Cracking the Code: The Genetic Basis of...
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Cracking the Code: The Genetic Basis of Disease
Dima Ter-Ovanesyan Molecular and Cellular Biology Program,
Harvard University
Michael Guo Biological and Biomedical Sciences Program,
Harvard University
SITN DayCon 2015
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What we will discuss today
Part 1: Basics of Genetics Part II: Genetic Variation
Part III: Genetic Basis of DiseasePart IV: Mutations to Therapeutics
![Page 3: Cracking the Code: The Genetic Basis of Diseasesitn.hms.harvard.edu/wp-content/uploads/2015/04/CrackingtheCode.pdf · Part IV: Mutations to Therapeutics. Nature vs. Nurture Image](https://reader033.fdocuments.in/reader033/viewer/2022041904/5e625caef20d616f9e09466d/html5/thumbnails/3.jpg)
Nature vs. Nurture
Image by hepingting via Wikimedia Commons
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The cell is the unit of life
Organism Organ Tissue Cell
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All cells contain DNA
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DNA contains genes
Gene: portion of DNA that encodes one protein
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Proteins are the molecular machines of the cells
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Central Dogma of Molecular Biology
DNA
RNA
Protein
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Central Dogma – car analogy
DNA
RNA
Protein
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Human Genome
Full sequence of DNA – 3 billion letters (ATCG)
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QUESTIONS?
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What we will discuss today
Part 1: Basics of Genetics Part II: Genetic Variation
Part III: Genetic Basis of DiseasePart IV: Mutations to Therapeutics
![Page 13: Cracking the Code: The Genetic Basis of Diseasesitn.hms.harvard.edu/wp-content/uploads/2015/04/CrackingtheCode.pdf · Part IV: Mutations to Therapeutics. Nature vs. Nurture Image](https://reader033.fdocuments.in/reader033/viewer/2022041904/5e625caef20d616f9e09466d/html5/thumbnails/13.jpg)
Genetic mutations
ATGCAGCGTCATGCTGCGTC
ATGCTGCGTCATGCTGCGTC
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Genetic mutations
ATGCAGCGTCATGCTGCGTC
ATGCTGCGTCATGCTGCGTC
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Genetic mutations can get passed on to offspring
ATGCAGCGTCATGCTGCGTC
ATGCTGCGTCATGCTGCGTC
ATGCAGCGTCATGCTGCGTC
ATGCTGCGTCATGCTGCGTC
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Genetic variant: Any DNA change that is present in the populationMutation: A genetic variant with an effect
We’ll use them interchangeably…
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Mutation to Disease: Sickle Cell
DNA
RNA
Protein
Normal Sickle Cell
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Human Genetic VariationHumans are 99.9% identical: differ on average 1 in 1000 base pairs
Image by hepingting via Wikimedia Commons
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Genetic variants may be common or rareReference ATGTGTCGTGCTGCTCPerson 1 ATGTGTCGTTCTGCTCPerson 2 ATGTGTCGTGCTGCTCPerson 3 ATGAGTCGTGCTGCTCPerson 4 ATGTGTCGTGCTGCTCPerson 5 ATGAGTCGTGCTGCTCPerson 6 ATGAGTCGTGCTGCTCPerson 7 ATGAGTCGTGCTGCTCPerson 8 ATGTGTCGTGCTGCTCPerson 9 ATGTGTCGTGCTGCTCPerson 10 ATGAGTCGTGCTGCTC
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Genetic variants may be common or rareReference ATGTGTCGTGCTGCTCPerson 1 ATGTGTCGTTCTGCTCPerson 2 ATGTGTCGTGCTGCTCPerson 3 ATGAGTCGTGCTGCTCPerson 4 ATGTGTCGTGCTGCTCPerson 5 ATGAGTCGTGCTGCTCPerson 6 ATGAGTCGTGCTGCTCPerson 7 ATGAGTCGTGCTGCTCPerson 8 ATGTGTCGTGCTGCTCPerson 9 ATGTGTCGTGCTGCTCPerson 10 ATGAGTCGTGCTGCTC
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Genetic variants may be common or rareReference ATGTGTCGTGCTGCTCPerson 1 ATGTGTCGTTCTGCTCPerson 2 ATGTGTCGTGCTGCTCPerson 3 ATGAGTCGTGCTGCTCPerson 4 ATGTGTCGTGCTGCTCPerson 5 ATGAGTCGTGCTGCTCPerson 6 ATGAGTCGTGCTGCTCPerson 7 ATGAGTCGTGCTGCTCPerson 8 ATGTGTCGTGCTGCTCPerson 9 ATGTGTCGTGCTGCTCPerson 10 ATGAGTCGTGCTGCTC
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Genetic variants may have a range of effects
Benign
Beneficial
Damaging
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Summary
• Genes code for proteins that perform cellular functions
• Individuals differ at some sites in their DNA• These genetic variants may be common or rare• Genetic variants are mostly benign, but can be
beneficial or damaging
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What we will discuss today
Part 1: Basics of Genetics Part II: Genetic Variation
Part III: Genetic Basis of DiseasePart IV: Mutations to Therapeutics
![Page 25: Cracking the Code: The Genetic Basis of Diseasesitn.hms.harvard.edu/wp-content/uploads/2015/04/CrackingtheCode.pdf · Part IV: Mutations to Therapeutics. Nature vs. Nurture Image](https://reader033.fdocuments.in/reader033/viewer/2022041904/5e625caef20d616f9e09466d/html5/thumbnails/25.jpg)
Basis of Disease• Environmental
– Snake bite– Car accident
• Genetic– Sickle cell anemia– Cystic Fibrosis
• Genetics and Environment– Cholesterol levels– Obesity
Images courtesy of Geoff Gallice, sicklecellanemia.org and ParentingPatch via Wikimedia Commons
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Genetic Diseases
Common Polygenic
• Many common genetic variants of small effect
• Often strong role of environment
• Type 2 diabetes, obesity
Rare Monogenic
• Single mutations of large effect
• Environment less important
• Cystic fibrosis, sickle cell anemia, Duchenne muscular dystrophy
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Cholesterol/LDL
LDL
LDL LDL
Bloodstream
Liver
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Cholesterol in the blood is in LDL
LDL
Bloodstream
LDL
LDL
LDL
LDL
Liver Cell
LDL Receptor
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LDL
LDL Binds to LDL Receptor
LDL Liver Cell
Bloodstream
LDL LDL
LDL
LDL Receptor
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LDL
Liver cells take LDL out of blood
LDL
Liver Cell
Bloodstream
LDL LDL
LDL
LDL Receptor
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LDL LDL
LDL LDL
Increased LDL leads to heart attack
LDL Levels
Hea
rt at
tack
risk
Blood Vessel
Clot
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Variation in LDL
LDL Levels
Per
cent
of P
eopl
e
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LDL Levels
Per
cent
of P
eopl
e
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LDL Levels
Per
cent
of P
eopl
e
Genes + Environment
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LDL Levels
Per
cent
of P
eopl
e
Genes only
Genes + Environment
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Genes + Environment
Environment only
Genes only
LDL Levels
Per
cent
of P
eopl
e
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• Previously, a few dozen genes for cholesterol (cell models, model organisms)
• Need to find genes relevant for cholesterol in humans
• Find mutations in genes that alter cholesterol levels in humans– Genome wide association study (GWAS)
– Family-based linkage studies
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GWAS• GWAS: Genome Wide Association Study• Perform in large numbers of people• Find variants in genes associated with
cholesterol levels• For each common genetic variant:
– Test whether variant is associated with differences in cholesterol levels
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T: Average 100 A: Average 120
Variant 1
Reference ATGTGTCGTGCTGCTCPerson 1 ATGTGTCGTTCTGCTCPerson 2 ATGTGTCGTGCTGCTCPerson 3 ATGTGTCGTGCTGCTCPerson 4 ATGTGTCGTGCTGCTCPerson 5 ATGTGTCGTGCTGCTCPerson 6 ATGAGTCGTGCTGCTCPerson 7 ATGAGTCGTGCTGCTCPerson 8 ATGAGTCGTGCTGCTCPerson 9 ATGAGTCGTGCTGCTCPerson 10 ATGAGTCGTGCTGCTC
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Reference CTCGTGCAGTGCGATCPerson 1 CTCGTGCAGTGCGATCPerson 2 CTCGTGCAGTACGATCPerson 3 CTCGTGCAGTACGATCPerson 4 CTCGTGCAGTGCGATCPerson 5 CTCGTGCAGTGCGATCPerson 6 CTCGTGCAGTGCGATCPerson 7 CTCGTGCAGTACGATCPerson 8 CTCGTGCAGTACGATCPerson 9 CTCGTGCAGTGCGATCPerson 10 CTCGTGCAGTACGATC
G: Average 100 A: Average 100
Variant 2
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Cholesterol: Findings from GWAS
• Performed in ~200,000 people• Identified 157 genes associated with
cholesterol levels– Many genes known to play role in cholesterol
– Some genes are known drug targets– Many new genes
• New biology
• New drug targets
Global Lipids Genetics Consortium. Nature Genetics. 2013.
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Monogenic DisordersFamilial Hypercholesterolemia (FH)• Rare disease (1 in 500)• Very high cholesterol levels
• Cholesterol deposits• Heart disease by age 60
Image by A. Kumar via Wikimedia Commons
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Linkage Study
• Which mutations are “linked” with disease?• Search for rare mutations of large effect• Mutations in gene for LDL receptor (LDLR)
Female
Male
Disease
No Disease
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LDL
Normal LDL Receptor
LDL
Liver Cell
Bloodstream
LDL LDL
LDL
LDL Receptor
LDL
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LDL receptor mutation leads to increased LDL
LDL
LDL
Bloodstream
LDL LDL
LDL
Liver Cell
LDL Receptor
Increased LDL in blood
LDL
LDL
LDL
LDL
LDL
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Summary• For rare monogenic diseases, genetics plays
a primary role• For common polygenic diseases, genetics
and environment are both important
• Genes for disease can be found through genetic association studies
• Genetic studies have unveiled new biology and drug targets
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QUESTIONS?
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What we will discuss today
Part 1: Basics of Genetics Part II: Genetic Variation
Part III: Genetic Basis of DiseasePart IV: Mutations to Therapeutics
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X-Men Mutants
http://marvel-movies.wikia.com/wiki/X-Men_(team)
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Rare mutations in humansGene Effect
CCR5 resistant to HIV infection
PCSK9 lower blood cholesterol levels and reduced risk of cardiovascular disease
LRP5 extra strong bones
MSTN abnormally large muscles
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Natural Myostatin (MSTN) Mutants
http://www.whatisgenetic.com http://discovermagazine.com/sitefiles/resources/image.aspx?item=%7B41CD5607-53C2-42FD-A8C0-7D05CE163CF0%7D
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People with PCSK9 Mutations
A very small number of people have an inactivating mutation in the PCSK9 gene: -lower blood cholesterol/LDL levels -greatly reduced (up to 90% in some cases) risk of cardiovascular disease (heart attacks, etc)
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People with PCSK9 Mutations
Cohen et al, NEHM 2006
Cha
nce
of H
eart
Dis
ease
(Per
cent
)
0
2
4
6
8
10
12
Normal PCSK9 Mutation
![Page 54: Cracking the Code: The Genetic Basis of Diseasesitn.hms.harvard.edu/wp-content/uploads/2015/04/CrackingtheCode.pdf · Part IV: Mutations to Therapeutics. Nature vs. Nurture Image](https://reader033.fdocuments.in/reader033/viewer/2022041904/5e625caef20d616f9e09466d/html5/thumbnails/54.jpg)
Cholesterol in the blood is in LDL
LDL
Liver Cell
Blood Stream
LDL
LDL
LDL
LDL
LDL Receptor
![Page 55: Cracking the Code: The Genetic Basis of Diseasesitn.hms.harvard.edu/wp-content/uploads/2015/04/CrackingtheCode.pdf · Part IV: Mutations to Therapeutics. Nature vs. Nurture Image](https://reader033.fdocuments.in/reader033/viewer/2022041904/5e625caef20d616f9e09466d/html5/thumbnails/55.jpg)
LDL
LDL Binds to LDL Receptor
LDL Liver Cell
Blood Stream
LDL LDL
LDL
LDL Receptor
![Page 56: Cracking the Code: The Genetic Basis of Diseasesitn.hms.harvard.edu/wp-content/uploads/2015/04/CrackingtheCode.pdf · Part IV: Mutations to Therapeutics. Nature vs. Nurture Image](https://reader033.fdocuments.in/reader033/viewer/2022041904/5e625caef20d616f9e09466d/html5/thumbnails/56.jpg)
LDL
Liver cells take LDL out of blood
LDL
Liver Cell
Blood Stream
LDL LDL
LDL
LDL Receptor
![Page 57: Cracking the Code: The Genetic Basis of Diseasesitn.hms.harvard.edu/wp-content/uploads/2015/04/CrackingtheCode.pdf · Part IV: Mutations to Therapeutics. Nature vs. Nurture Image](https://reader033.fdocuments.in/reader033/viewer/2022041904/5e625caef20d616f9e09466d/html5/thumbnails/57.jpg)
PCSK9 degrades LDL Receptors
LDL
Liver Cell
Blood Stream
LDL
LDL
LDL
LDL
LDL Receptor
PCSK9
![Page 58: Cracking the Code: The Genetic Basis of Diseasesitn.hms.harvard.edu/wp-content/uploads/2015/04/CrackingtheCode.pdf · Part IV: Mutations to Therapeutics. Nature vs. Nurture Image](https://reader033.fdocuments.in/reader033/viewer/2022041904/5e625caef20d616f9e09466d/html5/thumbnails/58.jpg)
PCSK9 degrades LDL Receptors
LDL
Liver Cell
Blood Stream
LDL
LDL
LDL
LDL
LDL Receptor
PCSK9
![Page 59: Cracking the Code: The Genetic Basis of Diseasesitn.hms.harvard.edu/wp-content/uploads/2015/04/CrackingtheCode.pdf · Part IV: Mutations to Therapeutics. Nature vs. Nurture Image](https://reader033.fdocuments.in/reader033/viewer/2022041904/5e625caef20d616f9e09466d/html5/thumbnails/59.jpg)
PCSK9 degrades LDL Receptors
LDL
Liver Cell
Blood Stream
LDL
LDL
LDL
LDL
LDL Receptor
PCSK9
![Page 60: Cracking the Code: The Genetic Basis of Diseasesitn.hms.harvard.edu/wp-content/uploads/2015/04/CrackingtheCode.pdf · Part IV: Mutations to Therapeutics. Nature vs. Nurture Image](https://reader033.fdocuments.in/reader033/viewer/2022041904/5e625caef20d616f9e09466d/html5/thumbnails/60.jpg)
Less LDL receptors to bind LDL
LDL
Liver Cell
Blood Stream
LDL
LDL
LDL
LDL
LDL Receptor
PCSK9
![Page 61: Cracking the Code: The Genetic Basis of Diseasesitn.hms.harvard.edu/wp-content/uploads/2015/04/CrackingtheCode.pdf · Part IV: Mutations to Therapeutics. Nature vs. Nurture Image](https://reader033.fdocuments.in/reader033/viewer/2022041904/5e625caef20d616f9e09466d/html5/thumbnails/61.jpg)
Less LDL receptors to bind LDL
LDL
Liver Cell
Blood Stream
LDL
LDL
LDL
LDL
LDL Receptor
PCSK9 Increased cholesterol/LDL levels in blood
![Page 62: Cracking the Code: The Genetic Basis of Diseasesitn.hms.harvard.edu/wp-content/uploads/2015/04/CrackingtheCode.pdf · Part IV: Mutations to Therapeutics. Nature vs. Nurture Image](https://reader033.fdocuments.in/reader033/viewer/2022041904/5e625caef20d616f9e09466d/html5/thumbnails/62.jpg)
Some people have mutation in PCSK9
PCSK9Gene
PCSK9RNA
PCSK9 Protein
![Page 63: Cracking the Code: The Genetic Basis of Diseasesitn.hms.harvard.edu/wp-content/uploads/2015/04/CrackingtheCode.pdf · Part IV: Mutations to Therapeutics. Nature vs. Nurture Image](https://reader033.fdocuments.in/reader033/viewer/2022041904/5e625caef20d616f9e09466d/html5/thumbnails/63.jpg)
PCSK9 mutation leads to more LDL Receptors
Normal PCSK9 Mutated PCSK9
LOW Cholesterol/LDL levels in blood!
LDL
LDL
LDL
LDL
LDL
LDL
LDL
LDL
LDL
LDL
![Page 64: Cracking the Code: The Genetic Basis of Diseasesitn.hms.harvard.edu/wp-content/uploads/2015/04/CrackingtheCode.pdf · Part IV: Mutations to Therapeutics. Nature vs. Nurture Image](https://reader033.fdocuments.in/reader033/viewer/2022041904/5e625caef20d616f9e09466d/html5/thumbnails/64.jpg)
Can we use our knowledge of PCSK9���mechanism?
LDL
Liver Cell
Blood Stream
LDL
LDL
LDL
LDL
LDL Receptor
PCSK9
![Page 65: Cracking the Code: The Genetic Basis of Diseasesitn.hms.harvard.edu/wp-content/uploads/2015/04/CrackingtheCode.pdf · Part IV: Mutations to Therapeutics. Nature vs. Nurture Image](https://reader033.fdocuments.in/reader033/viewer/2022041904/5e625caef20d616f9e09466d/html5/thumbnails/65.jpg)
PCSK9 inhibitor
Liver Cell
Drug that blocks PCSK9
LDL Receptor
PCSK9
![Page 66: Cracking the Code: The Genetic Basis of Diseasesitn.hms.harvard.edu/wp-content/uploads/2015/04/CrackingtheCode.pdf · Part IV: Mutations to Therapeutics. Nature vs. Nurture Image](https://reader033.fdocuments.in/reader033/viewer/2022041904/5e625caef20d616f9e09466d/html5/thumbnails/66.jpg)
PCSK9 inhibitor
Liver Cell
Drug that blocks PCSK9
LDL Receptor
PCSK9
PCSK9 inhibitor drug mimics PCSK9 mutation
Low LDL/Cholesterol!
![Page 67: Cracking the Code: The Genetic Basis of Diseasesitn.hms.harvard.edu/wp-content/uploads/2015/04/CrackingtheCode.pdf · Part IV: Mutations to Therapeutics. Nature vs. Nurture Image](https://reader033.fdocuments.in/reader033/viewer/2022041904/5e625caef20d616f9e09466d/html5/thumbnails/67.jpg)
Conclusions
-People have different DNA -Combination of genes and environment cause disease -We can find genetic variants that are associated with disease risk -We can use knowledge of genetics to find new drugs
![Page 68: Cracking the Code: The Genetic Basis of Diseasesitn.hms.harvard.edu/wp-content/uploads/2015/04/CrackingtheCode.pdf · Part IV: Mutations to Therapeutics. Nature vs. Nurture Image](https://reader033.fdocuments.in/reader033/viewer/2022041904/5e625caef20d616f9e09466d/html5/thumbnails/68.jpg)
QUESTIONS?
![Page 69: Cracking the Code: The Genetic Basis of Diseasesitn.hms.harvard.edu/wp-content/uploads/2015/04/CrackingtheCode.pdf · Part IV: Mutations to Therapeutics. Nature vs. Nurture Image](https://reader033.fdocuments.in/reader033/viewer/2022041904/5e625caef20d616f9e09466d/html5/thumbnails/69.jpg)
Thank you! SITN would like to acknowledge the following
organizations for their generous support of this event.