Sex-Linked Inheritance & Mitochondrial Inheritance Flashcards
What is X-inactivation? What are three characteristics of X-inactivation?
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
What is the Lyon Hypothesis? What cell structure is it associated with/was it confirmed by?
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
What are Barr bodies? What is the rule for how Barr bodies are quantified?
Barr bodies: inactive X chromosomes
- Number of Barr bodies in somatic cells is one less than the number of X chromosomes
What is the mechanism of X-inactivation? (include what gene is involved)
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
What is incomplete X-inactivation? On what region of the chromosome does this typically occur?
Incomplete X-inactivation: 15% of genes on X chromosome escape inactivation and remain active in all copies
- Occurs on PAR1 and PAR 2 regions
What are the three genotypes found with X-linked Recessive diseases in females?
- Homozygous for normal allele (X1X1)
- Heterozygous (X1X2)
- Homozygous for disease allele (X2X2)
What is random X-inactivation and what genotype does it affect in females with X-linked Recessive diseases? Why is this?
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
What are the two genotypes found with X-linked Recessive diseases in males?
Can only have one X chromosome that will either be normal or diseased
- If disease allele is present, it will behave dominantly
What are the three characteristics of an X-linked Recessive disease?
- More frequent in males than females
- NO father-to-son transmission (father only passes on Y)
- Can skip generations because of carrier females (heterozygous females)
What are four examples of X-linked Recessive diseases?
- Lesch-Nyhan Syndrome
- Duchenne Muscular Dystrophy
- Becker Muscular Dystrophy
- Hemophilia B
What is the gene name and function (normal and disease-state), and symptoms/features (7) of Lesch-Nyhan Syndrome?
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
What is the gene name and function of Duchenne MD and Becker MD? What is the mutation found with each disease?
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
What are the symptoms/features of Duchenne MD and Becker MD? Which disease presents more severely?
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
What is the gene name, gene mutation, and general feature of Hemophilia B? What gender does this disease primarily affect?
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
What are the five characteristics of an X-linked Dominant disease?
- Males are more strongly affected (only have 1 X chromosome so if it is diseased, they are affected)
- Disease show more frequently in females (usually lethal in males)
- NO father-to-son transmission (father only passes on Y)
- Affected males will pass on the disease to 100% of daughters (one X comes from father)
- Vertical transmission pattern
What are two examples of X-linked Dominant diseases?
- Rett Syndrome
- Fragile X Syndrome
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?
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
Why is symptom variation often seen in females with Rett Syndrome? How do symptoms often present in females in terms of severity?
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)
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?
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
In terms of number of genes and overall appearance, what do Y chromosomes look like?
Y-chromosomes have a small number of genes with PAR regions at each end
What is the gene for “male determining factor” in Y chromosomes? What is another term used to describe “male determining factor”?
SRY gene: “male determining factor”, or testis determining factor (TDF)
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?
- Short arm: genes involving bone growth
- Long arm: azoospermia (AZF) genes involved in sperm production
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?
- Langer Mesomelic Dysplasia
- Leri-Weill Dyschondrosteosis
Found on the short arm so involved in bone growth
What is one disease associated with mutations in the SR gene? Where is the SRY gene located on the Y chromosome?
- Swyer Syndrome
SRY gene is located on the short arm
What is another name for Swyer Syndrome? How does this disease present symptomatically?
Swyer Syndrome = 46, XY Gonadal Dysgenesis
- A genotypic male will develop as a female
Mutations in what gene type primarily affect male fertility?
Azoospermia (AZF) genes
What two diseases involve possession of an extra Y chromosome?
- 47, XYY
- 48, XXYY
What is the name of mitochondrial DNA? How many genes do mitochondrial DNA contain and what is their primary function?
Mitochondrial DNA (mtDNA) - 37 genes that are mostly used for oxidative phosphorylation
What are three unusual factors of mitochondria? Describe each
- 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
How is the severity of mitochondrial inherited diseases determined?
Severity is based on number of mitochondria carrying mutation (more mitochondria carrying mutation = more severe)
What are the two characteristics of mitochondrial inheritance?
- 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
In terms of offspring, what are the chances that an affected father or affected mother will pass on the disease?
- 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)
What are seven examples of Mitochondrial diseases?
- 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
