Unit 1 Ch.15: Gene Mutation and DNA Repair

what is a mutation?

source of disease, disorders, and genetic variation

Types of mutations including sub types

insertions: frameshift and in-frame

deletions: frameshift and in-frame

substitutions: missense, nonsense, and silent

Substitution

1 base pair changes

missense substitution

creates new codon= new amino acid= different amino acid sequence

nonsense substitution

new codon signals early stop in translation

silent mutation

new codon codes the same amino acid= no sequence change

transition vs transversion

substitution between purine to purine and pyrimidine to pyrimidine

substitution between purine to pyrimidine

Deletion

loss of nucleotide

Insertion

gain a nucleotide

frameshift mutation

translation triplet reading is shifted

inframe mutation

insert/ delete a nucleotide group of 3, reading frame stays intact

what are tri-nucleotide repeats?

DNA regions with repeats of the same nucleotide codon

DNA strands separate and replicate, hairpin forms in new strand makes part of strand be replicated twice, two strands of new DNA separate and the strand with extra copies serves as a template for the next replication, resulting in DNA with additional copies of codons

forward vs reverse mutation

forward: changes wildtype to mutant phenotype

reverse: changes mutation back to wild type gene and phenotype

neutral vs loss of function vs gain of function mutation

neutral: occurs in noncoding regions, doesn’t alter expression

loss of function: eliminates function of gene product, mostly recessive, null makes complete loss of function

gain of function: gene product with enhanced function, mostly dominant

lethal mutation

deadly mutation

suppressor mutation

hides or suppresses the effect of another mutation

suppressor mutation: intragenic

mutation happened at same gene of original mutation

suppressor mutation: intergenic

different site than original mutation

germline vs somatic mutations

germline: in cells that make gametes, meisosis means mutations can go to next generation

somatic: in nonreproductive cells and passes through mitosis

what affects mutation rates?

frequency of changes in DNA

probability that any changes will be repaired

probability that changes will be detected

spontaneous replication errors

natural nucleotide sequence change

Wobble base pairing: DNA separates for replication, T pairs with G through wobble, next replication round C and G pair= transition mutation

tautomers

alternate base pairing, how they link up changes how they react with other atoms, different flexible H bonding

deletions and insertion causes

replication slippage: newly synthesized strand loops out creating additional nucleotide in new strand, template strand loops out and results in omission of a nucleotide on new strand

spontaneous chemical changes

depurination

deamination

chemical damage

spontaneous chemical changes: depurination

loss of purine base makes apurinic site= incorrect base insertion= permanent mutation

spontaneous chemical changes: deamination

loss of amino group, changes which nucleotide is present

chemically induced mutations

alkylating agents

deamination

hydroxylamine

oxidative reaction

alkylating agents

chemicals that mutate DNA

EMS and mustard gas

hydroxylamine

acid that causes DNA mutations

oxidative radicals

damage from byproducts of normal cell processes

oxidative reaction

generated through aerobic respiration or exposure to radiation, produces chemical modifications

intercalating agents

molecules inserting between DNA bases, disturbs helix structure

radiation: pyrimidine dimers

two adjacent thymine become covalently attached; skin damage from UV

mutations introduced by transposons

shifts the reading frame- insertion

what are transposable elements

sequences that move about the genome

what structural features are required for the movement of transposable elements

short direct repeats

inverted terminal repeats

open reading frame

steps of DNA transposon movement

transposase cleaves DNA at inverted terminal repeats

transposase staggers cuts in chromosomal DNA

transposase inserts transposon at target site

gaps filled by DNA pol and ligase

what are retrotransposons

transposable elements that move within genome using RNA intermediate

what are the 2 types of retrotransposons

long terminal repeats

non long terminal repeats

what are the steps of retrotransposition

retrotransposon transcribed and translated by cellular enzymes

reverse transcriptase creates dsDNA copies of each retrotransposon RNA

integrase inserts dsDNA copies into chromosomal DNA

what are the effects of retrotransposons

accumulate rapidly to create mutations in genome

what are some transposable elements in humans?

~50% of human genome made of transposable element DNA, most is inactive

mismatch repair

mismatch made in DNA replication

repair protein cuts out new DNA strand until it reaches the mismatch

DNA poly replaces nucleotides, ligase seals backbone

base excision repair

DNA glycosylase removes damaged base= apyrimidinic site

AP endonuclease cuts phosphodiester bond on 5’ side of AP site and removes deoxyribose sugar

DNA pol adds new nucleotides to exposed 3’ OH

DNA ligase seals backbone

nucleotide excision repair

DNA damaged by thymine dimer

nuclease cuts out damaged region

DNA pol I fills gap

DNA ligase seals backbone

ds break repair: non homologous end joining

error prone because breaks aren’t clean, causes frame shift mutation

two blunt DNA ends ligated together

ds break repair: homologous recombination

most accurate

uses identical sister chromated as template for repair

ssDNA H bonds to sister chromatid and replicates through

ds break repair: alternate end joining

error prone

short regions of homology to align broken DNA, sister chromatid not required, loses nucleotides in the flaps