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A Zero-Knowledge Based Introduction to Biology
Karthik Jagadeesh, Bo Yoo 28 September 2016
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Q: What is your genome?
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Q: What is your genome? A: The sum of your hereditary information.
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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!
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What does the rest of the genome do?
3 billion base pairs – 2% coding, % regulatory Organism’s complexity NOT correlated with 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
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Quick Recap
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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)
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From DNA to Organism You are composed of ~ 10 trillion cells
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From DNA to Organism Cell
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From DNA to Organism Cell Protein
Proteins do most of the work in biology
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Q: How does one genome encode a variety of cell types in a complex organism?
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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
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Controlling Gene Expression
Transcription factors (TFs): Proteins that recognize sequence motifs in enhancers, promoters Combinatorial switches that turn genes on/off
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How does the genome influence human disease?
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Disease Implications SHH MUTATIONS Brain Limb Other Bejerano Lab
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Limb Enhancer 1Mb away from Gene
SHH Bejerano Lab
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Enhancer Deletion limb SHH DELETE Limb Bejerano Lab
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Enhancer 1bp Substitution
limb SHH MUTATIONS Limb Lettice et al. HMG : Bejerano Lab
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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
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How exactly do genes code for proteins?
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Central Dogma of Biology
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DNA: “Blueprints” for a cell
Genetic information encoded in long strings Deoxyribonucleic acid comes in four bases: adenine, thymine, guanine, and cytosine
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Nucleobase Complementary Pairing
purines Adenine (A) Guanine (G) Thymine (T) Cytosine (C) pyrimidines
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DNA Double Helix
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DNA Packaging
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Q: What is your genome? A:The sum of your hereditary information.
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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
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Central Dogma of Biology
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DNA vs RNA 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
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RNA Nucleobases purines pyrimidines Adenine (A) Guanine (G) Uracil (U)
Cytosine (C) pyrimidines
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Gene Transcription G A T T A C A . . . 5’ 3’ 3’ 5’ C T A A T G T . . .
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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
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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)
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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
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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’
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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
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Gene Structure introns 5’ 3’ promoter exons 3’ UTR 5’ UTR coding
non-coding
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Central Dogma of Biology
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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
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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
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Translation G GGG Gly GAG Glu GCG Ala GUG Val A GGA Gly
GAA Glutamic acid (Glu) GCA Ala GUA Val C GGC Gly GAC Asp GCC Ala GUC Val U GGU Glycine (Gly) GAU Aspartic acid (Asp) GCU Alanine (Ala) GUU Valine (Val) AGG Arg AAG Lys ACG Thr AUG Methionine (Met) or START AGA Arginine (Arg) AAA Lysine (Lys) ACA Thr AUA Ile AGC Ser AAC Asn ACC Thr AUC Ile AGU Serine (Ser) AAU Asparagine (Asn) ACU Threonine (Thr) AUU Isoleucine (Ile) CGG Arg CAG Gln CCG Pro CUG Leu CGA Arg CAA Glutamine (Gln) CCA Pro CUA Leu CGC Arg CAC His CCC Pro CUC Leu CGU Arginine (Arg) CAU Histidine (His) CCU Proline (Pro) CUU Leucine (Leu) UGG Tryptophan (Trp) UAG STOP UCG Ser UUG Leu UGA STOP UAA STOP UCA Ser UUA Leucine (Leu) UGC Cys UAC Tyr UCC Ser UUC Phe UGU Cysteine (Cys) UAU Tyrosine (Tyr) UCU Serine (Ser) UUU Phenylalanine (Phe)
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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
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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.
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Single Nucleotide Changes
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Single Nucleotide Changes
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Central Dogma of Biology
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Different Cell Types Subsets of the DNA sequence determine the identity and function of different cells
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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
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Central Dogma of Biology
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Transcription Regulation
Transcription factors link to binding sites Complex of transcription factors forms Complex assists or inhibits formation of the RNA polymerase machinery
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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
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Transcription Regulation
TF A Binding Site Gene B Transcription Factor A
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Q: What if the transcription/translation machinery makes mistakes?
Q:What is the effect in coding regions?
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Evolution = Mutation + Selection
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Mutation: Structural Abnormalities
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Single Nucleotide Changes
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Single Nucleotide Changes
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Evolution = Mutation + Selection
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Selection time Harmful mutation Beneficial mutation
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Evolution = Mutation + Selection
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Evolution = Mutation + Selection
Summary Evolution = Mutation + Selection
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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
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Further Reading See website: cs273a.stanford.edu
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Extra Slides
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Gene Regulatory Region
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