Mutation: The Source of Genetic Variation

1. Mutation: The Source of Genetic Variation Chapter 11

2. 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.

3. 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

4. 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

5. 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

6. 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

7. Pedigree Analysis: Sudden Appearance of a Dominant Trait Fig. 11-1, p. 246

8. 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

9. Pedigree: An X-Linked Recessive Trait • Queen Victoria and hemophilia

10. 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

11. Mutation Rates for Selected Genes Table 11-1, p. 249

12. 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

13. 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

14. 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

15. 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 • Frameshiftmutations • 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)

16. Hemoglobin Variants: MissenseMutations Fig. 11-8, p. 254

17. Sense mutations in Alpha Globin Proteins Table 11-3, p. 255

18. Genomic analysis has revealed that deletions and insertions account for 5-10% of known mutations 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 Fig. 11-9, p. 256

19. 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

20. Diseases due to Expanded Tri-Nucleotide Repeats Table 11-4, p. 257

21. 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

22. Anticipation of Myotonic Dystrophy

23. 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

24. Rates of DNA Damage Table 11-5, p. 258

25. Maximum DNA Repair Rates Table 11-6, p. 258

26. 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