AGBT 2010 - Keynote Speaker: Debbie Nickerson

Debbie Nickerson - University of Washington, Department of Genome Sciences

Exon reseqeuncing: Next Generation Mendelian Genetics and Beyond."

Start with Acknolegements: Sarah Ng, Jay Shendure, Emily Turner, Mike Bamshad

Exome Sequencing: 180,000 exons, 30 megabases (inc. splice sites & rna

Why? Only 1%, so we can sequence more exoms for the cost.

Disadvantage: Missing non-coding variants

Larger effect Sizes,

more interpretable,

easier to follow up.

Many different approaches (just 3)

- most of todays work is array hybridization. However, it doesn't scale

In solution hybridization scaled better

Also, molecular inversion probes

Exome captured by Nimblegen:

compare GAIIx vs HiSeq: 2.7 times more data. (50x -> 138X). Will now do multiple exomes per lane

Why tackle mendelian disorders?

Most impactful

foundation of human genetics

more insights into gene function

thousands remain unsolved.

Example published last year: Feemen-sheltman syndrome? Sequenced individuals and identified gene that was alreadyknown.Example current presented: mMiller Syndrom. (Potaxial acrofacial dystosis) Presumed autosomal recessive. (Recessives will be easier.)

Sequenced 4 exomes from 3 families

Two individuals were siblings

Includes CF-like lung function in siblings

other: facial deformities, limb development problems

Recently published.

Process:

First (~2,000 snps)

Filter on dbsnp129 (may not be valid in the future... more and more complex traits won't work well at all.)

Brings down to 12

Start filtering further on Hapmap (8 individuals), brings it down to 3 genes

Candidate genes quickly become apparent - recessive diseases are relatively easy this way.

Turns out gene is key enzyme in novel pyrimidine biosynthesis. (DHODH) Important in limb development - analogous to drosophila wing mutations. (Found originally in 1975)

What about lung phenotype - found a gene that is common to sibblings

Back to Exome capture, not all diseases have worked out this way. Some have been unsuccessful.

Starting a project to scale exome analysis to complex traits. (Heart and lung)

Looking at other rare traits - including early onset and extremes of phenotypes

Early onset MI

Extremes of LDL Cholesterol

Extremes of BMI

Lung Diseases = pulmonary Hypertension

COPD... etc

How do we replicate this study? Following up on 1000's of samples with ~50 genes is daunting. We'll have to work out how these findings can be replicated in the future.

[missed some stuff at the end when blogger crashed and lost the end of the lecture. - sorry]