Mutations and single gene disorders

===Lecture Details===
Melanie Pritchard; Week 4 MED 1011; Biochemistry
===Lecture Content===
Somatic mutations occur in non gamete body cells, may be passed by mitosis to all subsequent somatic germ cell mutations of the particular cell line. Germ line mutations occur in gametes. Mutations can be induced (drugs or ionising radiation), spontaneous (DNA repair problems), and may be in coding or non-coding regions of a gene. Neutral if no effect on phenotype, is simply a polymorphism. Some loci may have few or many alleles, but the max an individual can have is 2.
Length mutations are insertions, deletions, repeat sequence changes (usually amplification). Point mutations have a change in a single base pair, can be silent, nonsense, missense and frame shift.
Point mutations are silent when they do not alter the amino acid sequence. Silent mutations are polymorphisms. Missense point mutations cause a change in the amino acid code. Nonsense point mutations form a stop codon. Missense mutations can also be point insertions or deletions, as they affect all amino acids.
Mutations can cause gain of function or loss of function. Haploinsufficiency can be where activity of other (non-mutated) gene is insufficient for normal function (eg familial hypercholesterolaemia). Dominant-negative function is where a nonfunctional protein inhibits the function of the normal protein product at the other allele (dominates other allele by mutation).
Haemoglobinopathies are most common single gene mutations. Up to 10% of the world are carriers. Marked difference in carrier rates between populations. This is because there is a biological advantage of carrier state in some populations. Sickle cell is most common, sickle allele is a missense mutation, homozygous individuals have sickle cell disease. Heterozygous or carrier state for the sickle cell allele is resistant to malaria; sickle allele survives well in malaria populations. CFTR gene is 27 exons, 70% caused by 3bp mutation at position 508; mutation thought to have GIT advantage in preventing dysentery and cholera.
Mutagens cause mutations (ionising and non-ionising radiation, chemicals and drugs)
===Readings===
Life (9th) 316-323, 328