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Office hours 304A Stanley Hall next week 3-4pm Monday Nov 24. Heritability in exptal organisms. Genetically identical. Genetically different. Heritability in exptal organisms.  e .  t . Genetic variance = total var - “environmental var” Heritability H 2 = .  g  =  t  -  e .

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slide2

Heritability in exptal organisms

Genetically identical

Genetically different

slide3

Heritability in exptal organisms

e

t

Genetic variance = total var - “environmental var”

Heritability H2 =

g = t -e

g/t

slide4

Heritability in humans: MZ twins

http://www.sciam.com/media/inline/15DD5B0E-AB41-23B8-2B1E53E8573428C5_1.jpg

http://www.twinsinsurance.net/images/twins.jpg

http://www.twinsrealm.com/othrpics/twins16.jpg

http://www.twinsrealm.com/othrpics/sarahandsandra.jpg

Mean each pair = zi

Each individual = zij

b2 w2

(zij - z)2

 

h2 =

Total mean sq =

= t2

t2

T

(zij - zi)2

 

Within pairs mean sq =

= w2

N

(zi - z)2



= b2

Between pairs mean sq =

N-1

slide5

Significance of heritability?

mRNA expression

all

progeny

P1

P2

progeny, marker genotype

P1

progeny, marker genotype

P2

mapping imprecision
Mapping imprecision

wide mapped interval

mapping imprecision9
Mapping imprecision

wide mapped interval

You should now know from the first problem set why the LOD score is highest for markers close to the causal variant locus…

mapping imprecision10
Mapping imprecision

wide mapped interval

But why not just look at the single marker with the best LOD score?

single best locus isn t the answer
Single best locus isn’t the answer

True distance 30 cM

Disease-causing mutation

Restriction fragment length polymorphism

observed recombination fraction = 1/8 = 12.5 cM

this is our observation

The observed number of recombinants is just a point estimate, with some error associated.

variation in submergence tolerance
Variation in submergence tolerance

http://www.a2mediagroup.com/data/images/news/categories/riceplant.jpg

linkage mapping
Linkage mapping

intolerant

tolerant

transgenic test
Transgenic test

http://www.plantsci.cam.ac.uk/Haseloff/SITEGRAPHICS/Agrotrans.GIF

transgenic test20
Transgenic test

From Prof. Garriga problem set

http://www.plantsci.cam.ac.uk/Haseloff/SITEGRAPHICS/Agrotrans.GIF

transgenic test23
Transgenic test

Only expressed upon submergence

transgenic test24
Transgenic test

Expressed all the time…

now in a real crop strain
Now in a real crop strain

Swarna INTOL

x

IR49830 TOL

x

Swarna INTOL

Check for Sub1A+

F1

now in a real crop strain26
Now in a real crop strain

Swarna INTOL

x

IR49830 TOL

x

Swarna INTOL

F1

x

Swarna INTOL

Check for Sub1A+

B1

now in a real crop strain27
Now in a real crop strain

Swarna INTOL

x

IR49830 TOL

x

Swarna INTOL

F1

x

Swarna INTOL

B1

x

Swarna INTOL

B2

now in a real crop strain28
Now in a real crop strain

Swarna INTOL

x

IR49830 TOL

x

Swarna INTOL

F1

x

Swarna INTOL

B1

x

Swarna INTOL

B2

Result: Sub1A in Swarna genome

common in plant breeding
Common in plant breeding

Wild: resistant to fungus

Cultivated: bred for yield, etc.

http://www.anbg.gov.au/cpbr/program/sc/barl_mole.htm

every linkage study faces this problem
Every linkage study faces this problem

What is the causative variant linked to the marker?

how to formulate a guess33
How to formulate a guess?

Here a very obvious hypothesis. Often not such a large gain or loss.

fine mapping
Fine-mapping

Fig. 11.17

fine mapping new markers36
Fine-mapping: new markers

Between two humans, 1 polymorphism every 1000 bp; linkage study probably started with a tiny fraction of total.

fine mapping new markers37
Fine-mapping: new markers

Position of true causal variant

A simulation of a qualitative trait in a large mouse cross; sparse marker set

Best marker

fine mapping new markers38
Fine-mapping: new markers

Position of true causal variant

Peak looks pretty close—why bother improving resolution?

Best marker

fine mapping new markers39
Fine-mapping: new markers

Position of true causal variant

Because you have to hunt through by hand to find the causal gene, and test experimentally. The smaller the region, the better.

Best marker

fine mapping new markers40
Fine-mapping: new markers

Position of true causal variant

Increased marker density

fine mapping new markers41
Fine-mapping: new markers

Position of true causal variant

Why did the LOD score go up?

More markers increases multiple testing, which boosts LODs in the region.

Closer markers have more significant linkage, increasing their LODs.

Peak is narrower, so LODs increase in the region.

The LOD score scales with the number of markers, so actually it isn’t different if you normalize correctly.

coding variants46
Coding variants

http://homepages.strath.ac.uk/~dfs99109/BB310/CFTRgene.jpg

Fig. 2B

coding variants47
Coding variants

http://homepages.strath.ac.uk/~dfs99109/BB310/CFTRgene.jpg

New amino acid

Fig. 2B

coding variants48
Coding variants

http://homepages.strath.ac.uk/~dfs99109/BB310/CFTRgene.jpg

Premature STOP

Fig. 2B

coding variants49
Coding variants

http://homepages.strath.ac.uk/~dfs99109/BB310/CFTRgene.jpg

Regulatory change, not coding!

Fig. 2B

nucleotide repeat diseases
Nucleotide repeat diseases

http://graphics.jsonline.com/graphics/badger/img/may02/5martin506.jpg

Fig. 11.13

nucleotide repeat diseases51
Nucleotide repeat diseases

http://geneticsmodules.duhs.duke.edu/Design/Print.asp

Fig. 7A,B

slide52
Think about it: most identified variants are rare alleles with strong effect.Most likely to be coding changes.
promoter variants55
Promoter variants

Fig. 9.22

Promoter mutations can cause misregulation and disease/phenotype.

promoter variants57
Promoter variants

Subtle single-nucleotide promoter variants probably very common, but hard to find. Stay tuned.

DOC