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GS351 Final Review

GS351 Final Review. June 6, 2014. GS 351 Final. Time/data: June 9, 8:30-10:20 a.m. Location: here Test info: 7-9 problems Should take less time than the midterm Matching, true/false, s hort answer Bring a calculator. Recommendations for Studying. Pay attention now

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GS351 Final Review

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  1. GS351 Final Review June 6, 2014

  2. GS 351 Final Time/data: June 9, 8:30-10:20 a.m. Location: here Test info: • 7-9 problems • Should take less time than the midterm • Matching, true/false, short answer • Bring a calculator

  3. Recommendations for Studying • Pay attention now • Go over problem sets • Reread all lecture slides • Read the articles on the course website

  4. Advise for Taking the Test • Be early • Bring a calculator (NOT A PHONE) • Do the easy problems first • Don’t spend too much time on one problem • Ask for clarification

  5. Some Key Topics • Human Genome Project (public vs private) • How hominids are related • Calculating how long ago two species diverged • Genetic Anticipation: mechanism and effects • Unequal crossing: mechanism and effects • Fragile X syndrome • Autism: causes and risks • Tay-Sachs disease: cause and prevention • Genetic concordance • Determining the mode of inheritance of disease • Out of Africa theory: genetic effect on different populations • Gene Therapy

  6. Review of Topics

  7. Spectrum of Genetic Variation Sequence • Single base pair changes – point mutations • Small insertions/deletions – frameshift, microsatellite, minisatellite • Structural variation (>10 kb) • Large-scale deletions, inversions, and insertions • Changes in copy (gains and losses) called CNVs (copy number variants) • Chromosomal variation – translocations, inversions, fusions Cytogenetics

  8. Two DIFFERENT Mechanisms for Mutation • Repeat Expansion • Triple repeats get varying in length • Threshold effect: more likely to grow • Once too big, they can cause disease • Copy Number Variants (CNVs) • Repetitive regions in genome can misalign • Can get unequal crossing over • Deletes or duplicates genes between repeats

  9. Unusual Inheritance Pattern for an X-linked Trait • T = normal transmitting male • Risk of mental retardation depended on position within the pedigree • Daughters of normal transmitting males = 0% risk • Grandsons’ risk = 40-50% • Later generations had a higher risk of developing disease then preceding generations • Genetic anticipation

  10. Molecular Explanation • CGG repeats are generally unstable and can increase and decrease in size but usually take many generations to change in copy • Once they reach 55 repeat units the chance that they will increase in the next generation increases very rapidly • Once they reach 200 repeats there is a 100% chance that they will jump to 1000 repeat units or more but this jump requires that it be transmitted from a mother • Once the repeat is >200 repeats it interferes with replication of the DNA (fragile site upon culture) and transcription—no transcription = no protein • The FMR1 protein is important in regulating other genes near the synapse—absence of protein = disease

  11. Genetic Anticipation Explained A fragile X family • Progressive increase in size of CGG repeat • Requires a female transmission to go to full mutation

  12. C G G G C C Errors during Replication or Repair falls off & re-lands on copied repeat nick & repair expanded repeat

  13. CNV mechanism

  14. 16p 16p 16p 16m 16m 16m Repeated sequence copies in meiosis A A Replication A Figure 12.7

  15. 16p 16p 16p 16m 16m 16m Normal alignment Recombination Correct pairing of homologs Figure 12.7

  16. 16p 16p 16m 16m Recombination Misalignment 16p One copy and deletion of a region 16m Three copies with duplication Similar sequences may lead to mispairing Figure 12.7

  17. A B C TEL A B C TEL NAHR GAMETES A B C A B C TEL TEL Intellectual Disability/Autism/Epilepsy As a result of dosage sensitivity of genes Interspersed Duplications Create Lots of Copy Number Variation in Humans

  18. Mouse Genome does not! • ~3% duplication • >20 kb, >95% • Feb. 2006; mm8 • 87% are tandem pairwise

  19. Human Genome has Large Repeatsthat are spread throughout! chr1 chr2 chr3 chr4 chr5 chr6 chr7 chr8 chr9 chr10 chr11 chr12 chr13 chr14 • ~4% duplication • >20 kb, >95% • ~4 average # duplicates • 59.5% interspersed (>1 Mbp) chr15 chr16 chr17 chr18 chr19 chr20 chr21 chr22 chrX chrY She, X et al., (2004) Nature 431:927-30

  20. (1920s) (1997) Height as a Quantitative Trait

  21. Human vs. Ape Genetic Variation • A tree comparing 70 humans, 30 chimpanzees, 5 bonobo, 11 gorilla and 14 orang-utan • Humans show ½ to 1/3rd of the genetic variation that we observe within other ape species.

  22. Humans nearly went extinct ~70,000 years ago! # at this value A lot 0 # of Differences

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