Module 1 Week 1: Genetic Influence in Disease

segment of DNA molecule that's composed of an ordered sequence of nucleotide bases (Adenine/Guanine/Cytosine/Thymine)

What is a Gene?

coding for synthesis of proteins that influence all aspects of body traits and function

What's the main functions of genes?

- Eye pigment

- Hair color

- Blood type

- Subtle inherited traits like outgoing personality AND

- Susceptibility to certain disease

Examples of genes that include "permanent" proteins include...

Hormones, antigens, antibodies, enzymes, etc.

Examples of genes that are "day to day" functional proteins include...

it often malfunctions

When there's a MUTATION of a gene, what happens to the protein for that gene?

lactose intolerance!

Example...if the gene that codes for lactase (breaks down lactose) becomes mutated, what might happen?

- A sequence of nucleotide bases form a gene; genes make up a DNA molecule which forms into a chromosome

- Chromosomes can be thought of as a string of multipurpose beads (beads = genes)

What's a Chromosome?

23 from each parent so 23 pairs or 46 total chromosomes

Describe how many chromosomes each person has and where they come from.

autosomal (not sex chromosomes) and each pair is closely alike

22 out of the 23 pairs of chromosomes are...

sex chromosomes—XX or XY

The 23rd pair of chromosomes is what?

- Per pair, each has genes that closely match "partners" on other chromosome

- Partner genes have same location ("locus") on each respective chromosome, code for same trait, and are called a pair of ALLELES

Describe Autosomal Chromosome Pairs (1-22)

- Pair of alleles almost exactly alike except one can be dominant & one can be recessive (or both dom/recess)

- Recessive are lowercase, Dominant are uppercase

- Combinations are called genotypes & represent what's inherited from mom/dad

Describe Alleles.

1. Homozygous Dominant

2. Homozygous Recessive

3. Heterozygous

Classify the following genotype combinations:

1. GG

2. gg

3. Gg

a disease caused by abnormalities in an individual's genetic material

What's the broad definition of Genetic Disorders?

- Inherited vs spontaneous

- Mitochondrial DNA, multifactorial, chromosomal, single-gene

What are the several ways of categorizing genetic disorders?

- Majority of DNA found in nucleus of cells BUT small bits also found in mitochondria

- Disorders of this DNA are very uncommon and won't be discussed here

Describe Mitochondrial DNA disorders.

combination of environmental triggers and variations/mutations of genes, plus sometimes inherited tendencies

Define Multifactorial Genetic Disorders.

- Various cancers like lung cancer

- Many common diseases like hypertension (HTN), coronary artery disease (CAD) & diabetes mellitus (DM) are now known to be caused or highly influenced by mix of environmental/inherited factors

Give examples of Multifactorial Genetic Disorders.

- Teratogen is any influence (drugs/radiation/viruses) that can cause congenital defects

- Congenital defects are abnormalities that are either detectable at birth and/or can be attributed to fetal development "glitches"

- So...teratogenic disorders and congenital defects are virtually interchangeable terms

Describe Teratogenic disorders.

Fetal Alcohol Syndrome (FAS)...occurs b/c toxicity of alcohol causes gene mutations during gestational development

What's an example of a Teratogenic disorder?

- Babies born w/ abnormal arms and legs b/c of mothers taking drug thalidomide during early pregnancy

- Thalidomide is a teratogen

What are Thalidomide Babies?

- Type of genetic disorder resulting from alterations to development or structure of a chromosome, which in turn alters "local" genes (genes in immediate area)

- The genes' functionality is disrupted and they don't CODE proteins correctly, giving rise to the phenotype (S&S) of the disorder

Define Chromosomal Disorders/Abberations.

1. Down's syndrome (Trisomy 21) is a disorder of abnormal numbers of chromosomes and is sometimes associated w/ pregnancies of women over 35 yrs old

2. It's a glitch that occurs in very early cellular division and chromosomal distribution of a fertilized egg; fetus ends up with 47 instead of 46 chromosomes

3. Extra chromosome occurs at site #21...21st chromosome pair has 3 instead of 2

Describe alteration to NUMBERS of chromosomes.

somy = having to do w/ numbers of chromosomes

Polysomy = more chromosomes than normal

What does "somy" and "Polysomy" mean?

- Includes mental retardation

- Physical characteristics like lowset ears, epicanthic fold to eyes, short limbs, larger than normal tongue

Describe the Phenotypes of Trisomy 21.

1. Some types of chromosomal aberrations caused by alterations in chromosome structure, like deletion, duplication, or rearrangement of gene sites (translocation) on chromosome

2. Example is Philadelphia chromosome which results from translocation & will be discussed later

Describe Alterations to STRUCTURE of chromosomes—Philadelphia chromosome.

- Usually due to inherited mutated gene

- Since genes code for proteins, when a gene mutates so that its protein product can no longer carry out its normal function, a disorder can resulst

Describe Single-gene Disorders.

1. Autosomal dominant

2. Autosomal recessive

3. Sex-linked

What are the 3 recognizable patterns that Single-Gene disorders can be inherited?

- Occurs when mutated ("diseased"), recessive ("weak") gene partners up w/ allele that's also recessive & diseased...those alleles are notated w/ 2 lowercase letters

- Protein that they code for then malfunctions & abnormality/disease/disorder will occur that relates to that "bad" protein

Describe Autosomal (1-22) Recessive disorders.

- Mutated gene that carries the disorder is WEAK

- Lowercase letter is the BAD gene

- Uppercase letter is the NORMAL gene

What's true in ALL recessive disorders?

1. At a certain locus on a certain pair of chromosomes, a pair of alleles has the job of coding for the production of normally shaped hemoglobin (Hgb)

2. If during fertilization a person inherits a sickle-cell gene from mom - ie, a recessive, mutated Hgb coding gene - and ALSO inherits a sickle cell disease gene from dad....

3. They'd have the genotype of dd (2 lowercase).

Sickle Cell Anemia is an example of Autosomal Recessive. Describe its genotype & patho development.

1. Abnormal recessive alleles will code for abnormal shaped Hgb (sickle shape) which makes RBC sickle shaped

2. Because THESE RBCs don't have the usual round, smooth shape, they're more easily damaged in the blood stream leading to less-than-normal #s of RBCs....aka anemia

Describe Sickle Cell Anemia now that you've described its genotype.

1. When you see "emia", think of something to do with the BLOOD

2. Anemia literally means no blood but it really means low # of RBCs

What does emia and Anemia mean?

"Has the disease" = Becomes sick, has S&S, etc

What does "Has the phenotype" =

- SOB, weakness, & fatigue due to decreased O2 being carried throughout tissues of body

- Decreased carrying capacity due to anemia...less RBC to carry Hgb which in turn carries O2

- Deformed Hgb can't carry usual numbers of O2 molecules

A phenotype/S&S of sickle cell is shortness of breath (SOB), weakness, & fatigue. Describe the patho development of this.

- Deformed RBCs "clog" up capillaries that usually carry O2-rich blood to tissues

- This results in distal tissues that are starved to O2 & "cry out" in pain

A phenotype/S&S of sickle cell is Ischemic Pain, especially in the joint. Describe the patho development of this.

1. Ischemia = cells not getting enough oxygen due to circulatory malfunction

2. Pain in tissue via not enough oxygen is Ischemic Pain

What exactly is Ischemia and Ischemic Pain?

being a Carrier...they don't have the phenotype but can pass it on.

In any recessive disorder, a heterozygous genotype equals...

Generally no...but RARELY will they have a milder phenotype/S&S of sickle cell

Can a carrier of sickle cell have the phenotype of the disease?

Sickle Cell Trait

If someone is a carrier of sickle cell and in the rare case they have mild S&S of sickle cell, what do we call them?

- STRONG gene carries disorder

- Uppercase letter is the BAD gene

- Lowercase letter is NORMAL gene

Autosomal (1-22) DOMINANT is the exact opposite of Autosomal Recessive. What's true for all of these?

Polycystic Kidney Disease (PKD)

Give an example of an Autosomal Dominant Disorder.

1. At a certain locus on a certain pair of chromosomes, a pair of alleles has job of coding for creation of normal kidney tissue

2. If during fertilization a person inherits kidney tissue gene that has a mutation, that gene "wants" to code for abnormal kidneys

3. In a dominant disease like PKD, mutated gene is the strong one, so even if it's paired with a normal allele, it overrides normal allele's coding

4. In PKD, this results in kidney tissue developing cysts, reducing various kidney functions and lead to kidney failure as a person goes thru life

Describe the Genotype and Patho development of PKD.

homozygous RECESSIVE (2 lowercase)

What's the only genotype someone can have to avoid an Autosomal Dominant disorder?

1. Hematuria (blood in urine), Proteinuria (protein in urine), & frequent kidney infections

2. Pain at costovertebral angles and abdomen

3. Kidney stones

What are the S&S of PKD?

a form of genetic engineering

What is Recombinant DNA?

1. Many alterations in DNA came about as natural parts of evolution, but we can now alter DNA in the interests of medicine/science

2. Recombinant DNA is a "new" DNA that results from purposely combining 2 or more different sources of DNA (ex: altering/engineering DNA codons in bacteria to make proteins bacteria wouldn't normally produce)

Describe Recombinant DNA.

1. Human growth hormone for children lacking it

2. Exogenous (from outside body) insulin for diabetics

3. Factor VIII (8) for hemophiliacs

4. Drugs like tPA & tenectaplase—given as "clot-buster" in patients having a myocardial infarction (MI, aka heart attack)

What are the 4 current applications of Recombinant DNA?