Complex trait analysis, develop ment, and genomics

The Complex Trait Consortium and the Collaborative Cross

Rob Williams, Gary Churchill, and members of the Complex Trait Consortium

Material included in handouts and on the CD

also see www.complextrait.org

“Solving the puzzle of complex diseases, from obesity to cancer, will require

a holistic understanding of the interplay between factors

such as genetics, diet, infectious agents, environment, behavior, and social

Elias Zerhouni: The NIH Roadmap. Science 302:63

structures.”

(2003)

Main catalysts and models ENU mutagenesis programs Sequencing and SNP consortia A group of ~150 mouse geneticists most of whom have interests in pervasive diseases and differences in disease susceptibility. General Aim: Improve resources for complex trait analysis using mice.

• Catalyze genotyping of strains • Simulation studies of crosses • Planning a collaborative cross • Improved use of resources

The short chronology of the CTC

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Established Nov 2001, Edinburgh (n = 20) 1st CTC Conference, May 2002, Memphis (n = 80; hosted by R Williams) CTC Collaborative Cross design workshop, Aug 2002, JHU (K Broman and R Reeves, host) CTC Satellite meeting at IMGC Nov 2003 (n = 40) 2nd CTC Conference, July 2003, Oxford (n = 80; hosted by R Mott and J Flint) CTC strain selection workshop, Sept 2003 (M Daly, host) 3rd CTC Conference, July 2004, TJL

Are mouse models appropriate? Yes and No.

“If you want to understand where the war on cancer has gone wrong, the mouse is a pretty good place to start.” –Clifton Leaf Fortune, March 2004 Lusis et al. 2002: Genetic Basis of Common Human Disease

Mixing mouse genomes

(reluctantly) Current practice: Keep it simple: high power with low

n

Genetic dissection

V p = V g + V e V p = V + 2(Cov GE) + G g X + V e E + V tech Aim 1: Convert genetic variation into a small set of responsible gene loci called QTLs.

Aim 2: Develop mechanistic insights into virtually any genetically modulated process or disease.

Standard recombinant inbred strains (RI)

fully inbred female C57BL/6J (B) B X D male DBA/2J (D) chromosome pair isogenic

F1

hetero geneous

F2 BXD RI Strain set

Inbred Isogenic siblings BXD1 Recombined chromosomes are needed for mapping BXD2

20 generations brother-sister matings

+ … + BXD80

Proposal for a Collaborative Cross www.complextrait.org

Integrative and cumulative analysis/synthesis physiology development anatomy pathology pharmacokinetics endocrine profile environment epigenetic modifications

Meta analysis

1K Reference Population immune response pathogens metabolism cancer susceptibility transcriptome proteomics

Design criteria for a Collaborative Cross         Broad utility: a resource that combines diverse haplotypes and that harbors a broad spectrum of alleles Freedom from genotyping. Lowering the entry barrier into this field Unrestricted access to strains, tissues, data, and statistical analysis suites (on-line mapping) Improved power and precision for trait mapping. Epistasis!

Powerful new approaches to analysis of complex systems. Pleiotropy Analysis of gene-by-environment interactions A systems biology resource A new type of complex animal model to study common human diseases

A set of 420 RI lines

Mapping with sequence data in hand

B6 and D2 haplotype contrast map of Chr 1

Celera SNP DB

Coincidence analysis

!

Integrative and cumulative analysis/synthesis physiology development anatomy pathology pharmacokinetics endocrine profile environment epigenetic modifications

Meta analysis

1K Reference Population immune response pathogens metabolism cancer susceptibility transcriptome proteomics

Wilt Chamberlain: 7 feet 1 inch Willie Shoemaker: 4 feet 11 inches 24th

6 6

1.44-fold Phenotypes: from highly complex such as body size to highly specific, such as transcript expression difference QTL/QT gene

www.webqtl.org

Grin2b

Cis QTL Trans QTL

Ret

mRNA correlations in a small data set

Ret

and

Sh3d5

Ret GO analysis

The App neighborhood

Handdrawn sketch of the

App

neighborhood

Associational Networks QTL networks add layer of shared causality

Integrative and cumulative analysis/synthesis physiology development anatomy pathology pharmacokinetics endocrine profile environment epigenetic modifications

Meta analysis

1K Reference Population immune response pathogens metabolism cancer susceptibility transcriptome proteomics

Cost Components: 24 –28 M over 7–8 yrs  Per diem for 8,000 to 10,000 cages (~1500 K/year)       Genotyping intermediate generations (~500 K/year) Prospective tissue harvesting and cryopreservation (~500 K/year) Molecular phenotyping of select tissue as proof-of principle (500 K/year) Bioinformatics, statistical modeling, administration, colony management (~500 K/year) Cryopreservation of final lines at F25+ (~200 K) Sequencing of parental strains (unfunded)

NIH Portfolio

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Collaborators

Lu Lu Elissa Chesler David Airey Siming Shou Jing Gu Yanhua Qu Ken Manly (UTHSC) David Threadgill (UNC Chapel Hill) Bob Hitzemann (OHSU) Gary Churchill (TJL) Fernando Pardo Manuel de Villena (UNC) Karl Broman (JHU) Dan Gaile (SUNY Buffalo) Kent Hunter (NCI) Jay Snoddy (ORNL) Jim Cheverud (Wash U) Tim Wiltshire (GNF) Supported by: NIAAA-INIA Program, NIMH, NIDA, and the National Science Foundation (P20-MH 62009), NEI, a Human Brain Project and the William and Dorothy Dunavant Endowment.