Complexity, Complex Traits, and the CDCV

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Complexity, Complex Traits, and the CDCV
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Simple Monogenic Diseases

• Mendel 1866
• Alcaptonuria (Garrod) 1902
• Sickle Cell Anemia I.D.ed (Herrick) 1910
• Pauling shows SC is molecular disease 1949
• RFLP (DNA polymorphism as marker) 1980
• Chronic granulomatous disease gene 1986
• How many monogenic disease genes do we have
  today?

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Common DNA Markers

• RFLP
• Sequence Tagged Site
• Microsatellite
• SNP

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Linkage Analysis
A/A
a/A

a/A
A/A


a/A
A/A
a/A
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Resolution can be a Problem
a
Disease allele
B
c
e
Case 1 no recombination Case 2 low
recombination Case 3 high recombination
Typical families can map to 1-10 cM or 1-10
MB (tens to hundreds of genes)
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Possible Solutions

• Really Large Families
• Hard to find.
• Multiple families
• Different genes?
• Linkage Disequilibrium Studies in Isolated
  Populations

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Linkage Disequilibrium for Fine Mapping (board)
Typically use SNPs Haplotypes versus SNPs Founder
Effect Non-disease Haplotypes can reduce power In
some ways similar to Linkage, but dont have top
of pedigree Most (90) Mendelian disease genes
I.D.ed by Linkage.
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Common Diseases

• Low penetrance!
• Multifactorial (environment, other genes)
• How many to date?

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The common disease, common variant hypothesis

• Most variation in your genome is common
• 90 of alleles in your genome are common.
• Human population went through a recent
  bottleneck.
• Hypothesis Diseases that were evolutionarily
  neutral during human history may be significantly
  influenced by common variants.

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The Hap Map and Association Studies
Board
Under what circumstances will this work?
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Battle 1
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From Reich and Lander (2001)
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From Reich and Lander (2001)
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From Reich and Lander (2001)
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From Reich and Lander (2001)
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Battle 2
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What can we learn from Mendelian disease?
From Botstein and Risch 2003
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How many common disease SNPs are there?
From Botstein and Risch 2003
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Yeah, but does it apply to common diseases?
From Botstein and Risch 2003
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Head to Head Comparison
From Botstein and Risch 2003