carlos alvarez bcmm/cmhg/cgt joint meeting september 15 th , 2011
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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
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