Lecture 7 - Mutation Flashcards
Why are mutations important
Most mutations are deleterious because most genes have been subject to natural selection. Tinker with a well made machine and you are likely to make the machine breakdown. Mutations thus commonly causes genetic diseases and disorders.
Some mutations are beneficial. Mutation is thus the raw material for adaptive evolution.
Mutagenesis is an important tool for probing fundamental biological processes
What is Antennapedia
a HOM-C gene first discovered in Drosophila which controls the formation of legs during development. Loss-of-function mutations in the regulatory region of this gene result in the development of the second leg pair into ectopic antennae
What is mutagenesis
tools to understand genetic & developmental mechanisms
What is the affect of polymorphisms
Increase susceptibility to particular diseases
What is the main context to mutations
Deleterious - disease and disorder links
What do beneficial mutations lead to
adaption
How can a mutation be beneficial (eg.)
The human immunodeficiency virus (HIV) infects certain cells of the immune system.
HIV can enter a cell by interacting with two cell surface receptors: CD4, and either CCR5 or CXCR4.
A particular polymorphism results in a CCR5 protein that is truncated by 32 base pairs. This truncation (called delta 32) prevents the virus from using it to bind to and enter the cell.
In people infected with HIV but homozygous for the delta32 mutation, progression to AIDS is rarely observed.
What is polymorphism
any genetic difference among individuals that is present in multiple individuals in a population
What is replica plating?
each colony/clone is inoculated onto another plate according to a numbered scheme (slide 9&10)
What is Somatic mutations
Mutations that occur in non-productive (body) cells, and are passed onto new cells creating a clone of cells having the mutant gene (slide 11)
Wha are Germ-line mutations
Occur in cells that give rise to gametes
Meiosis and sexual reproduction allow germ-line mutations to be passed to approximately half the members of the next generation (slide 11)
What is variagation
varied phenotype
Key points of somatic mutations
Non-heritable variation in fitness
Most cancers caused by somatic mutations
Key points of germ-line mutation
Heritable
raw material for evolution
(plants don’t have a segregated germ line…?)
Describe the multiple mutation model for cancer development
Most human cancers require more than the overactivation of one oncogene or the inactivation of a single tumor suppressor.
When several different cell-cycle regulators fail, it is likely that cancer will develop.
The cancer may be benign, meaning that it is slow growing and non-invasive to surrounding tissue.
Alternatively, it may be malignant, which means it grows rapidly and invades surrounding tissues.
The gradual accumulation of mutations in multiple genes over a period of years can be correlated with the stepwise progression of the cancer from benign to malignant forms
How are mutation factors related
Genome size, generation time, mutation rate are all correlated
Why is there a male mutation bias
Ovum - 24 cell divisions
Sperm - 30-1800+ cell divisions, increases with paternal age, more chance for mutation to occur (slide 18) (4x as many mutations come from males than females)
What are some affects of older parentage
Autism, schizophrenia etc… are more common
What are point mutations
Changes in a single nucleotide
What is wobble base pairing
when a base pair become temporarily mismatched because DNA polymerase mistakenly inserts a another base eg. G-T instead of a A-T
Proofreading of DNA polymerase fails to catch error
During next replication, the G in the new template strand specifies a C in the daughter strand (matched correctly
One base pair (T–A) is replaced by a different base pair (C–G), and a nucleotide substitution or point mutation has occurred
What is a transition
A transition is the substitution of a purine for a purine or of a pyrimidine for a pyrimidine
What is the difference between transitions and transversion
Point mutations swapping between classes are transversions (Tv).
Point mutations swapping within a class are transitions (Ts).
What is the ratio in humans of Ts:Tv
2:1
What is an indel
typically can’t distinguish insertion or deletion
What is CNV
Copy-number variations
CNV is a common form of genetic variation in the human population.
The regions involved in CNVs are large and include one or more genes.
Approximately 10% to 15% of the human genome is subject to CNV.
Some CNVs are present in coding regions of the genome, so they result in tandem copies of the same gene. (slide 28)
What are Tandem repeats (or Short tandem repeats (STRs)) - micro satellites?
Special type of CNV
These short sequences (usually between 2 and 50 base pairs long) are repeated in multiple tandem copies.
Each location with a tandem repeat typically has many alleles differing in copy number.
The number of tandem repeats is unique to an individual.
Looking at 6–8 tandem repeat sites typically provides enough genetic information to identify an individual.
This is the basis of DNA typing and DNA fingerprinting.
How do mutations occur
Spontaneous and caused by mutagens
The presence of a mutagen can increase the probability of mutation by a factor of 100 or more.
What are some examples of mutagens and their affects
X-rays can cause breaks in the sugar–phosphate
backbone, In either one strand or both strands
UV light can cause adjacent pyrimidines to cross-link, which most commonly leads to the formation of thymine dimers.
Chemicals that are highly reactive tend to be mutagenic, often because they add bulky side groups to the bases that hinder proper base pairing.
Bleach or hydrogen peroxide can cause a loss of a base, resulting in a gap in one strand of the DNA.
Tobacco smoke can add bulky side groups to the bases, resulting in improper base pairing.
Strand slippage
denaturation and displacement of the DNA strands, resulting in mispairing of the complementary bases
What does unequal crossing produce
Insertions and deletions
Describe the process of unequal crossing over (slide 35)
If homologous chromosomes misalign during crossing over, one crossover product contains an insertion, the other a deletion
What is a repeat expansion
Special case of insertion
Increase copies of group of nucleotides eg. Fragile X
What are transposons
Transposable elements, or transposons, are DNA sequences that can move from one position to another in the genome.
Transposons can insert into a gene and disrupt its function
Repeat expansion mechanism
Slide 38
How is DNA damage repaired
DNA ligase: seals breaks in the sugar–phosphate backbone.
(This enzyme uses the energy in ATP to join the 3’ hydroxyl of one end to the 5’ phosphate of the other end.)
Postreplication mismatch repair: a single mispaired base is repaired by removing and replacing a DNA segment.
Base excision repair: the incorrect base and its sugar are excised from the strand, then replaced.
Nucleotide excision repair: recognizes multiple mismatched bases in a region.
Slide 42
