1. A little about how DNA works David Sloane, MD Special Studies, HGSE Brigham and Women’s Hospital Harvard Medical School des770@mail.harvard.edu 2/10/2014David E. Sloane, MD1

2. Nature and Nurture What is meant by “Nature”? Is it the same for all human beings regardless of space, time, and context? What is meant by “Nurture”? Is it the same for all human beings regardless of space, time, and context? What is epigenetics? David E. Sloane, MD22/10/2014

3. Overview What is genetics? What does DNA have to do with genetics? What is DNA? How does DNA copy itself? How does the information in DNA get expressed? What are gene regulatory networks? What is epigenetics and how does it work? What are some DNA tests germane to mind-brain research? Let’s have a (nice) fight…. David E. Sloane, MD32/10/2014

4. References All colour images and tables are from Watson et al, Recombinant DNA, 3 rd Edition, 2007. Except that some are not: they’re from Korf and Irons Human Genetics and Genomics 4 th Edition, 2013. Original paper quotes and figure are from Watson, JD, and Crick, F; Nature, 1953. David E. Sloane, MD42/10/2014

5. What is genetics? What is a trait? – An observable characteristic in an organism, such as seed colour. What is a gene? – A factor that determines a trait David E. Sloane, MD52/10/2014

6. What does DNA have to do with genetics? Deoxyribonucleic Acid (DNA) is the substance that encodes genetic information; “The genotype is the complete genetic composition of an organism.” (Recombinant DNA 2007) Its physical expression leads to the appearance of traits in an organism, which is called the “phenotype” Example: a stretch of DNA encodes instructions for the construction of a protein that determines eye colour (say, brown). Those DNA instructions are the genotype. The actual eye colour is the phenotype. A ridiculously overextended metaphor: the cookbook. David E. Sloane, MD62/10/2014

7. What is DNA? An un-branched polymer of Nucleotides David E. Sloane, MD72/10/2014 What the heck is a polymer?

8. What is DNA? The Double Helix (Nature, 1953) 23 Chromosomes 3.08 x 10 9 base pairs David E. Sloane, MD82/10/2014

9. How does DNA copy itself? DNA replication – (50 nucleotides per second) Exercise 1 What are mutations? What are variations? thedogwasbigandfatandsadandbadbutthecatwasfunandherearwasred thedogwasbigandfatandmadandbadbutthecatwasfunandherearwasred thedogwasbigandfatandadandbadbutthecatwasfunandherearwasred thedogwasbigandfatandsmadandbadbutthecatwasfunandherearwasred David E. Sloane, MD92/10/2014

10. How does the information in DNA get expressed? The flow of information: the central dogma of biology – DNA → RNA → Protein DNA → RNA = “transcription” RNA → Protein = “translation” – But in HIV: RNA → DNA → RNA → Protein RNA is ribonucleic acid, moves from nucleus (where DNA is sequestered) to cytoplasm Proteins are un-branched polymers of amino acids David E. Sloane, MD102/10/2014

11. Transcription David E. Sloane, MD112/10/2014 Exercise 2

12. Twenty Amino Acids David E. Sloane, MD122/10/2014

13. Encoding Amino Acids David E. Sloane, MD132/10/2014

14. The RNA siblings: m, t, and r David E. Sloane, MD142/10/2014

15. Translation David E. Sloane, MD152/10/2014 Exercise 3

16. Exons, Introns, Alternative Splicing 2/10/2014David E. Sloane, MD16 Figures from Korf and Irons 2013

17. What are gene regulatory networks? In a word “epigenetics” – some proteins affect DNA replication, transcription, and translation – So the “end products” of the linear sequence DNA → RNA → Protein feed back on the system. So it’s not really linear at all. Nature vs. Nurture David E. Sloane, MD172/10/2014

18. A (super) simple gene regulatory network David E. Sloane, MD182/10/2014

19. Epigenetics What parts of the genome are expressed, How much a given gene is expressed, and In what context the gene is expressed…. are influenced by the environment! Metaphorically speaking, the restaurant customers influence the reading of the cookbook. But how do the genome and the environment interact to result in a given phenotype? 2/10/2014David E. Sloane, MD19

20. Mechanisms of Epigenetics DNA Methylation 2/10/2014David E. Sloane, MD20 Figure from Korf and Irons 2013

21. Mechanisms of Epigenetics microRNAs (miRNAs) 2/10/2014David E. Sloane, MD21 Figure from Korf and Irons 2013

22. What are some DNA tests germane to mind-brain research? rtPCR The Human Genome Project Gene Chip Analysis David E. Sloane, MD222/10/2013

23. Single Nucleotide Polymorphism (SNP) Detection 2/10/2014David E. Sloane, MD23

24. MicroArray David E. Sloane, MD24

25. Let’s have a (nice) fight… One of western medicine’s big problems: – one dose treats all But let’s extend this (reducto ad absurdum) 3/6/2013David E. Sloane, MD25

26. Homeopathy David E. Sloane, MD262/10/2013

27. Homeopathy 2/10/2013David E. Sloane, MD27

28. Thanks! des770@mail.harvard.edu David E. Sloane, MD282/10/2013