Mutations

Learning Objectives

By the end of this class you should understand:

The pedigree of a spontaneous mutation

The concept of mutation rates and how they can be measured

Sources of mutations

Types of mutations

The consequences of lengthening repeated sequences of DNA

Mechanisms of DNA repair

The role of gender in DNA imprinting

Mutation

Any change in the DNA of a cell is a mutation

A certain number of mutations occur every time DNA is replicated or exposed to mutagens

– If a somatic cell (adult or stem cell) mutates it may affect the individual

– If the gametes mutate, the mutation is passed on to offspring

Mutation Rate

The number of new mutations can be measured indirectly

– Much easier to do on dominant mutations

Pedigree can track where a mutation originated

Mutation Rate

The more vital a gene is, the lower its mutation rate

– Why? Most mutations are lethal!

This can be used to estimate how closely related animals are to each other

Mutation Rates of Genes

Mutagens

There are many mutagens

– Similar list to teratogens

Radiation

– Includes ordinary radiation from space (background radiation)

Chemicals

– Typically bind to DNA

Radiation Sources

Radiation Damage

High-energy light (UV, X-rays) and nuclear radiation can alter DNA

Prominent example: UV light can cause two adjacent thymines to connect (thymine dimer)

This interferes with DNA replication, causing many errors around the dimer

Mutagenic Chemicals One class of chemical

mutagen is base analogs that mimic a DNA base

5-bromouracil is added to DNA as though it were thymine, but pairs with guanine

If not repaired, mutates DNA after replication

5'-ACGTAGA-3' #13'-TGCABCT-5' #2

Replication:

5'-ACGTAGA-3' #13'-TGCATCT-5'

5'-ACGTGGA-3'3'-TGCABCT-5' #2

5-Bromouracil

Base Modification

DNA bases are also sensitive to modification by chemicals such as nitrous acid

Other Chemical Mutagens

Acridine Orange and Ethidium Bromide bind to DNA and twist its shape

Damages DNA in a way that is not easy to repair

– Ethidium bromide is a DNA fluorescent stain

May cause more complex mutations than the previous point mutations

Mutation Types There are structural and

functional classifications of mutations

Structural: what has happened to the DNA sequence

– Point mutation/Substitution

– Insertion

– Deletion

– Inversion

Functional Classifications If a mutation has not effectively changed

anything it is a silent mutation If a mutation changes the amino acid sequence

it is a missense mutation If a mutation causes the amino acid sequence

to lengthen it is a sense mutation If a mutation ruins the amino acid sequence it is

a nonsense mutation

Frameshift Mutations

Many insertions and deletions (of 1 or 2 bases) cause the reading frame to change

THE FAT CAT ATE HIS HAT (normal) THE FAT BAT ATE HIS HAT (point) THF ATC ATA TEH ISH AT (frameshift)

These may produce nonsense or sense mutations, rarely a missense and never a silent

Functional Mutation Classifications

Allelic Expansion

Some genes have repeated sequences that may be accidentally expanded

– This is called allelic expansion These sequences, usually three

repeated DNA bases, may be vital to the gene function

Expansion may reduce expression or completely deactivate the gene

Allelic Expansion A number of genetic disorders are caused by

allelic expansion of the repeated sequence This expansion may also get worse with each

generation

Anticipation

If a genetic disorder appears sooner and/or stronger in each subsequence generation it may be suffering from anticipation

Caused by ever-increasing allelic expansion of the defective gene

DNA Repair

DNA is subject to normal errors in addition to radiation and chemicals

Many repairs are caught and fixed automatically in DNA replication and when cells are inactive

DNA Repair Failure

Xeroderma pigmentosum is a genetic failure of DNA repair molecules Normally repair thymine

dimers and other UV damage

Extremely sensitive to sunlight and blacklights

Individuals are at great risk of skin cancer

Mutations and Proteins

Hemoglobin is a prominent example of a single point mutation causing sickle cell anemia

Cystic fibrosis is caused by many different possible mutations on the CFTR gene

– Some more severe than others!

Mutation and Cancer

Thursday's lesson!