Mutation And Single Gene Defects 3 Notes

Mutation and single gene defects

Mutation: change in the DNA base sequence that affects a single gene

Polymorphism: a non pathogenic alteration in DNA which may alter protein function but is not usually deleterious

Causes of mutations-mutagenesis

a) Endogenous

due to the chemical properties of the nucleic acids

a) deaminations- spontaneous deamination is the hydrolysis reaction of cytosine into uracil releasing ammonia in the process. When a strand with the deaminated cytosine is replicated it results in the 2^nd strand with the complentary base of A instead of G

-Methylated cytosine, regulates expression and involved in silencing genes- spontaneously hydrolyses- removal of NH3 causes the conversion of methylated cytoseine into thymine – evidence is that over generations there are fewer CG sequences and more AT sequences

b) depurination- spontaneous hydrolysis of the base-sugar link results in the loss of adenine or guanine bases. After depurination, sugar phosphate remains whilst guanine is lost. Consequence of this mutation leads to the loss of the base pair- base pair deletion.

-problems during replication of cell division- error in replication can lead to the mutation being propagated. Or repeat region can be extended as a result of the polymerase slipping.

b) Exogenous

-radiation- UV light causes dimerisation of thymines- two thymines being covalently linked. This affects the structure of the DNA and normal DNA replication can’t take place normally.

-Melonoma: Mutations in repair enzymes

-chemicals

Mutations are occurring all the time, but most of the time they have no effect- due to efficient repair mechanisms

-Direct repair, damaged nucleotide is directly repaired

-Mismatch repair

-Excision repair

-Non homologous repair- double stranded DNA

-Mutation occurs and survives repair mechanism- then it has varying effects- cause for surving repair mechanisms is mutations in the repair mechanisms, Single nucleotide repair- Xeroderma pigmentosa, DNA mismatch repair-MLH1, MSH2-heridatory non polyposis colorectal cancer, BRCA1

-Mutations occurs in the somatic cells- less dangerous- but accumulations can lead to cancer Mutations which occur in the DNA of somatic cells are not inherited by the next generation. Some such mutations will kill the cell in which they occur or have no effect. Ageing may be largely due to the accumulation of mutations in somatic cells. Cancer occurs when a mutation allows a cell to divide more frequently or start to mutate DNA.

-Germ cell mutations- mendelian inheritance0 – if effects nuclear gene

1 : point mutations/ substitution

-arise due to spontaneous errors in DNA replication and repair/errors induced by mutagens

-Transitions: purine to a purine (adenosine <-> guanosine) or a pyrimidine to pyrimidine (cytosine <-> thymine )

-Transversion: Purine to a pyrimidine

SUBSTITUTIONS IN CODING REGIONS OF GENOME

i) Least consequence More consequence order

-synonymous/silent : does not change the amino acid sequence due to the redundancy of the genetic code, some have effect especially splicing mutations

-mis-sense: replacement of the amino acid by another: The effect of this mutation depends on what part of the protein it takes place, minimal if it affects in amino acid involved in scaffolding, but can lead to loss of function of a protein if occurs in the active site

E.g Sickle cell anaemia, GAG coding for glutamic ACID is mutated to GTG coding valine- valine is a non polar molecule and severly affects the folding of the protein.

-Nonsense: codon specifying an amino acid is replaced by a stop codon- a premature terminating codon -NO protein- due to nonsense mediated decay-mRNA

SUBSTITIONS IN NONCODING REGIONS OF GENOME

Splicing mutations - Splicing mutations- 20% of all single gene defects

-point mutations in noncoding regions of genes: splice sites for intron removal, either mutation in 5’ splice site or 3’ splice site

Effects:

a) Intron retention, where the intron remains in the mRNA- this results in the mRNA remaining in the nucleus and is not translated.

b) Exon skipping:

-if the frame is maintained, where the number of nucleotides in the skipped exon is a multiple of 3, a truncated protein is formed

-if the frame is not maintained, there is a frameshift, a premature termination codon arises and RNA is degraded.

mRNA regulatory element mutations

-point mutations in the enhancer/promoter/splice enhancer/poly adenylation sites can prevent formation of a functional protein

-insertion can adversely affect a regulatory element

2: SMALL Insertations/ Deletions

-Cause- chromosomes misalign during prophase of meiosis 1 when homolgous chromosomes pair and recombine

-can range from 1 base pair to megabases

-can affect the entire gene or part of a gene

-If the insertation/deletion is not an exact multiple of 3 nucleotides, there is a frameshift and the premature codon is inserted.

-this type of mutation can also affect the normal regulation of the gene

i) Triplet deletion

-Cystic Fibrosis- loss of...

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