Michael Cummings

David Reisman • University of South Carolina

Mutation: The Source of Genetic Variation

Chapter 11

What comes to mind when you hear the word mutation?

Often this word has a negative connotation, but mutation has made the immense variety of life on earth possible.

11.1 Mutations Are Heritable Changes in DNA

Mutations are the ultimate source of all genetic variation in humans and other organisms

Mutation can occur spontaneously as a result of errors in DNA replication or is induced by exposure to radiation or chemicals

An agent that causes a mutation is called a mutagen

Two Categories of Mutations

Somatic Mutations• Occur in cells of the body that do not form gametes• Occurs in mitosis• Is not transmitted to future generations

Germ-line Mutations• Occur in cells that produce gametes• Occurs during meiosis• Transmitted to future generations - inherited

11.2 Mutations Can Be Detected in Several Ways

How do we know that a mutation in a gene has occurred?• Change in a phenotype that is passed on

Mutations that do not cause a change in phenotype would most likely only be detected by sequencing an individual’s DNA

Identification of Dominant Mutation

Dominant mutations are easiest to detect; they are expressed in the heterozygous condition

Sudden appearance of a dominant mutation in a family can be observed in a single generation

Accurate pedigree information can be used to identify the individual in whom a mutation arose

Pedigree Analysis: Sudden Appearance of a Dominant Trait

Fig. 11-1, p. 246

Recessive and Sex-Linked Recessive Mutations

It is more difficult to detect a recessive mutation• Can be detected only in the homozygous condition

It is extremely difficult to identify the origin of a recessive mutation

It is even more difficult to determine the origin of a sex-linked recessive mutation• Generally will only appear in males in a family tree

Pedigree: An X-Linked Recessive Trait

Queen Victoria and hemophilia

11.3 Measuring Spontaneous Mutation Rates

Mutation rate • ranges from approx 1 in 10,000 to 1 in 1,000,000

copies of a gene Several factors influence mutation rate• Size of the gene: Larger genes have higher mutation

rates• Nucleotide sequence: Presence of nucleotide repeats

are associated with higher mutation rates• Spontaneous chemical changes: C/G base pairs are

more likely to mutate than A/T pairs

Mutation Rates for Selected Genes

Table 11-1, p. 249

Known Mutagens: Radiation

Radiation • The process by which electromagnetic energy travels

through air

In the US, the average person is exposed to about 360 mrem/year, 81% of which is from natural background sources (cosmic rays, sunlight, dirt and rocks)

A dose of 5,000 mrem is need to cause somatic cell mutations and increase susceptibility to cancer

Known Mutagens: Chemicals

Base analogs structurally resemble nucleotides and are incorporated into DNA or RNA during synthesis (causes insertion of G rather than A so that an A/T base pair is converted to a G/C in the helix

Chemical modifiers directly change the bases in DNA, Nitrous acid changes cytosine into uracil, resulting in a G/C to A/T mutation

Intercalating agents generally distort the double helix, addition or deletion of a base pairs during DNA replication

Exposure to Chemical Mutagens

Not in text, not included on exam questions

Aflatoxin – in peanuts Nitrophenols, anisoles, toluene – hair dyes Furylfofuramide – food additive Nitrosamines – pesticides, herbicides cigarette smoke Sodium nitrite – smoked meats PBDEs – flame retardant

Types of Mutations

Point Mutations or Nucleotide substitutions • Missense mutation – replaces one amino acid with another• Nonsense mutations – an amino acid codon is changed to

a stop codon• Sense mutation – a termination codon is changed into a

one that codes for an amino acid, producing elongated proteins

• Silent mutation – no effect on phenotype

Frameshift mutations • Bases are added to or removed from DNA, causing a shift in

the codon reading frame (nucleotide changes in multiples of 3 will NOT cause a frame-shift, but very likely alter the phenotype)

Hemoglobin Variants: Missense Mutations

Fig. 11-8, p. 254

Sense mutations in Alpha Globin Proteins

Table 11-3, p. 255

Fig. 11-9, p. 256

mRNA transcribed from the DNA

DNA TEMPLATE STRAND

Resulting amino acid sequence Arginine Glycine Tyrosine Tryptophan Asparagine

Altered message in mRNA

A BASE INSERTION (RED) IN DNA

The altered amino acid sequence Arginine Glycine Leucine Leucine Glutamic acid

Genomic analysis has revealed that deletions and insertions account for 5-10% of known mutations

Trinucleotide Repeats and Gene Expansions

Trinucleotide repeats • A three base-pair repeating sequence (example:

CGGCGGCGGCGG)

Allelic expansion • Increase in gene size caused by an increase in the

number of trinucleotide sequences• Potential for expansion is a characteristic of a specific

allele

Diseases due to Expanded Tri-Nucleotide Repeats

Table 11-4, p. 257

Gene Expansion is Related to Anticipation

Anticipation • Onset of a genetic disorder at earlier ages and with

increasing severity in successive generations• Due to increasing number of repeats with successive

generations

Anticipation of Myotonic Dystrophy

11.6 Mutations and DNA Damage Can Be Repaired Not all mutations cause permanent genetic damage

Cells have enzyme systems that repair DNA• Mismatch repair – enzymes detect nucleotides that do

not base pair in newly replicated DNA; the incorrect base is excised and replaced

• Excision repair - enzymes cut out the 1-30 bases of DNA with the mistake and resynthesize the small fragment

• End-joining – when both strands of the DNA molecule are cut, proteins simply take the ends and stick them back together

Rates of DNA Damage

Table 11-5, p. 258

Maximum DNA Repair Rates

Table 11-6, p. 258

Genetic Disorders Can Affect DNA Repair Systems Several genetic disorders,

including xeroderma pigmentosum, are caused by mutations in genes that repair DNA

Fig. 11-15, p. 259