Genomics, Computing,
Economics & Society
10 AM Tue 11-Oct 2005 week 4 of 14
MIT-OCW Health Sciences & Technology 508/510
Harvard Biophysics 101
Economics, Public Policy, Business, Health Policy

Photo removed due to copyright reasons.
(1) Topic priorities for homework since last class
(2) Quantitative exercises: psycho-statistics, combinatorials, random/compression, exponential/logistic, bits, association & multihypotheses
(3) Project level presentation & discussion
(4) Sub-project reports & discussion:
Personalized Medicine & Energy Metabolism
(5) Discuss communication/presentation tools
(6) Topic priorities for homework for next class

ApoE allele
ε
4 : Alzheimer’s dementia,
& hypercholesterolemia
20% in humans, >97% in chimps
HbS 17% & G6PD 40% in a Saudi sample
CCR5
∆
32 : resistance to HIV
9% in caucasians

e4 20% ApoE e3 80%
Figure removed due to copyright reasons.
Ancestral = Arg 112 Thr 61

Figure removed due to copyright reasons.

Association test for CCR-5 & HIV resistance
Alleles Obs Neg ObsSeroPos total
CCR-5+
∆ ccr-5 total
1278
130
1408
1368
78
1446
2646
208
2854
ExpecNeg ExpecPos
1305 1341
103 105 dof=(r-1)(c-1)=1 ChiSq=sum[(o-e)^2/e]= 15.6
P
0.00008
Figure removed due to copyright reasons.
Samson et al. Nature 1996 382:722-5

1E+10
1E+9
1E+8
1E+7
1E+6
1E+5
1E+4
1
1E+3
|
1E+2
0.1
But what if we test more than one locus?
Y= Number of Sib Pairs (Assocation)
X= Number of Alleles (Hypotheses) Tested
Y= Number of Sib Pairs (Association)
X= Population frequency (p)
GRR=1.5, p= 0.5 (population frequency)
GRR=1.5, #alleles=1E6 1,600
1,400
1,200
1,000
800
600
400
200
0
1E+4
|
[based on Risch & Merikangas
(1996) Science 273: 1516]
1E+6 1E+8 1E+10 1E+12 1E+14 1E+16 1E+18 1E+20 1E+22
[based on Risch & Merikangas
(1996) Science 273: 1516]
Y= Number of Sib Pairs (Association)
X= Genotypic Relative Risk (GRR) 0.01
0.001
0.0001
0.00001
1E-06 1E-07 1E-08 1E-09
#alleles=1E6, p=0.5 (population frequency)
The future of genetic studies of complex human diseases.
Ref
GRR = Genotypic relative risk
1E+8
1E+7
1E+6
1E+5
1E+4
1E+3
|
[based on Risch &
Merikangas (1996)
Science 273: 1516]
0.001
1E+1
0.01
0.1
1 10 100 1000
1.001 1.01 1.1 2 11 101 1,001 10,001
10000
1-GRR
GRR

How many "new" mutations?
G= generations of exponential population growth = 5000
N'= population size = 6 x 10 9 now; N= 10 4 pre-G m= mutation rate per bp per generation = 10 -8 to 10 -9 (ref)
L= diploid genome = 6 x 10 9 bp e kG = N'/N; so k= 0.0028
Av # new mutations <
Σ
Le kt m = 4 x 10 3 to 4 x 10 4 per genome t=1 to 5000
Take home: "High genomic deleterious mutation rates in hominids" accumulate over 5000 generations & confound linkage methods
And common (causative) allele assumptions.

(1) Topic priorities for homework since last class
(2) Quantitative exercise
(3) Project level presentation & discussion
(4) Sub-project reports & discussion
(5) Discuss communication/presentation tools
(6) Topic priorities, homework for next class