1. Michael Cummings David Reisman University of South Carolina 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  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)

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

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

18. Fig. 11-9, p. 256 mRNA transcribed from the DNA DNA TEMPLATE STRAND Resulting amino acid sequenceArginineGlycineTyrosineTryptophanAsparagine Altered message in mRNA A BASE INSERTION (RED) IN DNA The altered amino acid sequenceArginineGlycineLeucine Glutamic acid Genomic analysis has revealed that deletions and insertions account for 5-10% of known mutations

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