Lecture 7 - Mutation

Question 1

Why are mutations important

Answer 1

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

Question 2

What is Antennapedia

Answer 2

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

Question 3

What is mutagenesis

Answer 3

tools to understand genetic & developmental mechanisms

Question 4

What is the affect of polymorphisms

Answer 4

Increase susceptibility to particular diseases

Question 5

What is the main context to mutations

Answer 5

Deleterious - disease and disorder links

Question 6

What do beneficial mutations lead to

Answer 6

adaption

Question 7

How can a mutation be beneficial (eg.)

Answer 7

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.

Question 8

What is polymorphism

Answer 8

any genetic difference among individuals that is present in multiple individuals in a population

Question 9

What is replica plating?

Answer 9

each colony/clone is inoculated onto another plate according to a numbered scheme (slide 9&10)

Question 10

What is Somatic mutations

Answer 10

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)

Question 11

Wha are Germ-line mutations

Answer 11

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)

Question 12

What is variagation

Answer 12

varied phenotype

Question 13

Key points of somatic mutations

Answer 13

Non-heritable variation in fitness
Most cancers caused by somatic mutations

Question 14

Key points of germ-line mutation

Answer 14

Heritable
raw material for evolution
(plants don’t have a segregated germ line…?)

Question 15

Describe the multiple mutation model for cancer development

Answer 15

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

Question 16

How are mutation factors related

Answer 16

Genome size, generation time, mutation rate are all correlated

Question 17

Why is there a male mutation bias

Answer 17

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)

Question 18

What are some affects of older parentage

Answer 18

Autism, schizophrenia etc… are more common

Question 19

What are point mutations

Answer 19

Changes in a single nucleotide

Question 20

What is wobble base pairing

Answer 20

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

Question 21

What is a transition

Answer 21

A transition is the substitution of a purine for a purine or of a pyrimidine for a pyrimidine

Question 22

What is the difference between transitions and transversion

Answer 22

Point mutations swapping between classes are transversions (Tv).

Point mutations swapping within a class are transitions (Ts).

Question 23

What is the ratio in humans of Ts:Tv

Answer 23

2:1

Question 24

What is an indel

Answer 24

typically can’t distinguish insertion or deletion

Question 25

What is CNV

Answer 25

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)

Question 26

What are Tandem repeats (or Short tandem repeats (STRs)) - micro satellites?

Answer 26

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.

Question 27

How do mutations occur

Answer 27

Spontaneous and caused by mutagens
The presence of a mutagen can increase the probability of mutation by a factor of 100 or more.

Question 28

What are some examples of mutagens and their affects

Answer 28

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.

Question 29

Strand slippage

Answer 29

denaturation and displacement of the DNA strands, resulting in mispairing of the complementary bases

Question 30

What does unequal crossing produce

Answer 30

Insertions and deletions

Question 31

Describe the process of unequal crossing over (slide 35)

Answer 31

If homologous chromosomes misalign during crossing over, one crossover product contains an insertion, the other a deletion

Question 32

What is a repeat expansion

Answer 32

Special case of insertion

Increase copies of group of nucleotides eg. Fragile X

Question 33

What are transposons

Answer 33

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

Question 33

Repeat expansion mechanism

Answer 33

Slide 38

Question 34

How is DNA damage repaired

Answer 34

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.

Question 35

Slide 42