1. A Zero-Knowledge Based Introduction to Biology
Bo Yoo and Yatish Turakhia
January 15, 2019

2. Announcements TA Office Hours (starting this Friday – Jan 18):
Mondays 4:30PM-6:30PM in Beckman B381
Tuesdays 3:00PM-5:00PM in Beckman B381
Wednesdays 4:00PM-6:00PM in Beckman B475
Fridays 4:00PM-6:00PM in Beckman B381
Attendance will be taken starting this Thursday (Jan 17) lecture
There will be a sign-up sheet by the door
You get two free absences
If you have a valid reason, one of the TAs before the class

3. Announcements Homework 1 will be released this Thursday (Jan 17)
Due 11:59PM January 31
You have 3 late days (can use on homework only)
Read the instructions carefully (what files to submit etc.)
No Jupyter notebooks
Post questions on Piazza instead of ing us
Include question number on the subject line
3 questions
Questions 1 and 2 will require UCSC Genome Browser (tutorial 1/24)

4. Q: What is your genome?

5. Q: What is your genome?
A: The sum of your hereditary information.

6. Human Genome 3 billion base pairs: A,T,G,C
Full DNA sequence in virtually all cells
DNA is the blueprint for life:
Cookbook with many “recipes” for proteins - genes
Proteins do most of the work in biology
Yet, only ~2% of the genome is protein-coding genes!

7. What does the rest of the genome do?
3 billion base pairs – 2% coding,10-20% regulatory
Seemingly less complex organisms may have large number of genes!
Human (20-25k genes) vs. Rice (51k genes)
1 million Regulatory elements (switches) enable:
Precise control for turning genes on/off
Diverse cell types (lung, heart, skin)
Analogy: Making specific recipes (genes) from a large cookbook (genome) at a given time

8. Quick Recap

9. DNA: “Blueprints” for a cell
Genetic information encoded in long strings
Deoxyribonucleic acid (DNA) comes in four bases: adenine (A), thymine (T), guanine (G) , and cytosine (C)

10. From DNA to Organism
You are composed of ~ 10 trillion cells

11. From DNA to Organism Cell

12. From DNA to Organism Cell Protein
Proteins do most of the work in biology

13. Q: How does one genome encode a variety of cell types in a complex organism?

14. Regulatory Elements ~ 20-25k genes CS analogy:
Expression Modulated by Regulatory elements
Enhancer, Promoters, Silencers
CS analogy:
Genes are like variable assignments (a = 7)
Regulatory elements are control flow, complex logic

15. Controlling Gene Expression
Transcription factors (TFs):
Proteins that recognize sequence motifs in enhancers, promoters
Combinatorial switches that turn genes on/off

16. How does the genome influence human disease?

17. Disease Implications
SHH
MUTATIONS
Brain
Limb
Other
Bejerano Lab

18. Limb Enhancer 1Mb away from Gene
SHH on
off
Bejerano Lab

19. Enhancer Deletion
limb
SHH on
off
DELETE
Limb
Bejerano Lab

20. Enhancer 1bp Substitution
limb
SHH on
off
MUTATIONS
Limb on
off
Lettice et al. HMG :
Bejerano Lab

21. Genome Wide Association Study (GWAS):
80% of GWAS SNPs are noncoding (hard to interpret) Active area of research
GWAS is a study that takes the entire genetic variants from multiple individuals  and try to associate variants to traits. Usually it particularly focuses on single nucleotide polymorphisms or SNPs which is if the majority of the population has A in a particular location in the genome and a person has G instead. if an individual has a distinctive trait and a genetic variant that is not found in any other population,then the researcher may try to associate that trait with the SNPs. However since 80% of GWAS SNPs are noncoding which is difficult to analyze since the genomic region where that SNP is contain in does not have a well-known function compared to a protein coding gene 
Bejerano Lab

22. How exactly do genes code for proteins?

23. Central Dogma of Biology

24. DNA: “Blueprints” for a cell
Genetic information encoded in long strings
Deoxyribonucleic acid comes in four bases: adenine, thymine, guanine, and cytosine

25. Nucleobase Complementary Pairing
purines
Adenine (A)
Guanine (G)
Thymine (T)
Cytosine (C)
pyrimidines

26. DNA Double Helix

27. DNA Packaging

28. Q: What is your genome?
A:The sum of your hereditary information.

29. Q: What is your genome?
A:The sum of your hereditary information. Humans bundle two copies of the genome into 46 chromosomes in every cell

30. Central Dogma of Biology

31. DNA (Deoxyribonucleic acid) vs RNA (ribonucleic acid)
5' end has phosphate group and 3' has hydroxyl group (OH), number comes from the number of carbon in the sugar attached to the base
Deoxyribose in DNA Ribose in RNA

32. RNA Nucleobases purines pyrimidines Adenine (A) Guanine (G) Uracil (U)
Cytosine (C)
pyrimidines

33. Gene Transcription (DNA -> RNA)
G A T T A C A . . . 5’ 3’ 3’ 5’
C T A A T G T . . .

34. Gene Transcription
G A T T A C A . . . 5’ 3’ 3’ 5’
C T A A T G T . . .
RNA polymerase binds to the DNA at the promoter site near the transcription starting site, RNA polymerase synthesizes the RNA from the DNA template

35. Gene Transcription Strands are separated (DNA helicase)
G A T T A C A . . . 5’ 3’ 3’ 5’
C T A A T G T . . .
DNA helicase are class of enzymes that open the double helix structure of DNA to allow RNA Polymerase to synthesize RNA
Strands are separated (DNA helicase)

36. Gene Transcription
G A T T A C A . . . 5’ 3’ 3’
G A U U A C A 5’
C T A A T G T . . .
Read and add complements of the template
An RNA copy of the 5’→3’ sequence is created from the 3’→5’ template

37. Gene Transcription 5’ 3’ 3’ 5’ pre-mRNA 5’ 3’ G A T T A C A . . .
C T A A T G T . . .
G A U U A C A . . .
pre-mRNA 5’ 3’

38. RNA Processing
5’ cap
poly(A) tail
exon
intron
regions near the ends are called UTR or untranslated region and are never translated to protein
mRNA
5’ UTR
3’ UTR

39. Gene Structure introns 5’ 3’ promoter exons 3’ UTR 5’ UTR coding
non-coding

40. Central Dogma of Biology

41. From RNA to Protein
Proteins are long strings of amino acids joined by peptide bonds
Translation from RNA sequence to amino acid sequence performed by ribosomes
20 amino acids → 3 RNA letters required to specify a single amino acid

42. Amino Acid There are 20 standard amino acids H O H N C C OH H R
Alanine
Arginine
Asparagine
Aspartate
Cysteine
Glutamate
Glutamine
Glycine
Histidine
Isoleucine
Leucine
Lysine
Methionine
Phenylalanine
Proline
Serine
Threonine
Tryptophan
Tyrosine
Valine H O H N C C OH H R
There are 20 standard amino acids

43. Translation

44. 5’ . . . A U U A U G G C C U G G A C U U G A . . . 3’
Translation
5’ A U U A U G G C C U G G A C U U G A ’
UTR
Met
Start Codon
Ala
Trp
Thr
Stop Codon

45. Translation
The ribosome (a complex of protein and RNA) synthesizes a protein by reading the mRNA in triplets (codons). Each codon is translated to an amino acid.

46. Central Dogma of Biology

49. Different Cell Types
Subsets of the DNA sequence determine the identity and function of different cells

50. Gene Expression Regulation
When should each gene be expressed?
Why? Every cell has same DNA but each cell expresses different proteins.
Signal transduction: One signal converted to another: cascade has “master regulators” turning on many proteins, which in turn each turn on many proteins

51. Transcription Regulation
Transcription factors link to binding sites
Complex of transcription factors forms
Complex assists or inhibits formation of the RNA polymerase machinery

52. Transcription Regulation
TF A
Binding Site
Gene B
Transcription Factor A

53. Transcription Factor Binding Sites
Short, degenerate DNA sequences recognized by particular transcription factors
For complex organisms, cooperative binding of multiple transcription factors required to initiate transcription
Binding Sequence Logo

54. Mutations in the Genome
Over our lifetime, our DNA replicates trillions of times with the help of DNA polymerase
But even polymerase is “imperfect”, every now and then (roughly 1 in every 100,000 bp), DNA polymerase makes a mistake in replication resulting in “mutations”
There are other sources of mutation, including smoking, sunlight and radiation

55. Single Nucleotide Changes

56. Single Nucleotide Changes

57. Mutation: Structural Abnormalities

58. Evolution = Mutation + Selection

59. Selection
time
Neutral mutation
Harmful mutation
Beneficial mutation

60. Summary All hereditary information encoded in double- stranded DNA
Each cell in an organism has same DNA
DNA → RNA → protein
Proteins have many diverse roles in cell
Gene regulation diversifies protein products within different cells

61. Further Reading
See website: cs273a.stanford.edu