Contribution of Genetic Changes to Human Disease Flashcards
Definition of DNA variation/variant
Specific loci within the genome at which 2+ alleles may be present
Definition of polymorphism
Common DNA variant
Definition of mutation
Pathogenic DNA variant
Definition of lariat acceptor
Part of premRNA/hnRNA that is involved in transcriptome folding
Definition of polypyramidine tract
Region of premRNA/hnRNA that promotes spliceosome assembly
Definition of cryptic splice sites
mRNA sequence that has the potential for interacting with the spliceosome
Describe the relationship between the frequency of a mutation in the population and the recency of the mutation
Selection dictates what variation remains in the gene pool
Old mutation events not subject to negative selection is likely to be common in the population
Recent mutation events may be unique to ourselves/somatic
What is a single nucleotide substitution
1 base in substituted for another
What are the 2 types of single nucleotide substitution
Describe them
What is the frequency of each type of single nucleotide substitution?
Transition
- substitution that conserves base chemistry (pyramidines swap with other pyramidines, purines swap with other purines)
- more common
Transversion
-substitution that changes base chemistry
What is a deletion
1+ loss of bases
What is a insertion
-what are the 2 types
1+ gain of bases between 2 previously adjacent bases
Normally material has been duplicated from previous material
Tandem duplication
-inserted material is the same as the adjacent sequence
Repeat expansion
-inserted material only repeats the last few bases
What is an inversion
Inverted sequence is replaced with reverse compliment
What is translocation
DNA exchanged between chromosomes
What are the effects of DNA mutations
- how many bases could be involved in a mutation
- what are the effects on genes
Deletions, insertions, tandem duplications, inversions range from 1-1mn bases
Rearrangements are often imperfect so sequences at the ends of the blocks may also be disrupted
Inversions and translocations may be benign if breakpoints do not disrupt genes
What is functional variation
Not all variation will have a functional/phenotypic consequences
Functional consequence defined by its effect on the functional region of the genome
Almost all reported disease causing variants directly affect functional parts of genes
What are the 3 effects of variants in coding regions
Silent
- will not affect protein directly
- may affect splicing
Missense
- single AA change
- effect may be neutral/harmful
Nonsense
- premature termination of the reading frame
- effect => truncated protein/NMD
What are the functions of
- lariat acceptor
- polypyramidine tract (bases associated with region?)
- splice acceptor (bases associated with region?)
- splice donor (bases associated with region?)
Lariat acceptor
-involved in transcriptome folding
Polypyramidine tract
- CT rich
- promotes spliceosome assembly
Splice acceptor
- AG rich
- flank exon
Splice donor
- GT rich
- flank exon
What are the effects of variants in the splice sites
What does the severity of the mutation depend on
Variants in splice recognition elements => disrupts splicing process Result depends on -relative strengths of elements -severity of change -proximity of alternatives
Consequences
- exon skipping
- use of cryptic splice sites in exon or intron
- small intron retention
- combination of all the above
What is the effect of large genetic rearrangements
Whole exons in a gene can be affected
Critical determinant of effect is whether the reading frame is affected
What is the effect of variants in promotor regions
Rare as promotors relatively insensitive to variation
- result in tissue specific phenotypes
- result in developmental stage specific phenotypes
What is the effect of variants in UTRs
Some UTRs are more highly conserved than coding regions or promoters
Functions poorly understood
Very few confirmed pathogenic variants
What is the effect of variation in polyadenylation
Few characterised variant => reduced transcript levels
What are the 2 morphs that lead to loss of function
Amorph
-complete loss of gene function
Hypomorph
-partial loss of gene function
What are the 3 morphs that lead to gain of function
Hypermorph
-increase in gene function
Antimorph
-dominant alleles act in opposition to normal gene function
Neomorph
-new gene function
What are the effects when the protein loses its function due to variation (recessive)
-3 outcomes
What can prevent loss of function?
Little/no protein produced
Protein is unstable/inappropriately targeted and is degraded
Residue essential for function is missing/critically altered
Presence of a 2nd normal allele can rescue phenotypes => normal heterozygotes
Therefore, loss of function variation is normally recessive
What are the effects when the protein loses its function (dominant)
-3 outcomes
Haploinsufficiency
-50% reduction in quantity => loss in protein function
Dominant negatives
- homomultimeric proteins that form => gain in function
- also disrupts normal functioning counterpart
Somatic second hit
- organism can function with 1 mutated gene but a somatic 2nd mutation => rare clones of null cells that don’t function
- recessive at cellular level but dominantly inherited
What are the effects when the protein gains functions (dominant)
-2 outcomes
Loss of regulation
- activity of protein loses spatial/temporal specificity
- due to loss of regulatory region/mislocalisation
Novel function
- new function is not typical
- formation of insoluble aggregates
