7. dynamic mutations

Question 1

dynamic mutations def

Answer 1

-trinucleotide repeats undergo high frequency mutagenesis (microsatellite regions) and this causes expansion of the DNA
-they are polymorphic and tend to be expanded with following generations
-can be found in the coding region, in promoter regions or in 3’ UTR

Question 2

what 3 diseases are caused by dynamic mutations

Answer 2

1. Huntington’s
2. Fragile X syndrome
3. Myotonic dystrophy

(usually the diseases are neuromuscular/ neurodegenerative)

Question 3

mechanism behind dynamic mutations (2)

Answer 3

1. error at the level of mitosis
2. unequal crossing over

Question 4

describe how an error in mitosis can cause dynamic mutations

Answer 4

-DNApol can sometimes stop during DNA replication which causes a forwards or backwards slippage
-a backwards slippage causes the same section to be added twice, hence an insertion
-a forwards slippage causes a section to be missed, hence deletion

if this occurs on a microsatellite it could be pathogenic and cause a dynamic mutation (typical of spermatogenic mitosis cycles)

Question 5

describe how unequal crossing over can create dynamic mutations

Answer 5

-during meiosis a mispairing sister chromatids of homologous chromosomes can result in an insertion or deletion (but usually insertion bcos the sequence is expanded)

-the gamete therefore contains a number of repeats

!! common to female gametogenesis bcos it happens during meiosis not mitosis

Question 6

what are the common featuers of trinucleotide mutation

Answer 6

1. germline instability: successive transmission throughout the generations show the EXPANSION rather than the contraction of DNA
2. anticipation: an earlier age of onset is seen with increasing severity of phenotypes in subsequent generations (ie originating from larger repeat lengths)
3. the parental origin of the diseased allele can often influence anticipation (ie sometimes only the father or the mother can expand the allele)

Question 7

what are the 3 classes of diseases that can b einduced by unstable repeat expansions

Answer 7

CLASS 1: disease due to expansion of NON coding repears that cause protein loss of function (fragile X + friedrich ataxia)

CLASS 2: diseases due to expansion of NON coding regions that cause novel properties to the RNA (myotonic dystrophy)

CLASS 3 = called polyglutamine disorders - MOST FREQUENT: diseases due to repeated expansion of a codon (ie coding region) that causes novel properties of the AFFECTED protein. Usually this codon is CAG for glutamine. (eg huntington’s )

Question 8

description of polyglutamine disorders

Answer 8

CLASS 3 dynamic mutation disorders:
-neurodegenerative
-eg huntingtons

-cause by the repeat of the glutamine CAG codon in the coding region
-often there is a threshold: a certain number of repeats is normal, but above that number it becomes pathological