2. Abnormal Gene Function DNA mRNA Transcription Translation Protein DNA -> RNA -> Protein Synthesis of Abnormal Proteins Mutations Often Result in the X X X

3. Future-Shaping Techologies Genetic Screening - Marfan Case Gene Replacement - Bubble Babies Stem Cells Cloning - Dolly the Sheep Agriculture - Crop Modification

5. mf/mf = 1/4 offspring = Marfan +/+ = 1/4 offspring = Normal or+/mf mf/+= 1/2 offspring = Normal ++ mf + + One quarter of the offspring from two Marfan carrier parents will have Marfan Syndrome + mf Two types of mother’s eggs + mf Two types of father’s sperm +/mf +/+ mf/+ mf/mf

6. Genes, Chromosomes, and Genomes Gene = Basic Unit of Inheritance Gene 1Gene 2Gene 5Gene 3Gene 4 Genome = 30,000-50,000 Genes Chromosome = 1,000-5,000 Genes ≈ 5,000 Genes Cause Disease When Mutant

7. Mutations Carried in Father’s Genome + Mass Scale IVF Mutations Carried in Mother’s Genome

8. Normal red blood cells Sickle cell red blood cells

9. +++ sc + + + Two types of mother’s eggs Two types of father’s sperm One half of the offspring from two Sickle Cell carrier parents will be protected from Malaria +/+ = 1/4 offspring = Normal/ Malaria Sensitive sc/sc = 1/4 offspring = Sickle Cell +/sc +/+ sc/+ sc/sc +/scor sc/+= 1/2 offspring = Normal/Malaria Resistant

10. Resistance to Malaria Low Blood Pressure Longevity Musical Ability Resistance to Flu Low Cancer Risk Reduced Risk for Alzheimer Disease Desirable Traits Can be Linked to Disease Genes Immunity to Plague

11. SCID “Bubble” Baby

12. Dolly and Kid Cloned Sheep

13. A/P Axis Abdomen Head Tail A possible picture of the most recent commonancestor of vertebrate and invertebrates Mouth Anus/ Genitals Nervous System Non-neural Ectoderm D/V Axis Photosensitive organs Sensory Appendages? Eyespot? Gills? Protrusions or appendages

14. http://homophila.sdsc.edu

15. Fly Genes similar to Human Angelman Gene

16. Alignment of Human and Fly Angelman Genes Human Protein: LRLKVRRDHIIDDALVRLEMIAMENPADLKKQL Fly Protein:LKLTVRRDQLINDALIGLEMVAMSNPKDLKKQL Match/Similar: L+L*VRRD*+I+DAL+*LEM+AM*NP*DLKKQL

17. Human Disease Genes in Flies >2,400 of 5,000 Human disease genes identified Many disease genes have fly counterparts –75% disease genes related to a fly gene –30% disease genes highly similar to a fly gene Disease genes with counterparts in flies fall into all major categories of disorders

18. Appropriate Disease Genes to Study in Flies Human Disease Gene Function Poorly Understood Fly Counterpart Highly Related to Human Gene Facility of Genetic Analysis in Fly Identified Loci Subject to Explicit Test in Humans: “Closing-the-Loop”

19. Closing-the-Loop in Humans Identify New Candidate Disease Genes –Alzheimer Disease (FAD) Identify Human Modifier Loci –Primary Congenital Glaucoma (PCG) Dissect Complex Polygenic Trait –Cardiac Defects in Down syndrome (DS) Identify Candidate Protein Targets –Angelman Syndrome (AS) Study host-pathogen interactions –Bacterial toxin function Place Disease Gene in a Pathway –Dyggve-Melchoir-Clausen syndrome (DMC)

20. Placing DMC in a genetic pathway Goal: Identify genetic pathway in which DMC functions Method: 1) Mis-express human and Drosophila DMC genes in Drosophila. 2) Mutate single Drosophila dmc orthologue 3) Determine if the pathway identified in Drosophila is also affected in human DMC or SMC patients.

21. DMC: a gene in search of a function DMC Phenotype –Short trunk dwarfism –Psychomotor retardation –Radiologically Identical to Smith-McCort Dysplasia –Encodes multispan transmembrane protein: Dymeclin –Unknown function in regulating bone growth NormalDMC patient

22. DMC: a gene in search of a function DMC Phenotype –Short trunk dwarfism –Psychomotor retardation –Radiologically Identical to Smith-McCort Dysplasia –Encodes multispan transmembrane protein: Dymeclin –Unknown function in regulating bone growth Normal Growth PlateDMC patient Nakamura et al., Am J Med Genet 72:11-17, 1997

23. The fly wing as genetic assay system BMP Pathway Mutant L4 L5 L2 L3 Hh Pathway Mutant L2 L3 L4 L5 L3 Normal Wing L2 L4 L5 BMP Hh M Notch & Wg Notch Pathway Mutant L2 L3 L4 L5

24. ptc, dpp L2 L3 L4 L5 sal Veins form at Gene Expression Boundaries A P En En -> Hh -> Diffuses -> dpp in A/P Organizer L3 L4 Organizer A/P pct L2 L3 L4 L5 hh Dpp Dpp -> Diffuses -> sal -> L2 vein A P dpp sal brk L2 omb brk L5 L3 L4

25. Reduced hh function L2 L3 L4 L5 WT L2 L3 L4 L5 Hh Determines Positions of L3 and L4 Veins Reduced hh function dpp A P L3 L4 hh dpp En En -> Hh -> Diffuses -> dpp in A/P Organizer ptc, dpp A P En L3 L4 hhdpp

26. Ectopic dmc reduces the response to Hh ptcGAL4>dmc L3 L4 L2 L5 enGAL4>dmc L3 L4 L2 L5 ubiGAL4>dmc L3 L4 L2 L5 wt L3 L4 L2 L5

27. New Covenant Jesse Bier Nobody tells the flowers what to do, they grow the way they please. They don't take orders from me and you— nor do the grasses or trees. But that was long ago, before the age of science. Now that we know what we know, we splice them to compliance. Soon trees must do what they are told, according to special genes. Nothing the same as of old— and grasses, flowers know what that means. Next to come are you and me after the flowers, trees and grasses. But: Who will decide and oversee newfounded families, permanent classes?