Genomes, mutations and molecular pathology Flashcards
What is genetic variation?
differences between the DNA sequences of individual genomes
How is cystic fibrosis caused?
cystic fibrosis transmembraneconductance regulator (CFTR) –conducts chloride ions across epithelial cell membranes, involved in production of sweat, digestive fluids, and mucus, mutations: secretions which are usually thin instead become thick
Why are some mutations are associated with pancreatic sufficiency?
–Differential splicing/expression pattern of CFTR in different tissues
What is a mutation?
changes to DNA that are not corrected by DNA repair mechanisms
What is the outcome of deamination of cytosine?
produces uracil (found in RNA, not DNA) Recognised as a damaged base and repaired
Consequence of deamination of 5methylcytosine?
produces thymine (base normally found in DNA) GT mismatch may escape detection of repair machinery. Subsequent round of replication the T will form a TA base pair – producing a C to T mutation
How does UV cause cancer?
UV-rays in sunlight promotes covalent linkage between adjacent pyrimidine (T and C) bases so thymine dimers
What is a synonymous mutation?
changes a codon into another that codes for the same amino acid (redundancy in the genetic code)
Types of nonsynonymous mutations
- Missense mutations replaces one amino acid for another (effect greatest when replacement has very different physiochemical properties) e.g. GGG (glycine) to AGG (arginine) in ABCC11
- Nonsense mutations replace an amino acid with a STOP codon. Results in unstable RNA or a truncated protein e.g. GGA (glycine) to UGA (STOP)
- Splice site mutations create or destroy splicing signals
What does mutations in regulatory DNA sequences affect?
Increased vs reduced amount of gene product level
What is non-allelic homologous recombination?
Repeated segments (identical/similar sequence) can mispair when sister chromatids align Cross-over at mismatched repeats –deletion or duplication of intervening sequence
What is frameshift?
deletion or insertion in a DNA sequence that shifts the way the sequence is ‘read’
What is polyploidy?
additional extra genome
triploid embryos resulting from 2 sperm fertilizing a single egg
What is aneuploidy?
extra or missing copies of chromosomes
Trisomy: 3 copies of a particular chromosome in a diploid cell
Monosomy: a chromosome is lacking in an otherwise diploid state
What is nondisjunction?
when paired chromosomes fail to separate during meiotic anaphase I and then migrate to same daughter cell, or sister chromatids fail to disjoin at meiosis II
How does genetic variation cause disease?
- Changes the sequence of the gene product (protein): (i) loss of function (protein is incapable or severely reduced in its capacity to carry out its normal function) (ii) protein function is altered in some way that is positively harmful
- Change to the amount of gene product made (i) too little (ii) too much
How is phenotype modified by genetic background?
β-thalassemia blood disorder
• Genetic deficiency in β-globin gene (HBB)
α-globin & β-globin normally produced with 1:1 stoichiometry , Excess α-globin production (relative to β-globin) leads to red blood cell (RBC) death
How is phenotype modified by the environment?
Phenylketonuria (PKU) metabolic disease
• Mutation in gene encoding the liver enzyme: phenylalanine hydroxylase (PAH) converts phenylalanine to tyrosine
Readily treated by placing infant on low phenylalanine diet
