MIT-OCW Health Sciences & Technology 508/510

Harvard Biophysics 101 

Economics, Public Policy, Business, Health Policy

For more info see: http://karma.med.harvard.edu/wiki/Biophysics_101

10 AM Tue 11-Oct 2005 Fairchild 177 week 4 of 14

Genomics, Computing, Economics & Society

Class outline

(1) Topic priorities for homework since last class(2) Quantitative exercises: psycho-statistics, combinatorials, random/compression, exponential/logistic, bits, association & multi-hypotheses

(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

Common Disease – Common Variant Theory. How common?

ApoE allele 4 : Alzheimer’s dementia, & hypercholesterolemia20% in humans, >97% in chimps

HbS 17% & G6PD 40% in a Saudi sample

CCR532 : resistance to HIV 9% in caucasians

SNPs & Covariance in proteins

e4 20% ApoE e3 80%

Ancestral = Arg 112 Thr 61

One form of HIV-1 Resistance

Association test for CCR-5 & HIV resistanceAlleles Obs Neg ObsSeroPos total ExpecNeg ExpecPosCCR-5+ 1278 1368 2646 1305 1341 ccr-5 130 78 208 103 105total 1408 1446 2854

Pdof=(r-1)(c-1)=1 ChiSq=sum[(o-e) 2̂/e]= 15.6 0.00008

Samson et al. Nature 1996 382:722-5

But what if we test more than one locus?

The future of genetic studies of complex human diseases. Ref (Note above graphs are active spreadsheets -- just click)

Y= Number of Sib Pairs (Association)X= Population frequency (p)

GRR=1.5, #alleles=1E6

1E+2

1E+3

1E+4

1E+5

1E+6

1E+7

1E+8

1E+9

1E+10

1E-091E-081E-071E-060.000010.00010.0010.010.11

[based on Risch & Merikangas (1996) Science 273: 1516]

| Y= Number of Sib Pairs (Association)X= Genotypic Relative Risk (GRR)

#alleles=1E6, p=0.5 (population frequency)

1E+1

1E+2

1E+3

1E+4

1E+5

1E+6

1E+7

1E+8

0.001 0.01 0.1 1 10 100 1000 10000

1.001 1.01 1.1 2 11 101 1,001 10,001

1-GRRGRR

[based on Risch & Merikangas (1996) Science 273: 1516]|

|

Y= Number of Sib Pairs (Assocation)X= Number of Alleles (Hypotheses) Tested

GRR=1.5, p= 0.5 (population frequency)

0

200

400

600

800

1,000

1,200

1,400

1,600

1E+4 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]|

GRR = Genotypic relative risk

How many "new" mutations?

G= generations of exponential population growth = 5000N'= population size = 6 x 109 now; N= 104 pre-Gm= mutation rate per bp per generation = 10-8 to 10-9 (ref)L= diploid genome = 6 x 109 bp ekG = N'/N; so k= 0.0028 Av # new mutations < Lektm = 4 x 103 to 4 x 104

per genome t=1 to 5000

Take home: "High genomic deleterious mutation rates in hominids"accumulate over 5000 generations & confound linkage methodsAnd common (causative) allele assumptions.

Class outline

(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