Sex Linked Diseases Flashcards
Who were the scientists that proposed the Chromosome theory of Inheritance? What did the chromosome theory involve?
Theodore Boveri and Walter Sutton proposed the There chromosome Theory of inheritance (1902)
Basis of Chromosome Theory:
-Chromosomes (like genes) occur in matched pairs
-Chromosome pairs (like genes) Segregate from each other when gametes are formed
-Chromosomes are essential for development
- * Chromosomes are the underlying physical basis for genes
Who was Eleanor Carothers and what did she discover?
Eleanor Carothers - scientist who did a lot of chromosome staining with different organisms
-She discovered (in grasshoppers) that **Nonhomologous chromosomes Assort independently **
(sometimes see orange chromosome with centrosome in middle, or you would see one with centromere to the side)
(she also noted there was one chromosome that did Not pair with any other one- sex chromosomes)
(hence this was evidence that chromosomes segregate independently just like genes (Mendel’s Laws)
What led to the the Discovery of Sex Linkage? Who discovered this?
Drosophila genetics led to Discovery of Sex Linkage
-Thomas Hunt Morgan: founded fruit fly genetics (to work out laws of genetics)
-He helped created modern scientific culture
Why did Thomas Morgan choose fruit flies for his genetic experiment ?
He chose fruit flies because:
-They grown Quickly (for reproductive cycle)
-fruit flies grow ROBUSTLY an din LARGE numbers
What controls the Drospholia Sex?
Drospholia Sex is controlled by chromosomes
Fruit flies that are female have 2 Identical X chromosomes
Fruit flies that are male: have 2 NON-identical chromosomes (1 X chromosome, 1 Y chromosome (oddly shaped; curved)
hence XX or XY would be determine factor for sex of fruit fly
(proving that sex linked gene was on sex chrosome; able to prove genes are located on chromosomes and know how sex-linked genes worked for humans)
Describe the mutation that can be seen in Fruit flies that affects eye color.
In fruit flies, wild type (normal) flies have red eyes
-flies with White mutant gene (W1 mutant) have white eyes
(This mutant show up spontaneously in lab)
Describe the sex-limited inheritance that was observed when working with fruit flies.
They observed that when wild type fly with red eyes crossed with white mutant fly with White eyes, you would get BIASED ratios of phenotypes (for eye color)
-found white eyed male and crossed red eyed sisters
all offspring (for F1 generation) had red eyes, except 3 flies (that were white)
Then the F1 hybrids (all red eyed) were inbred, and all the females were red eyed, meanwhile half of the male offspring were red eyed and half of the males were white-eyed
Hence unequal phenotypes between female and male flies.
what was used to explain the unequal phenotypes of male and female fruit flies?
Morgan was able to propose that White gene (mutant allele that leads to white eyes) is on the X chromosome
-(gene being inherited with sex chromosome)
Hence they observed that P0 generation have White eyed male with X^w1 Y (X ^w1; mutant white gene) that crossed with Red eyed female fly (X^w+ X^w+ ) would produce:
F1 generation with Red eyed male (X^w+ Y) and Red eyed female (X^w+ X^w1) with mutant allele
(hence all male get X from mom, Y chromes from dad; meanwhile females get a copy of X^w+ from both mom and dad)
-When F1 mated together: X^w+ Y x X^w+ X ^w1:
offspring would be; 1/2 Red-eyed females X^w+ X^w+ , X^w+ X^w1. 1/4 Red eyed males X^w+ Y 1/4 white-eyed males X^w1 Y
(hence white allele is recessive)
The assumption is that white gene is located on X chromosme allowed them to explain the behavior of unusual cross )
What would happen if it was tested that some of F2 females were heterozygous for eye color in fruit flies?
Test; Some F2 females are heterozygous
Cross white eyed male with Red eye female (homozygous)
X^w1 Y x X^w+ X^w+
you get offspring of 1/2 Red eyed female X^w+ X^w1
1/2 red eyed male X^w+ Y
OR Cross white eyed male with Red eyed female (heterozygous)
X^w1 Y x X^w+ X^w1
you get offspring with 1/4 Red eyed females X^w+ X^w1
1/4 White eyed females X^w1 X^w1
1/4 Red eyed male X^w+ Y
1/4 white eyed male X^w1 Y
What kind of offspring are produced when you test a white female and cross red male fruit fly?
Test: white female produce White sons
Cross Red eyed male with white-eyed female
X^w+ Y x X^w1 X^w1
you will get offspring:
1/2 Red-eyed female X^w+ X^w1
1/2 White eyedmale X^w1 Y
What is Hemophilia A? What type of genetic disorder is it?
Hemophilia A: genetic bleeding disorder caused by a lack of blood clotting factor VIII.
This disorder is Sex-linked Recessive (as mutation is caused by gene on X chromosome)
Describe the clinical features and symptoms of Hemophilia A
Hemophilia A caused by mutation that impairs blood clotting
-prolonged and severe bleeding from wounds
-Severe bruising
-Hemarthroses occur- bleeding into joints
-platelets are normal and stop minor bleeding
(people with hemophilia A are also missing Complement that allows blood to coagulate(clot) , but platelets are still present to help overbreeding stop)
What is the popular example of sex-linkage in genetics? What is the assumption?
Queen Victoria’s family: most famous example of Sex-linked disease hemophilia A
a lot of males in each generation have hemophilia
-Assumption: Queen Victoria must have been carrier for hemophilia. Hence could have son who is affected and daughters who are carriers and will pass on mutated allele to their children.
What does a typical inheritance of Sex-linked recessive diseases (like hemophilia) look like? How does th
Typical inheritance of sex-linked recessive diseases (like Hemophilia) ;
Father who is unaffected (X+ Y) will mate with mother (X+ h) who is a carrier for the disease
They will cross and produce offspring:
1/4 X+ X+ normla girl
1/4 X+ Y normal boy
1/4 X^h X+ carrier girl
1/4 X^h Y Affected boy
Hence, in sex-linkage recessive diseases, males only need 1 mutated copy, so the frequency of males being affected with disease is HIGH
* Frequency of people with sex-linked recessive disorders are much HIGHER compared to other genetic disorders, and Only affect MALES*
How did Hemophilia influence the downfall of the Tsars?
Descendants of Queen Victoria (some family members who were affected with Hemophilia) married into royal families, like the Russian royal house
The Last Tsar of Russia (Tsar Nicholas) had son who inherited mutation from mother (descendent of Queen Victoria) and his father had Hemophilia. Hence family worried about son’s health.
(Gregory Rasputin: claim to use mystic arts to keep son healthy)
What type of mutation causes Hemophilia A? Differentiate between mutations that cause Severe vs Mild Hemophilia A
Mutations in Clotting Factor VIII gene (F8) cause Hemophilia A
Severe Hemophilia A
-Null Mutations that either:
-Prevent the production of clotting factor VIII (less than 1% of protein)
-Prevent clotting factor VIII from functioning
(Null mutation: mutations that stop gene from working together)
Mild Hemophilia A:
missense mutations that impair VIII function
(hence you still will make clotting factor, but it will not work as well)
(You will not have serious issue with clotting and stopping bleeding, but will have defects)
(side note; there are other genes that are involved in blood clotting; most autosomal, one is on X chromosome
Hemophilia is the dominant gene
What kind of treatment is provided for Hemophilia A? What can be used to help stop bleeding or breakdown clots that will be necessary for those with Hemophilia?
Treatment for hemophilia A:
**Clotting factor VIII can be given intravenously (frequent injections so patient can form blood clots if they get cut)
-Recombinant factor VIII is safest, since it carries No risk of contamination
-Human Derived factor VIII was purified from blood and transmitted the HIV virus to many hemophiliacs
-DDAVP (desmopressin acetate) is a version of vasopressin that helps stop bleeding
-Aminocaproic acid can be used to slow the breakdown of clots
(When HIV virus outbreak occurred, many people did not know what it was; hence they were unaware they had HIV disease, donated blood and AIDS virus was concentrated down with clotting factor 8 and was distributed in blood drive for people with hemophilia. Hence many hemophiliacs dies of AIDS due to blood distribution that had AIDS in blood along with clotting factor 8)
What is one benefit of having Hemophilia?
Hemophilia LOWERS Cardiovascular mortality
(since clotting is involved in heart issues, strokes, those with hemophilia benefit) However, tiny benefit
What is Duchenne Muscular Dystrophy and what are its symptoms?
Duchenne Muscular Dystrophy: Sex-linked recessive disorder
This disease causes progressive loss of muscles (causes little movement)
Symptoms:
Progressive weakness and loss of muscle
-Leakage of Creatine Kinase into blood from dying muscles
-Heart and lungs become impaired , leading to an early death. The heart problems cause cardiomyopathy
(Cardiomyopathy:harder for heart to pump blood to rest of body)
What Kind of mutation causes Duchenne Muscular Dystrophy (DMD). Discuss the frequency of disease in males vs females.
DMD is caused by sex-linked recessive mutation
-Carriers are women with two Xs (marked with a dot in pedigree); one of which has the mutation
- Most affected individuals are MALE, since they only have one X
-1/4000 males have DMD (very high rate)
Describe the Muscular Dystrophy gene and how it causes the disease (Duchenne muscular dystrophy)
What kind of Alleles cause DMD?
The Duchenne Muscular Dystrophy gene is LARGE (> 2 million base pairs) and Easily mutated
hence there a lot of places on gene where mutations can occur.
There is also an enormous Dystrophin protein (> 3600 amino acids) that contain many domains that help interact with other structuring proteins of muscle
- *This protein helps main integrity of other proteins which have to form fibers that give muscle its structure and low it contract
**Severe alleles and NULL Alleles cause DMD
What does the DMD gene code for? Describe the surroundings of dysytrophin protein and structure involved
DMD gene codes for the key muscle protein Dystrophin
Around the dystrophin protein there is cell membrane, extracellular matrix (maintains stabilty).
There are set of proteins embedded in membrane (allows for contraction)
The dystrophin protein is connected to actin filaments (actin and myosin) and play a role in muscle function
-Those with DMD, can assemble muscle
The dystrophin protein provides support, which helps keep everything in place, despite the sprain that muscles undergo due to contractions. Protein helps us have muscles last for a longer time
Discuss the treatment available for Duchenne Muscular Dystrophy?
Treatment for Duchenne Muscular Dystrophy:
-There is NO CURE
-Physical therapy can alleviate some muscle symptoms and slow down the course of the disease. Inactivity is harmful (you need some kind of movement)
-Drugs and othopedics can help with muscle function and movement
- Pacemakers and respiratory assistance can help with heart and lung function
(also gene therapy treatments are currently trying to be made to help with disease)
