Genetics and Genetic Medicine Flashcards
describe genetic variation
the normal differences between individual’s DNA. may be whole extra/missing chromosomes, extra/missing parts of chromosomes, extra/missing parts of DNA, extra/missing nucleotides, nucleotide changes
what is the difference between a single nucleotide variation and a copy number variation?
single nucleotide = change in one single nucleotide in a specific location in the genome
copy number = change in the number of copies of a gene/region of DNA. deletions or duplications of large sections.
methods of analysing DNA variations
see notes
p. and c. nomenclature
Changes in DNA sequence are described as “c.” (‘coding’ DNA)
Changes in peptide (AA) sequence are described as “p.” (‘peptide’)
For example: ACVRL1 C.32 T>G means that in this particular gene, at base 32, the T becomes a G.
Note: C. refers to changes to coding DNA; so actually a change to post-splicing mRNA sequences rather than DNA sequence.
For example: ACVRL1 p.Leu11Arg means that there has been a variation that has led to a change in the 11th AA from a leucine to arginine.
Ter.
terminus (premature stop codon)
types of variant (x4)
Synonymous variants
Changes in the DNA sequence that do not alter the AA sequence of the protein
Non-synonymous variants
Changes in the DNA sequence that result in a premature stop codon. This may lead to a non-functional protein.
Premature stop codons
Deletions/duplications variations
Loss of gain of DNA segments
Splice variations
Changes that affect RNA splicing
what is genetic penetrance?
The proportion of individuals with a specific genetic variant and the associated trait/disease describes the penetrance of a genetic variation.
Penetrance may increase with age: ex Huntington’s Disease
what is the chain of causality?
pathologies can arise due to genetic variations at different points in the chain. ex: transcription, splicing, translation, modifications, folding etc (is the gene deleted? are there early stop codons? is cellular signalling affected? does a different protein being made affect organ function?)
quantitative vs qualitative effects of genetic variations
Genetic variations may lead to quantitative effects; wherein the functioning protein stops being made.
Genetic variations may lead to qualitative effects; wherein the function of the protein is altered (usually missense).
what is the dominant negative effect?
a mutant protein disrupts the function of a normal protein. There may also be an activating effect; wherein protein activity is increased (may be pathogenic).
ex osteogenesis imperfecta type 2 (mutant collagen interferes with function of normal collagen)
give examples of quantitative and qualitative genetic variations
quant:
Spinal muscular atrophy type 1 (autosomal recessive; SMN1 gene)
Neurofibromatosis type 1 (autosomal dominant)
Duchenne muscular dystrophy (X-linked)
qual:
Hypochondroplasia (abnormal bone growth from activation of FGFR3 gene)
Osteogenesis imperfecta type 2 (mutant collagen interferes with function of normal collagen)
limitations of precision therapy for genetic disorders
expensive
may have toxicity to certain organs, especially the brain
may not last; and repeat (expensive) treatment needed
may also be irreversible
may need to be given early so screening is a must
types of pain
- Visceral –> from blood vessels and organs –> non-localised, dull, achy
- Somatic –> from skin, muscles etc –> localised, sharp/stabbing
- Referred –> pain is perceived in a location other than that of the stimulus. This is due to that area also being supplied by the same spinal nerve level and the exact source of the stimuli unable to be determined by the brain.
