5. Non-Traditional Genetics Flashcards
List the different categories of non-traditional inheritance (objective)
Answer later
Define mosaicism and distinguish between somatic and germline mosaicism (objective)
Answer later
Explain genomic imprinting including the multiple mechanisms that may cause disease (objective)
Answer later
List important diseases caused by trinucleotide expansion and how this expansion affects the genes involved (objective)
Answer later
Recognize a mitochondrial disease pedigree, the mode of mitochondrial DNA inheritance and to define heteroplasmy (objective)
Answer later
Non-Traditional Genetics (list)
Non-Mendelian or atypical inheritance
- Mosaicism
- Genomic imprinting
- Unstable triplet repeat mutations
- Mitochondrial inheritance
Mosaicism
2 or more genotypes in an individual from one zygote
Typically from mitotic error during development
Somatic- 1st then 2nd hit, unilateral Rb
Germline- reproductive organs, passed on
Chimerism
Two genomes present in one individual (twin zygotes fused)
Somatic Mosaicism
Mosaicism in the body which usually develops post-conception (mosaic trisomy 8)
Germline Mosaicism
Confined to the germ cells, also called gonadal mosaicism.
Consequently, an individual may produce multiple offspring with a mutation without manifesting the disorder him/herself
*Acquired post-conception: high risk to offspring that is not clinically present in parent (multiple offspring affected with what is usually felt to be a sporadic disease)
Ex. DMD son, tell family recurrence as high as 15% due to maternal germline mosaicism.
Congenital Hyper-pigmentation reflecting chromosomal mosaicism
Male with mental retardation and SWIRLING pigmentation (somatic mosaicism for chromosomal abnormality)
Differs from incontinentia pigmenti: pigment pattern present at birth and patient is a male.
Diagnosed by chromosome study-skin cells
Duchenne Muscular Dystrophy
5 brothers with it, X-linked recessive.
No other affected relatives. Mother does not have the mutation in her lymphocytes and likely has germline mosaicism for the DMD mutation (involving ovaries mutation)
Genomic Imprinting
Autosomal chromosomes also has X-inactivation type shutting off (ex. Chromosome 15)
Parent-of-origin difference in gene expression (dependent whether from mother or father)
Different functioning due to epigenetic modification, not a chance in DNA sequence, but a reversible regulation of gene expression
Genomic Imprinting (how)
Usually by methylation or changes in chromatin structure
Most imprints erased and restored each new generation
200 genes know to be imprinted
In every cell in body, monoallelic expression
Imprinting Disorders (list)
Number of different mechanisms by which imprinting disorders can occur:
- Uniparental disomy (both came from mom or dad)
- Microdeletion
- Imprinting Defects
Uniparental Disomy (UPD)
Both members of chromosome pair are inherited from one parent
Thought to be from trisomy with a loss of one of the extra chromosomes around fertilization
Human Imprinting Disorders
Prader-Willi Syndrome
Angelman Syndrome
Prader-Willi Syndrome
S: Neonatal hypotonia, cryptorchidism, hypothalamic dysfunction (lack of satiety and subsequent obesity, hypogonadotropic hypogonadism, growth hormone deficieny and short stature and diminished muscle), cognitive/behavioral impairment
M: Lack of expression of paternal genes at 15q11-13
Deletion of paternal 70%
Maternal UPD 25%
Imprinting defect (silence fathers) 5%
Angelman Syndrome
S: Severe mental retardation with limited speech; ataxic gait; spontaneously happy affect; seizures
1/15000 births
M: Lack of brain expression of the maternally inherited UBE3 gene at 15q11-13
Deletion 70%
UBE 3A mutation 11%
Paternal UPD 7%
Imprinting Defect (maternal silenced) 3%
Fragile X Syndrome
S: Long narrow face, prominent ears and jaw/forehead, enlarged testes, mental impairment, ADD and hyper, motor delays
Most common cause of mental retardation in males
Anticipation: number of triplet repeats may in subsequent generations cause worse mental deficiency (imprint expansion)
Female heterozygotes for triplet expansions often develop problems such as ovarian failure and ataxia
M: CGG repeats in 5’ UTR
Mitochondrial Diseases (general)
Energy production, fatty acid oxidation, urea cycle, porphyrin synthesis
Defects aerobic metabolism
Can affect any tissue and cause variety of signs and symptoms
Mostly neurologic, muscular and cardiac
Mitochondrial Diseases (list)
MELAS (mitochondrial encephalopathy lactic acidosis and stroke-like episodes)
MERRF (myclonic epilepsy and ragged red fibers)
NARP (neurogenic ataxia and retinitis pigmentosa)
CPEO (chronic progressive external ophthalmoplegia)
Mitochondrial DNA
Comes from the oocyte (maternally inherited)
Mutations in MC can occur anytime in life and passed on
Cells may end up with a mixture of normal and mutant mitochondria- Heteroplasmy
Heteroplasmy
Cells may end up with a mixture of normal and mutant mitochondria
Mitochondrial DNA Pedigree
Both males and females are affected
The condition is transmitted through the female to her offspring
If male has the trait and spouse does not, their offspring won’t have the trait
Probably will not skip generation
Mitochondrial Disorders (treatment)
No real effective treatment
Often try cofactors like coenzyme Q10, thiamine, vitamin E and carnitine
Diet manipulation not effective
Often progressive steadily with increasing involvement of additional systems
