Sex-Linked Inheritance & Mitochondrial Inheritance

Question 1

What is X-inactivation? What are three characteristics of X-inactivation?

Answer 1

X-inactivation: 1 of the 2 C chromosomes in females is inactivated in every somatic cell

• Occurs early in female embryonic development
• Random process
• Permanent process

Question 2

What is the Lyon Hypothesis? What cell structure is it associated with/was it confirmed by?

Answer 2

Lyon Hypothesis: suggested that dosage compensation in mammals is done so by inactivation of all but one X chromosome in cells with more than one X chromosome
- Associated with Barr bodies

Question 3

What are Barr bodies? What is the rule for how Barr bodies are quantified?

Answer 3

Barr bodies: inactive X chromosomes

- Number of Barr bodies in somatic cells is one less than the number of X chromosomes

Question 4

What is the mechanism of X-inactivation? (include what gene is involved)

Answer 4

XIST RNA gene on the X chromosome of placental mammals is expressed on the inactive chromosome (not on active one) – this RNA coats the inactive X chromosome, completely inactivating itself

Question 5

What is incomplete X-inactivation? On what region of the chromosome does this typically occur?

Answer 5

Incomplete X-inactivation: 15% of genes on X chromosome escape inactivation and remain active in all copies
- Occurs on PAR1 and PAR 2 regions

Question 6

What are the three genotypes found with X-linked Recessive diseases in females?

Answer 6

• Homozygous for normal allele (X1X1)
• Heterozygous (X1X2)
• Homozygous for disease allele (X2X2)

Question 7

What is random X-inactivation and what genotype does it affect in females with X-linked Recessive diseases? Why is this?

Answer 7

Random X inactivation: females are mosaics so even if X2 is present in about 50% of chromosomes, it is possible that X1 will balance it out and disease may be not expressed

Question 8

What are the two genotypes found with X-linked Recessive diseases in males?

Answer 8

Can only have one X chromosome that will either be normal or diseased
- If disease allele is present, it will behave dominantly

Question 9

What are the three characteristics of an X-linked Recessive disease?

Answer 9

1. More frequent in males than females
2. NO father-to-son transmission (father only passes on Y)
3. Can skip generations because of carrier females (heterozygous females)

Question 10

What are four examples of X-linked Recessive diseases?

Answer 10

• Lesch-Nyhan Syndrome
• Duchenne Muscular Dystrophy
• Becker Muscular Dystrophy
• Hemophilia B

Question 11

What is the gene name and function (normal and disease-state), and symptoms/features (7) of Lesch-Nyhan Syndrome?

Answer 11

Lesch-Nyhan Syndrome

• Gene name/symbol: HGPRT (Hypoxanthine-Guanine Phosphoribosyl Transferase)
• Gene function: normally involved in salvage pathway of purines (recycles 90% of purine nucleotides) AND Pathological (disease): HGPRT functions at less than 1% so purines are now degraded resulting in overproduction of uric acid
• Symptoms/Features: premature gout from uric acid accumulation, kidney stones in 25% of patients, decreased dopamine production in brain, low IQ, spastic cerebral palsy/dystonia, self-mutilation, aggressive behavior

Question 12

What is the gene name and function of Duchenne MD and Becker MD? What is the mutation found with each disease?

Answer 12

Duchenne MD and Becker MD

• Gene name: dystrophin
• Gene function: present in muscle fibers and maintains structural integrity of cell’s cytoskeleton

Duchenne MD mutation: small deletions that cause a frameshift, resulting in a complete loss of function in the protein

Becker MD mutation: larger deletions but without frameshift, resulting in a partially active protein

Question 13

What are the symptoms/features of Duchenne MD and Becker MD? Which disease presents more severely?

Answer 13

Duchenne MD and Becker MD
- Symptoms/features: progressive weakness and muscle loss, high serum creatinine levels, Gowers sign

Symptoms are more severe with Duchenne MD due to loss of function proteins

Question 14

What is the gene name, gene mutation, and general feature of Hemophilia B? What gender does this disease primarily affect?

Answer 14

Hemophilia B

• Gene name: Factor IX
• Gene function: A to G transition alters binding of key transcription factor needed for Factor IX gene expression (protein is functional, but not enough is being made)
• Feature: bleeding disorder

More common in males

Question 15

What are the five characteristics of an X-linked Dominant disease?

Answer 15

1. Males are more strongly affected (only have 1 X chromosome so if it is diseased, they are affected)
2. Disease show more frequently in females (usually lethal in males)
3. NO father-to-son transmission (father only passes on Y)
4. Affected males will pass on the disease to 100% of daughters (one X comes from father)
5. Vertical transmission pattern

Question 16

What are two examples of X-linked Dominant diseases?

Answer 16

• Rett Syndrome

- Fragile X Syndrome

Question 17

What is the gene name and function (normal and disease-state), and symptoms/features (7) of Rett Syndrome? In what gender is this disease typically lethal?

Answer 17

Rett Syndrome

• Gene name: MeCP2 (methyl-CpG binding protein 2)
• Gene function: controls expression of genes important in brain function
• Symptoms/features: some autistic behaviors, hand wringing, intellectual disability, seizures, gait ataxia, heartbeat issues, breathing issues

Lethal in males

Question 18

Why is symptom variation often seen in females with Rett Syndrome? How do symptoms often present in females in terms of severity?

Answer 18

Symptom variation in females is due to skewed inactivation patterns with the normal allele being more active
- Often very severe effects in females (unable to produce)

Question 19

What is the gene name and function, gene mutation, and symptoms (2) of Fragile X Syndrome? How is each gender affected in terms of severity of symptoms?

Answer 19

Fragile X Syndrome

• Gene name: FMR1
• Gene function: involves Fragile X Mental Retardation protein (part of cognitive development)
• Gene mutation: mutation in the CCG repeat expansion of promoter region (200-1000 repeats instead of 6-54)
• Symptoms: intellectual disability, distinctive facial appearance

Most severe in males and milder in females

Question 20

In terms of number of genes and overall appearance, what do Y chromosomes look like?

Answer 20

Y-chromosomes have a small number of genes with PAR regions at each end

Question 21

What is the gene for “male determining factor” in Y chromosomes? What is another term used to describe “male determining factor”?

Answer 21

SRY gene: “male determining factor”, or testis determining factor (TDF)

Question 22

What type of genes are found on the short arm of Y chromosomes? What type of genes are found on the long arm, and what are these genes called?

Answer 22

• Short arm: genes involving bone growth

- Long arm: azoospermia (AZF) genes involved in sperm production

Question 23

What are two diseases associated with mutations in the SHOX gene? Where is the SHOX gene located on the Y chromosome, and what does it affect?

Answer 23

• Langer Mesomelic Dysplasia
• Leri-Weill Dyschondrosteosis

Found on the short arm so involved in bone growth

Question 24

What is one disease associated with mutations in the SR gene? Where is the SRY gene located on the Y chromosome?

Answer 24

• Swyer Syndrome

SRY gene is located on the short arm

Question 25

What is another name for Swyer Syndrome? How does this disease present symptomatically?

Answer 25

Swyer Syndrome = 46, XY Gonadal Dysgenesis | - A genotypic male will develop as a female

Question 26

Mutations in what gene type primarily affect male fertility?

Answer 26

Azoospermia (AZF) genes

Question 27

What two diseases involve possession of an extra Y chromosome?

Answer 27

- 47, XYY | - 48, XXYY

Question 28

What is the name of mitochondrial DNA? How many genes do mitochondrial DNA contain and what is their primary function?

Answer 28

``` Mitochondrial DNA (mtDNA) - 37 genes that are mostly used for oxidative phosphorylation ```

Question 29

What are three unusual factors of mitochondria? Describe each

Answer 29

- Replicative segregation: random distribution of mtDNA between daughter mitochondria, AND random distribution of mitochondria between daughter cells - Homoplasmy: daughter cell receives a pure population of mitochondria, all with normal mtDNA or all with mutated mtDNA - Heteroplasmy: daughter cell receives a mixed population of mitochondria, some with normal mtDNA and some with mutated mtDNA

Question 30

How is the severity of mitochondrial inherited diseases determined?

Answer 30

Severity is based on number of mitochondria carrying mutation (more mitochondria carrying mutation = more severe)

Question 31

What are the two characteristics of mitochondrial inheritance?

Answer 31

- Strictly maternal inheritance (egg cell inactivates mitochondria from sperm cell) - Non-Mendelian: both females and males are affected, but only males can transmit the disease to offspring

Question 32

In terms of offspring, what are the chances that an affected father or affected mother will pass on the disease?

Answer 32

- None of offspring of affected males will manifest a mitochondrial disease (dad never passes on) - 100% of offspring of affected females will manifest the mitochondrial disease (mom always passes on)

Question 33

What are seven examples of Mitochondrial diseases?

Answer 33

- CPEO (Chronic Progressive External Ophthalmoplegia) - Kearns-Sayre Syndrome - Leigh Syndrome - LHON (Leber Hereditary Optic Neuropathy) - MERRF (Myoclonic Epilepsy with Ragged-Red Fiber Syndrome) - MELAS (Mitochondrial Encephalomyopathy and Stroke-like Disorders) - Pearson Syndrome