Contribution of genetic changes to human disease Flashcards
Define DNA variant/variation
specific locus/loci within genome at which two or more versions of alleles may be present
what are two types of singe nucleotide substitutions
transition- substitution which conserves the base chemistry (purine to purine or pyrimidine to pyrimidine)
transversion-substitution which changes the base chemistry (purine to pyrimidine or pyrimidine to purine)
what are the two types of deletions
single base pair, continuous block of sequence (e.g. three base pair)
what are the three types of insertions
single base pair, continuous block of sequence (e.g. three base pair), tandem duplicaiton
What is an inversion
block of sequences is inverted - because of the nature of DNA pairing, the inverted sequence is replaced with its reverse compliment e.g. gtca turns into tgac
What is translocation
when DNA is exchanged between chromosomes
What are silent, missense and nonsense mutations
silent-will not affect the protein directly but may affect splicing
missense-will cause single AA change whose affect may be neural or harmful (resulting in gain of function, direct/indirect loss of function)
nonsense-will cause premature termination of reading freame resulting in truncated protein or nonsense mediated decay
Give examples of splice recognition elements
lariat accceptor, polypyrimidine tract, splice acceptor, some exonic variants, splice donor
what are the consequences of disruption caused by splice recognition elements
exon skipping, use of cryptic splice sites (in exon or intron), intron retention (small introns only), combination of above
what are examples of large rearrangements and what are they affected by
deletion, duplication, inversion
determinant=whether or not removal/insertion affects the reading frame
What are less common functional variation
Variants in promoter (can result in tissue-specific and stage-specific phenotypes)
Variants in untranslated regions
Variants in polyadenylation signals
What subsections is Muller’s Morphs split into
Loss of function
Amorph: a variant that causes complete loss of gene function
Hypomorph: a variant that causes a partial loss of gene function
Gain of function
Hypermorph: a variant that causess an increase in normal gene function
Antimorph: dominant alleles that act in opposition to normal gene activity
Neomorphic: variants that causes a dominant gain of gene function that is different from the normal function
What happens in loss of function variation
protein product fails to perform its normal function. This may arise because:
little or no protein is produced
the protein is unstable or inappropriately targeted and is degraded
residue or domain essential for function is missing or critically altered
How do loss of function alleles exhibit dominnant form of inheritance
haploinsuffficiency-the organism is so sensitive to levels of protein that a 50% reduction in quantity causes a noticeable phenotype
dominant negative effect–the formation of homomultimeric complexes means that not only does the protein lose its function, it disrupts the function of its normal couinterpart
somatic second hits-organism largely normal but somatic 2nd mutation give rare clones of null cells which are defective. Recessive at cellular level but dominantly inherited in families
What happens in gain of function and what is it caused by
the protein may become less specific in its normal function and even acquire a novel function. Dominantly inherited
Loss of regulation: the activity of a protein loses its spatial or temporal specificity. This may be due to loss of regulatory region or mislocalisation
Novel function: the protein has a novel effect which is not characteristic of the normal product. Acommon novel function is the formation of inoluble aggregates
