Genetic variation in disease Flashcards
DNA packaging
heterochromatin
euchromatin
histones
looping structure
Start codon
AUG
encodes methianine
starts translation of all proteins
stop codon
3 codons stop protein translation
what are the types of DNA change?
single base substitutions
deletions of 1 or more nucleotides
insertions of 1 or more nucleotides
single base substitutions
SNPs
replacement of a single nucleotide by another
what are the categories of effects of changes to DNA sequences?
synonymous/ silent variation and non-synonymous mutations
synonymous variation
silent variation
no change to the amino acid sequence
no change in function
doesn’t cause disease
non-synonymous mutations
changes amino acid sequence of protein
can change structure of protein
can change function of protein
can cause disease and normal variation
different types of mutations
silent
missense
nonsense
silent mutation
does not alter the polypeptide product of gene
often single base-pair substitution at 3rd position of a codon
degeneracy of genetic code will often result in another triplet that codes for same amino acid
no alteration in the properties of resulting protein
could be outside of the coding region - intron(ic region)
Nonsense mutation
formation of stop codons causing premature termination of translation of a peptide chain . Premature stop codon may lead to expression of a truncated protein . BUT usually the mRNA is degraded by nonsense-mediated decay so no protein is made .
Nonsense mediated decay
RNA surveillance that degrades faulty mRNA/ truncated mRNA which protects the body from possible consequences of truncated proteins interfering with normal function .
stop codons
UAG
UAA
UGA
Missense mutations
coding for a different amino acid
synthesis of an altered protein
if the new amino acid is chemically dissimilar the structure of the protein will be altered
Non-conservative substitution
gross reduction or complete loss of biological activity
qualitative changes in the function of the protein may occur
what are the types of missense mutations?
non-conservative and conservative
conservative substitution
some single base pair substitutions result in replacement of a different amino acid that is chemically similar and so there is no or very little difference in the function
frameshift mutations
insertion or deletion
what happens when there is a frameshift mutation?
if a multiple of 3 nucleotides is not inserted or deleted the mutation will disrupt the reading frame so the amino acid sequence of the protein subsequent to the mutation bears no resemblance to the normal sequence
adversely effects function of the protein and usually results in a premature stop codon downstream to the mutation
variant
used to describe an alteration that may be benign, pathogenic or of unknown significance . being used in place of mutation
mutation
rare variant in DNA sequence - disease causing
polymorphism
common variant in DNA sequence - benign - non disease causing . present in more than 1% of the population
what are the CFTR mutations?
p. Gly542Ter (stop)
p. Gly551Asp
p. Phe508del
p. Ala455Glu
p. Arg347Pro
p.Gly542Ter (stop)
unstable mRNA, protein not made
p.Gly551Asp
protein reaches cell membrane but channel gate does not open and close. A potentiator drug may help
p. Phe508del
Protein misfolded so can not reach cell membrane . Targeted for degradation . A corrector drug may help
p.Ala455Glu
splicing errors mean insufficient protein is made . What is made gets to cell membrane and works properly . A potentiator drug may help .
p.Arg347Pro
protein is made and moves to cell membrane, appropriate amounts made but channel doesn’t work properly . A potentiator may work .
