2. 1 Bi 1 “Drugs and the Brain” Lecture 20 Tuesday, May 9, 2006 1.Formal and molecular genetics 2. A genetic animal: Drosophila melanogaster

3. 2 2. Genetic Diversity: A.Meiosis Formal genetics: Independent assortment B.Recombination Mapping genes Complementation X-linked genes Genetic animals, and an example of genetic analysis: Development genes in D. melanogaster

4. 3 Chromosomes of a male, arranged in pairs from Lecture 15: Humans have 22 pairs of chromosomes, plus the X and Y. Males are XY; females are XX. © Garland; Little Alberts Fig 5-12

5. 4 parents offspring (Human gametes are also monoploid, because half the somatic number = 1) Little Alberts 20-4 © Garland Publishing Greek, marry Somatic cells have two copies (maternal and paternal) of each chromosome; they are diploid. One copy is maternal, the other paternal. Gametes (egg and sperm) have half the somatic number of copies of each chromosome; they are haploid. Usually this means one copy; the copy is either maternal or paternal.

6. 5 Mendel’s Laws imply independent assortment. That is, genes on the same chromosome are inherited together; genes on different chromosomes are inherited independently. With 23 human chromosomes, there is a possible 2 23 = 8.4 x 10 6 distinct gametes. somatic cells Little Alberts 1 st edition 9-36 © Garland Publishing (2 nd Figure 20-11A is wrong) 1st mechanism for genetic diversity: independent assortment of chromosomes

7. 6 2nd mechanism for genetic diversity: recombination within chromosomes Little Alberts 20-11B © Garland Publishing

8. 7 Interphase is nearly absent between the two cell divisions of meiosis A later lecture will treat the cell cycle and mitosis (simple division by separating chromosomes) Big Alberts 17-2 © Garland Publishing

9. 8 2 nd Meiotic division Completion of 1 st Meiotic division Modified from Little Alberts 9-35 © Garland Publishing Meiosis differs from mitosis in two ways 2. No DNA replication between 1st and 2nd divisions diploid 1. Crossing-over (recombination)

10. 9 Thomas Hunt Morgan founder of Caltech’s Biology Division and of 20th-century genetics from Lecture 14

11. 10 If two genes are recombined x% of the time, they are said to be separated by a genetic map distance of x centimorgans (cM). paternal chromosome maternal chromosome dark eyes hairy legs dark eyes two DNA double helices with nearly identical sequences DNA molecules that have crossed over phenotype (Greek, to show) phenotype (Greek, to show) Quantitative measure of recombination

12. 11 paternal chromosome maternal chromosome dark eyes hairy legs dark eyes In mammals, 1 cM ~ 1.3 megabase of DNA. The human genome is 3 x 10 9 nt in 23 chromosomes, for an average of 130 megabases/chromosome (range 30 to 300). Therefore the average chromosome recombines about once per meiosis. two DNA double helices with nearly identical sequences DNA molecules that have crossed over Little Alberts 6-28 © Garland Publishing If two genes are recombined x% of the time, they are said to be separated by a genetic map distance of x centimorgans (cM). Quantitative measure of recombination

13. 12 The process involves (a) Enzymes that nick & “chew”; (b) Base pairing; (c) Enzymes that synthesize & ligate This sometimes leads to generation of a 3rd chromosome (“trisomy”). Little Alberts 6-26 © Garland Publishing Recombination at meiosis is based on cross-strand exchange

14. 13 OH       Little Alberts Fig 3-42 © Garland publishing ligate nick Latin, to tie from Lecture 17:

15. 14 gene A gene B genetic map: gene X Suppose (1) that A, B, and X are on the same chromosome, and (2) that the map distances: (gene A to gene B) > (gene A to gene X) and (gene A to gene B) > (gene B to gene X) Then, by definition, X lies between A and B on the genetic map. The relationship between classical genetics and molecular genetics gene A gene B physical (DNA) map: gene X And X also lies between A and B physically, on the chromosome (DNA)

16. 15 The genetic map and the physical map are colinear, but not quite proportional.

17. 16 Lander et al Figure 15. Distance in cM along the genetic map of chromosome 12 plotted against position in Mb in the genome sequence. Female recombination rates are much higher than male recombination rates. Increased slopes at either end of the chromosome reflect the increased rates of recombination per Mb. Chromosome 12 recombines about twice per meiosis The genetic map and the physical map are colinear, but not quite proportional.

18. 17 chromosomal shuffle or recombination or point mutation How do we know that a genetic event has taken place? 1.DNA chemistry (Expensive, new, unlikely) 2.detectable change in organism A phenotype! Requires clever experiments or observations on natural populations

19. 18 Now we’ll discuss phenotypes and genotypes wild type mutant a b mutant gene wild type genemutant gene wild type gene

20. 19 Genes are inferred from complementation groups (recessive mutations) homozygous mutant mother a a mutant phenotype homozygous mutant father b b mutant phenotype Complementation: mutations are in distinct genes a b hybrid offspring shows normal phenotype because one normal copy of each gene is present a1 a2 hybrid offspring shows mutant phenotype : there are no normal copies of the mutated gene homozygous mutant mother a1 mutant phenotype homozygous mutant father a2 mutant phenotype Noncomplementation: two independent mutations in the same gene

21. 20 There are only a few genes on the Y chromosome. Males are functionally haploid for genes on the X chromosome. 1. Most genes for rhodopsins (the 4 proteins responsible for photoreception in the retina) are on the X chromosome. Therefore color blindness is inherited maternally (X-linked). 2. One of the blood clotting proteins is also carried on the X chromosome. Therefore the most common form of hemophilia is X-linked. Chromosomes of a male, arranged in pairs

22. 21 Bi 1 Cameo Professor Angela Stathopoulos Drosophila as a model organism for early development http://biology.caltech.edu/Members/Stathopoulos

23. 22 More and more genomes are being sequenced: Mycoplasma genitalium (human genital tract bacterium) 468 genes Escherichia coli (bacterium) 4289 Saccharomyces cerevisiae (budding yeast) ~6300 Arabidopsis thaliana (wall cress) ~26,000 Caenorhabditis elegans (nematode worm) ~ 19,000 Drosophila melanogaster (fruit fly) ~ 14,000 Ciona intestinalis (sea squirt) ~16,000 Homo sapiens (humans) ~ 30,000

24. 23 FUGU What determines complexity if not gene number???

25. 24 Comparison of Human and Fugu huntingtin gene 67 exons align 1:1 180K versus 24K Size differential due to increased intron size in human gene

26. 25 Higher organisms typically contain many gene duplications -> complicated genetics! (yet another reason to work on Drosophila)

27. 26 Green- Yeast Blue - Yeast, worm Yellow - Only mouse Red- Mouse, worm Pink - Mouse,worm, human Drosophila contains genes conserved in higher organisms and exhibits less duplication

28. 27 FGF-ligands Vertebrates >20 many functioning redundantly Worm 2 egl17 and let756 Drosophila branchless + Pyr and Ths 2 FGF receptors (breathless and heartless) 3

29. 28 Thisbe and Pyramus are most similar to egl-17 and FGF-8 ths pyr egl-17 bnl viral FGF-like let-756 FGF-8/17/18/24

30. 29 Heartless FGF receptor activation controls mesoderm migration Movie courtesy of FlyMove: M.Leptin

31. 30 ths and pyr expression is dynamic thspyr

32. 31 pyramus and thisbe double in situ hybridization

33. 32 Bi 1 “Drugs and the Brain” End of Lecture 20