DNA Damage and Gene mutation

germ-line mutation

occur in gametes

inherited by next generation, present in all cells

ex: sickle cell anaemia, retinitis pigments, aniridia, LCA

somatic mutation

in somatic cell (any cell except gametes)

form clone of identical cells containing mutation (tumors is an ex)

not inherited by next generation

silent mutation

does not change sequence of protein

or occur in non-critical region of gene

polymorphism

normal variation in phenotype

ex: hair color, eye color, blood types

single gene mutation

affects 1 gene

chromosome mutation

affect multiple genes

typically cause defect

often affect multiple organ systems

epigenetic changes

chemical modification of DNA

can be inherited

ex: DNA methylation

DNA base substitution

base changes to a different one

ex: C → T

insertions

one or more bases is inserted

ex: CAT GCT → CGA TGC T

deletions

one or more bases are deleted

ex: CAT GCT → CAG CT

transition

purine → purine

pyramidine → pyramidine

ex: A → G, C → T

transversion

purine → pyramidine

or vice versa

ex: A → C

G → T

point mutation

• silent: no AA change / no effect

• missense: change AA

• non-sense: change to stop codon

can affect splicing

insertion/deletion = INDEL

add or removal of base(s)

often associated w diseases

large scale insertion

trinucleotide (codon) repeats - common

associate w diseases

depurination

purine is removed from deoxyribose by hydrolysis → affect replication

deamination

loss of amino group

turn cytosine (C) into uracil (U) in DNA
if not repaired, will result in a C → T transition when replicated

DNA template strand: TTC → TTU

DNA complementary strand: AAG

(G is mispaired to U)

After DNA replication: AAG → AAA

that A is a mutation

oxidative stress

reactive oxygen species and free radicals can oxidize the bases → block DNA replication or mislaid during replication

oxidized T = thymidine glycol → block DNA rep

oxidized G = 8-oxo-dG → mispairs w A

mutagens

agents that increase mutation

can be purposely induced for research purposes

can result from environmental exposure (UV light, pollution, pesticides, etc.)

mechanisms:

substitution → mispair

damage a base → can’t pair

Analogs

replace a base

base analogs = chemicals w structures similar to nucleotides

causes mispair

ex: 2-AP looks like an adenosine and can get read as A. then it will wrongly pair w C (supposed to be A→T but now we have 2-AP→C)

EMS

change a base

EMS: ethylmethan sulfonate → adds a ethyl to the base → result in transitions

ex: G → ethylguanine and pair w T

T → ethythymine and pair w G

DNA intercalating agents

mimic paired bases

chemical intercalates = fits into double helix between bp

result in insertions and deletions during DNA rep

irradiation

UV radiation: causes attachment between adjacent pyramidines

disturbs double helix structure

when not repaired, incorrect base is inserted during DNA rep

think about how high doses of UV and radiation can BREAK DNA DOUBLE HELIX causing large scale damage