David E. Sloane, MD 1

A little about how DNA works

David Sloane, MDSpecial Studies, HGSE

Brigham and Women’s HospitalHarvard Medical School

des770@mail.harvard.edu

2/10/2014

David E. Sloane, MD 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?

2/10/2014

David E. Sloane, MD 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….

2/10/2014

David E. Sloane, MD 4

References

• All colour images and tables are from Watson et al, Recombinant DNA, 3rd Edition, 2007.

• Except that some are not: they’re from Korf and Irons Human Genetics and Genomics 4th Edition, 2013.

• Original paper quotes and figure are from Watson, JD, and Crick, F; Nature, 1953.

2/10/2014

David E. Sloane, MD 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

2/10/2014

David E. Sloane, MD 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.

2/10/2014

David E. Sloane, MD 7

What is DNA?

• An un-branched polymer of Nucleotides

2/10/2014

What the heck is a polymer?

David E. Sloane, MD 8

What is DNA?

The Double Helix (Nature, 1953)

23 Chromosomes3.08 x 109 base pairs

2/10/2014

David E. Sloane, MD 9

How does DNA copy itself?

• DNA replication – (50 nucleotides per second)

• Exercise 1• What are mutations?

• What are variations?

thedogwasbigandfatandsadandbadbutthecatwasfunandherearwasred

thedogwasbigandfatandmadandbadbutthecatwasfunandherearwasred

thedogwasbigandfatandadandbadbutthecatwasfunandherearwasred

thedogwasbigandfatandsmadandbadbutthecatwasfunandherearwasred

2/10/2014

David E. Sloane, MD 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

2/10/2014

David E. Sloane, MD 11

Transcription

2/10/2014

Exercise 2

David E. Sloane, MD 12

Twenty Amino Acids

2/10/2014

David E. Sloane, MD 13

Encoding Amino Acids

2/10/2014

David E. Sloane, MD 14

The RNA siblings: m, t, and r

2/10/2014

David E. Sloane, MD 15

Translation

2/10/2014

Exercise 3

David E. Sloane, MD 16

Exons, Introns, Alternative Splicing

2/10/2014Figures from Korf and Irons 2013

David E. Sloane, MD 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

2/10/2014

David E. Sloane, MD 18

A (super) simple gene regulatory network

2/10/2014

David E. Sloane, MD 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?

2/10/2014

David E. Sloane, MD 20

Mechanisms of Epigenetics

• DNA Methylation

2/10/2014Figure from Korf and Irons 2013

David E. Sloane, MD 21

Mechanisms of Epigenetics

• microRNAs (miRNAs)

2/10/2014

Figure from Korf and Irons 2013

David E. Sloane, MD 22

What are some DNA tests germane to mind-brain research?

• rtPCR• The Human Genome Project• Gene Chip Analysis

2/10/2013

David E. Sloane, MD 23

Single Nucleotide Polymorphism (SNP) Detection

2/10/2014

David E. Sloane, MD 24

MicroArray

David E. Sloane, MD 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)

3/6/2013

David E. Sloane, MD 26

Homeopathy

2/10/2013

David E. Sloane, MD 27

Homeopathy

2/10/2013

David E. Sloane, MD 28

Thanks!

• des770@mail.harvard.edu

2/10/2013