Mutation Flashcards
Spontaneous - occur naturally
• Arise in all cells at low frequency
• Errors in DNA replication eg. due to tautomers
• Spontaneous lesions or damage
eg. depurination, deamination of cytosine
Induced - require a ‘mutagen’
• Chemical e.g. base analogues, intercalating agents, base modifiers.
e.g. Aflatoxins, benzopyrenes, nitrites
• Radiation e.g. UV light, electromagnetic ionizing agents (free radicals)
Tautomeric forms of DNA bases
Spontaneous
• Bases can be incorporated into DNA during replication in their rare tautomeric forms
• Base pairing will follow different rules
→ Base substitution
T-G AND C-A
Induced mutation example
Induced Mutation
Example: UVB Damage
• Pyrimidine dimer (T-T)
molecular lesions formed from thymine or cytosine bases in DNA
• → cyclobutane ring
potential to lead to mutation and cancer.—> Melanoma
Mutations occur all the time in every cell in the body
- Natural depurination
- => Total = 1017 depurinations/day/human body
- UV in sunlight causes ~50 thymine dimers/sec/cell
- Most are repaired and not passed on to cell progeny.
- Over a lifetime, errors accumulate and lead to age-related conditions and cancer
effect of mutation within genes
Prevention of protein forming= Lack of dystrophin (protein found in muscles) causes Duchenne muscular
Dystrophy
Reduced protein quantity= Slow blood clotting in haemophilia A due to reduction in clotting factor VIII
Reduced protein efficiency= Sickle cell anaemia: Haemoglobin
Change in protein function: Extra amino acids alter function in Huntington disease (CAG repeats)
CFTR Mutations
gene mutated in cystic fibrosis
Large gene with many known mutations
not all mutation lead to disease
Different mutation have different consequences on the protein
CFTR
• CFTR encodes for the Cystic Fibrosis Transmembrane Conductance Regulator
• Membrane protein
• Chloride channel
• Cystic Fibrosis: dysregulation of epithelial fluid transport
mutation results in decreased chloride channel activity and subsequently effect the fluid transport
Which DNA repair protein(s) is/are primarily responsible for correcting apurinic or apyrimidinic sites?
Select one:
a. Mismatch repair enzymes
b. A multienzyme/nuclease complex
c. DNA ligase only
d. DNA Glycosylase
e. AP Endonuclease
AP Endonuclease
CFTR common mutation Mutations
CFTR gene encodes for normal CFTR - chloride can pass the membrane channel
F508del mutation presents a deletion of three base pairs, involving the loss of an amino acid, phenylalanine, at position 508.
F508del results in low numbers of misfolded protein in the cell membrane
chlorine l cannot cross the channel
Human Variation
- We are different in large part because the sequence of our DNA is different
- On average <1 difference in every 1,000 bp
- This is still ~ 1 x 106 differences between individuals
- The majority of these differences occur in the non-coding regions of our DNA
- However, even amongst our 25,000 or so genes, at least one third are polymorphic within the healthy population
- Each different form of a gene is called an allele and has arisen as a result of mutation
bad, good mutation
good mutation —> evolution (heterozygote advantage )
bad mutation —> disease heterozygote advantage
neutral mutation —> scientific use
Mutation in Evolution:
natural selection
Some mutations that provide a selective advantage are perpetuated: natural selection
example High Altitude adaptation: Tibetans and Nepalese live altitude 4,000m
• air contains 40% less oxygen
• compensate with bigger chests: greater lung capacity
• evolution of few red blood cells with better blood flow in brains
mutation that provide advantage
HIV
CCR5 receptor helps HIV-1 enter cells
32 bp deletion – CCR5 32
Mutation lowers the amount of receptor
Without the receptor, HIV cannot infect cells
Beneficial mutation up to 14% in Northern Europe
Neutral Mutations
Neither advantageous nor disadvantageous • The majority of mutations are neutral • Can also spread in population • In humans in the form of single-nucleotide polymorphisms (SNPs) • 99.5% similarity
Disease mutation
• There are a multitude of conditions/diseases (> 4000) which result from the ‘bad’ or detrimental effects of mutations that are
passed on through the generations
Why do many disease-causing mutations persist in the population?
Many genetic diseases only manifest when the individual has inherited 2 mutated copies of the same gene
• Recessive inheritance: the affected person must be homozygous for a disease mutation or compound heterozygous for
two different disease-causing mutations for the condition to manifest.
• No working copy of the gene to provide sufficient function
• In these cases, heterozygotes with one normal gene copy and one mutant gene copy are healthy
• Their normal gene provides sufficient normal protein/function
• If the mutation confers some selective advantage to heterozygous individuals, it may be maintained in the population by natural
selection.
heterozygote advantage
people carrying the faulty gene are sometimes advantaged
e.g. people who have sickle cell anemia are protected against malaria
aa- fatal sickle cell anemia but resistance against malaria
Aa- resistant to malaria - mild sickle cell anemia
AA- susceptible to malaria no sickle cell anemia
New genes and genome evolution- mutation
DNA is not made in random sequences, it is generated from pre-existing DNA
• Changes in DNA sequence lead to changes in structure and the development of new functions for proteins
Gene mixing
Gene mixing • This uptake can occur from: alpha and beta • Bacterial transformation • Conjugation • Transduction • Viral reassortment
Gene Families: DNA duplications
Example
Genes evolve as families: members encode proteins with related structure and function
Globin gene family:
• Derived from common ancestral gene
• Encode globular proteins transporting oxygen
• Common to many species
• Essential for multicellular animals to grow to large size
Alpha gene translocated from chromosome 11 to chromosome 16
happens over millions of years
