Carlos AlvarezBCMM/CMHG/CGT Joint MeetingSeptember 15th, 2011

Multidimensional genomics in mammalian cohorts

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

Genetics

≥ 15,000 YA

150-200 YA

400 breeds

Why study CNV in dogs?

• 450 inherited diseases• Dog genome similar to human• 5-7X shorter lifespan v. humans• 75M dogs in USA• Low intra-breed variation; high inter

Variation(morphological, physiological & behavioral)

▪ 65X difference sm/largest breeds (wt.)

▪ ~250X smallest/largest individuals

Ongoing genetic studies in dogsa. DNA copy number variation (CNV; custom 1M feature)

b. Genome wide association in complex genetics (12x175k SNP)

Genome Res. 2008

Integrating CNV and SNP haplotypes

Rowell et al. TMM 2011

Kerns et al. (2007) Genetics 176:1679.

KBlack kbrindle kyellow> >

Coat color: Dominant Black locus

In humans, pigmentary mosaicism (not mutation, but effect of two genetic cell types)

CNV explains brindle

Dominant black gene

Identified CNV associated with brindleand developed first genetic test

Approach (for germ line):1. High OSA risk pop. w/ 100X reduced variation2a. Allele-wise GWA analysis 2b. Dimensional reduction of allele ratios

Complex genetics of osteosarcoma

SNP Chr PositionBICF2S23318678 3 22278940BICF2P756511 3 34630563BICF2S22958963 3 34806577BICF2S23713946 5 3741194G320f26S259 5 3814438BICF2P959468 5 24064707BICF2S23647041 5 25563084BICF2S23746914 6 71831263BICF2S22933176 6 72089371BICF2P643804 6 72282176BICF2P878053 6 72314083BICF2S23332924 6 72453644G439f54S214 7 23851944TIGRP2P97627 7 49152204BICF2P989771 9 27058611BICF2P395540 12 67862864BICF2P998637 14 39888317BICF2S23147465 14 51418412BICF2S2339350 18 23106621BICF2S23348607 18 23130080BICF2P950849 18 37553821TIGRP2P335678 25 54551661BICF2P691768 28 42235397BICF2P681391 31 39698895BICF2P623089 34 30054450

Multidimensional genomics in longitudinal cohorts

Conclusion

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