OBJ - Medical Genetics III: Atypical Patterns of Inheritance, Multifactorial Diseases

Question 1

Epigenetics

Answer 1

The science that studies changes in gene expression that are not associated with the changes in the DNA of this gene

Question 2

Chromatin

Answer 2

Nucleosome - “beads on a string”
string = DNA, beads = histones
Loops/Coils
Chromosome

Interphase = 10E2-3 - euchromatin (light)
- more accessible to trasncription factors

Metaphase = 10E4 -> heterochromatin (dark)

Question 3

Mosaic X inactivation

Answer 3

Random inactivation of one of the X chromosomes in females (some inactivated, some not)

Pseudoautosomal regions – not inactivated; pair with Y in meiosis (homologues - on both X & Y, act

X inactivation center: 
RNA spreads & covers chromosome, creating additional changes
- Altered chromatin structure
- DNA methylation of promoter
- High compaction of chromosome
              -> Barr body formation 

CONSEQUENCES:
If inherit mutant X chromosome:
-if it's inactivated -> not affected
-normal -> are affected
too many/too few

-more clinically variable in females

Question 4

Dosage compensation

Answer 4

Equalizing the contribution of X-linked genes in males and females

Question 5

Anticipation

Answer 5

Increasing severity of the disease in successive generations

**caused by unstable mutations
– earlier onset
– worsening of symptoms
– involve CNS

Question 6

Unstable Mutations

Answer 6

• Some normal genes have multiple tandem copies of tri-, tetra- or pentanucleotides.
• The number of repeats is polymorphic, within a limited range.
• Repeat regions can be unstable during DNA repair, recombination or replication.

Stages:
Expansion:
increase in the number of repeats

Premutation:
intermediate-size expansion that does not cause the disease but is unstable and is likely to be increased in size in the next generation

Unstable repeat expansion
- once passes a certain threshhold -> proliferates

Extra repeats can cause:
• loss of protein function
• gain of altered or enhanced protein function
• RNA gain of function

Examples:
Huntingtion's Disease
- CAG expansion in huntingtin gene coding region -> Toxic gain of function
- Shaky jerky movements
- Autosomal Dominant

Myotonic dystrophy - muscle wasting

• RNA gain of function (not trasnported from nucleus & attracts RNA binding proteins) -> stable hair pins & attract gene splicing proteins -> so no genes spliced
• Autosomal dominant

Fragile X syndrome - mental retardation

• Loss of function
• Fragile because breaks/gaps in X chromosome
• long stretches of CGG causes gene to be shut off, no protein produced -> loss of function
• X-linked recessive/dominant (depending on X inactivation)

Question 7

Mitochondrial genome

Answer 7

Mutation rate is much higher (because of radicals & no DNA repair mechanism)

Passed through mother - in eggs

Organs affected are organs that require lots of ATP => Muscle, Heart & Brain

LHON: Leber Hereditary Optic Neuropathy
• Optic nerve degeneration
• Missense mutations in any of three genes encoding respiratory enzymes

MERRF: Myoclonic epilepsy with ragged red fibers

Question 8

Heteroplasmy

Answer 8

the presence of more than one type of mitochondrial DNA

Normal & mutant Mitochondrial DNA in each cell

Question 9

Genomic imprinting

Answer 9

Parent-of-origin gene expression

For certain genes one allele is inactive in somatic cells (genetically diploid but functionally haploid)

Imprinting = normal
Paternal or maternal allele can be always inactive (depending on locus)

Genes are imprinted during gametogenesis and imprint is maintained into adulthood

Uniparental disomy - both copies of a chromosome are received from the same parent

Question 10

Prader-Willi Syndrome

Answer 10

Deletion on Paternal Chromosome 15
• Hypotonia
• Initial failure to thrive
• Distinctive facial features
• Mild/moderate mental retardation
• Hypogonadism
• Eating disorder (obesity)

i.e. lack of “red/paternal” proteins

Question 11

Angelman Syndrome

Answer 11

Deletion on Maternal Chromosome 15

• Hypotonia
• Seizures
• Jerky, uncoordinated movements
• Severe mental retardation
• Unprovoked smiling/laughter
• Lack of speech

i.e. lack of “blue/maternal” proteins

Question 12

Polygenic & Multifactorial diseases

Answer 12

Multifactorial diseases:
• caused by the combined actions of two or more genes and environmental factors

Polygenic diseases:
• 1+ genes
• caused by the combined actions of two or more genes
• usually quantitative in nature, such as height or blood pressure
• each contributing gene has small effects
• the effects of each gene are additive
• the offspring tends to be intermediate in appearance between the two parents

Both:
• Inconsistent with Mendelian inheritance
• The disease frequency is higher among relatives of affected individuals

Examples:
• diabetes mellitus
• hypertension
• coronary artery disease
• schizophrenia
• cleft lip, cleft palate
• most congenital heart diseases

Question 13

Twin studies

Answer 13

Monozygotic = 100% identical (1 sac)
Dizygotic = about 50% identical (siblings with same prenatal environment)

Question 14

Concordance

Answer 14

the presence of a given trait in both members of a pair of twins

When less than 100% -> indicated that environmental factors are influential on disease

For Multifactorial diseases, if genetic component then:
More genetic material shared (Mono>Dizygotic twins -> higher concordance & vice versa)