27
Encyclopedia of Genetic Disorders​; however, the process was exhausting with several late nights

and weekends taken up by long hours of research. Nevertheless, I believe that this research

experience has better prepared me for future projects and the “monster” senior project. It has

trained me how to be more efficient with my research, and I better understand that putting the

hard work in at the beginning will save you a lot of grief at the end. I have also learned that

quantity does not mean quality. While I do believe that all the research I completed was worth

my time, I think I would have benefited from focusing on a specific topic in the field of genetics.

I chose a rather large topic to tackle, and while I am proud that I was able to cover major

sections, I think it would have been more valuable to hone in on something more specific in the

field. In addition, my paper focused more on the research side of this project than the analytical

part. For future research, I now know to take more time to analyze what I have learned.

With my research I hope to continue studying genetics. Genetic counseling has become a

possible future career for me due to its applications inside and outside the lab. My research has

further piqued my interest in genetics disorders, specifically ones that involve the brain. I have

always enjoyed studying psychology and the mechanisms of the brain, and researching

Huntington’s disease opened the door to neurology. In addition, my interest in genetic

engineering has grown stronger; this field might become a potential topic that I study my junior

year and for my senior project.

This research project has also opened the door to careers in research. I have always

enjoyed conducting research and reading through the works of others, and this I-Search has

allowed me to obtain a better understanding of what true research is like. Although it was a long

process, I enjoyed the long days of sitting on my couch with me and my computer, researching
A FIRST LOOK INTO GENETIC MUTATIONS
28
for hours on end. It was a long but rewarding journey, and I have not only learned a considerable

amount about genetics but also a lot about my own interests.

A FIRST LOOK INTO GENETIC MUTATIONS
29
Cited References

1. “Basic Science: CFTR: Mutations.” ​Johns Hopkins Cystic Fibrosis Center​,

www.hopkinscf.org/what-is-cf/basic-science/cftr/mutations/. Accessed 5 May 2018.

2. Biesecker, Leslie G. “Point Mutation.” ​National Human Genome Research Institute

(NHGRI),​

www.genome.gov/glossary/index.cfm?id=156. Accessed 25 Mar. 2018.

3. “CFTR Gene - Genetics Home Reference.” ​U.S. National Library of Medicine​, National

Institutes of Health, Jan. 2008, ghr.nlm.nih.gov/gene/CFTR#. Accessed 5 May 2018.

4. “Cystic Fibrosis - Genetics Home Reference.” ​U.S. National Library of Medicine​, National

Institutes of Health, Aug. 2012, ghr.nlm.nih.gov/condition/cystic-fibrosis#. Accessed 5 May

2018.

5. “Diagnosed With Cystic Fibrosis.” ​CF Foundation​,

www.cff.org/What-is-CF/Diagnosed-With-Cystic-Fibrosis/. Accessed 5 May 2018.

6. Sickle Cell Disease. National Heart Lung and Blood Institute. [accessed 2018 Mar 25].

https://www.nhlbi.nih.gov/health-topics/sickle-cell-disease

7. Finegold, David N. “Genetic Diagnostic Technologies - Fundamentals - Merck Manuals

Consumer Version.” ​Merck Manuals Professional Edition​,

www.merckmanuals.com/home/fundamentals/genetics/genetic-diagnostic-technologies​.

Accessed 13 May 2018.

8. Firestone, Ross. “An Introduction to Genetic Mutations.” ​Khan Academy,​ Khan Academy,

www.khanacademy.org/test-prep/mcat/biomolecules/genetic-mutations/v/an-introduction-to-ge​n

etic-mutations. Accessed 15 Mar. 2018.

A FIRST LOOK INTO GENETIC MUTATIONS
30
9. “Huntington Disease - Genetics Home Reference.” ​U.S. National Library of Medicine​,

National Institutes of Health, June 2013, ghr.nlm.nih.gov/condition/huntington-disease#.

Accessed 5 May 2018.

10. “Interested in Becoming a Genetic Counselor?” ​National Society of Genetic Counselors​,

www.nsgc.org/page/becomeageneticcounselor. Accessed 12 May 2018.

11. Lanciego, José L., et al. “Functional Neuroanatomy of the Basal Ganglia .” ​NCBI,​ U.S.

National Library of Medicine, Dec. 2012, ​www.ncbi.nlm.nih.gov/pmc/articles/PMC3543080/​.

Accessed 5 May 2018.

12. Milunsky, Jeff Mark. “Waardenburg Syndrome Type I.” ​NCBI,​ U.S. National Library of

Medicine, 4 May 2017, www.ncbi.nlm.nih.gov/books/NBK1531/. Accessed 28 Apr. 2018.

13. “Timeline.” ​Genome: Unlocking Life's Code,​ unlockinglifescode.org/timeline?tid=4.

Accessed 19 May 2018.

14. “Waardenburg Syndrome - Genetics Home Reference.” ​U.S. National Library of Medicine​,

National Institutes of Health, Aug. 2016, ghr.nlm.nih.gov/condition/waardenburg-syndrome.

Accessed 4 June 2018.

15. “Waardenburg Syndrome.” ​Genetic and Rare Diseases Information Center​, U.S. Department

of Health and Human Services, 11 Feb. 2016,

rarediseases.info.nih.gov/diseases/5525/waardenburg-syndrome. Accessed 28 Apr. 2018.

16. “What Are the Types of Genetic Tests? - Genetics Home Reference.” ​U.S. National Library

of Medicine,​ National Institutes of Health, 29 May 2018, ghr.nlm.nih.gov/primer/testing/uses.

Accessed 13 May 2018.

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31

17. “What Is a Gene Mutation and How Do Mutations Occur? - Genetics Home Reference.” ​U.S.

National Library of Medicine​, National Institutes of Health, 29 May 2018,

ghr.nlm.nih.gov/primer/mutationsanddisorders/genemutation. Accessed 15 Mar. 2018.

18. “What Is Huntington's Disease?” ​Huntington's Disease Society of America,​

hdsa.org/what-is-hd/. Accessed 5 May 2018.

19. “What Is Mutation?” ​Learn.Genetics​, 1 Mar. 2016,

learn.genetics.utah.edu/content/basics/mutation/. Accessed 15 Mar. 2018.

20. “What Is the Human Genome Project?” ​National Human Genome Research Institute

(NHGRI),​ 4 May 2012, ​www.genome.gov/11511417/what-is-the-human-genome-project/​.

Accessed 19 May 2018.

21. “What Kinds of Gene Mutations Are Possible? - Genetics Home Reference.” ​U.S. National

Library of Medicine,​ National Institutes of Health, 29 May 2018,

ghr.nlm.nih.gov/primer/mutationsanddisorders/possiblemutations. Accessed 25 Mar. 2018.

22. “What Was the Human Genome Project and Why Has It Been Important? - Genetics Home

Reference.” ​U.S. National Library of Medicine,​ National Institutes of Health, 29 May 2018,

ghr.nlm.nih.gov/primer/hgp/description. Accessed 19 May 2018.