1. Carlos Alvarez BCMM/CMHG/CGT Joint Meeting September 15 th, 2011 Multidimensional genomics in mammalian cohorts in mammalian cohorts

2. Lab background PhD, mol. genetics of vision (Drosophila) Postdoc, mol. neurosci. & genomics (rodents) Lab Head, Novartis (hum., rodent)  Themes – evolution, bioinformatics, genomics

3. Genetics ≥ 15,000 YA 150-200 YA 400 breeds Why study CNV in dogs? 450 inherited diseases450 inherited diseases Dog genome similar to humanDog genome similar to human 5-7X shorter lifespan v. humans5-7X shorter lifespan v. humans 75M dogs in USA75M dogs in USA Low intra-breed variation; high interLow intra-breed variation; high inter Variation (morphological, physiological & behavioral) ▪ 65X difference sm/largest breeds (wt.) ▪ ~250X smallest/largest individuals

4. Ongoing genetic studies in dogs a. DNA copy number variation (CNV; custom 1M feature) b. Genome wide association in complex genetics (12x175k SNP) Genome Res. 2008

5. Integrating CNV and SNP haplotypes Rowell et al. TMM 2011

6. Kerns et al. (2007) Genetics 176:1679. K Black k brindle k yellow >> Coat color: Dominant Black locus In humans, pigmentary mosaicism (not mutation, but effect of two genetic cell types)

7. CNV explains brindle Dominant black gene Identified CNV associated with brindle and developed first genetic test

8. Approach (for germ line): 1.High OSA risk pop. w/ 100X reduced variation 2a. Allele-wise GWA analysis 2b. Dimensional reduction of allele ratios Complex genetics of osteosarcoma SNPChrPosition BICF2S23318678322278940 BICF2P756511334630563 BICF2S22958963334806577 BICF2S2371394653741194 G320f26S25953814438 BICF2P959468524064707 BICF2S23647041525563084 BICF2S23746914671831263 BICF2S22933176672089371 BICF2P643804672282176 BICF2P878053672314083 BICF2S23332924672453644 G439f54S214723851944 TIGRP2P97627749152204 BICF2P989771927058611 BICF2P3955401267862864 BICF2P9986371439888317 BICF2S231474651451418412 BICF2S23393501823106621 BICF2S233486071823130080 BICF2P9508491837553821 TIGRP2P3356782554551661 BICF2P6917682842235397 BICF2P6813913139698895 BICF2P6230893430054450

9. Multidimensional genomics in longitudinal cohorts longitudinal cohorts Multidimensional genomics in longitudinal cohorts longitudinal cohorts

10. ConclusionConclusion Longitudinal cohorts will enable determination of genetic alterations (SNPs, CNV) contributing to disease initiation, progression and promotion … and of the relative contributions of genetics and environment … and of the relative contributions of genetics and environment