Centre for Integrative Genetics
Stig W. Omholt
Mission statement
Contribute to a deep causal understanding of complex genetic characters in fish, plants and animals
for
scientific and commercial exploitation based on
a conceptual and methodological integration of
nonlinear system dynamics, mathematical statistics, biological
physics, biological theory, and genomic and phenotypic data.
Bridging the genotype
Bridging the genotype - - phenotype gap phenotype gap
{GxE} Æ {P}
DNA/RNA-extraction
Quantification of DNA Victor3 (Perkin-Elmer)
Pre PCR Workstation BiomekFX (Beckman)
Sequencing, Microsatellites, SNPlex (ABI3730) MassARRAY (Sequenom)
PCR MJR-tetrads
Post PCR Workstation Multimek96 (Beckman)
BioTek Elx405UV Competitor
BiomekNX (Beckman)
DATABASE CiLIMS
Experimental service resources
Norwegian Red Norwegian Red Limousin
Limousin
Holstein Holstein
Jersey Jersey Angus
Angus
Hereford Hereford
BOVINE GENOME SEQUENCING
Technology transfer
High-throughput quality ensured technology for detection, validation &
genotyping of SNPs
Gene & allele expression analysis
DNA-methylation analysis
Technology Technology
Methodology Methodology
Methodology transfer
Optimal structure of QTL-mapping populations
Approaches for fine mapping QTL
Functional characterisation of QTL -> identify QTN
Determine LD and haplotype structures
Study evolutionary history across breeds and genome
Implementation of genome information in breeding programmes
Optimal approach for genome sequencing & experience with wgs
cGRASP cGRASP
Consortium for Genomic Research on All Salmonids Project Consortium for Genomic Research on All Salmonids Project
Ben Koop
Willie Davidson Stig Omholt
Caird Rexroad Chris Secombes Vanya Ewart
Patricia Gallaugher Michael Burgess Bill Driedzic
Bob Devlin
Graham van Aggelen Ruth Phillips
Genome BC
Establishment of Consortium for Genomic Research on All Salmonid Establishment of Consortium for Genomic Research on All Salmonid s s Programme
Programme (cGRASP), Norwegian University of Life Sciences, October
25-26, 2005
Hva har du gjort med meg Unni?
CIGENE
CIGENE ’ ’ s s proof of principle trait: proof of principle trait:
flesh colour in Atlantic salmon flesh colour in Atlantic salmon
Rationale: important complex trait
genetic variation
commercial importance
evolutionary enigma
Proximate understanding of astaxanthin metabolism
Ultimate understanding of the trait as such
Instrumental and epistemic
exploitation of identified
polymorphisms
The freshwater form of sockeye salmon has 15 times better carotenoid utilization than Atlantic salmon – you could use 1/15 of the amount of
astaxanthin you use today
Discovery
Discovery strategy strategy
Genomics line Experimental line
Individuals/ families with high contrast
Profiling techniques
- mRNA, proteins, metabolites - contrast populations
Other biochemical techniques
SNP-map SalHapMap Physical map
Genome scan
Fine mapping Comparative genomics
Identification of candidate genes
Identify primary targets for exp. p
Refine model
Increased biological knowledge of the astaxanthin metabolism Dynamic modelling line
New targets
Causal genetic polymorphisms Changed practice in:
- feeding, management
Gyrodactylus salaris tolerance in wild Atlantic salmon
Owners of
Drammenselva
NINA
AKVAFORSK
UiO
UMB
Further development
under the CIGENE
umbrella
What is modelling?
Modelling
according
to Google
The heuristic attributes of mathematical modelling
Connects a comprehensive amount of empirical data into a functional whole
Enforces more explicit formulations of various hypotheses
Increases the prediction space of hypotheses
Initiates and canalizes experimental or empirical work by pointing out key questions and the type of data needed
Functions as intellectual meeting meeting places places for for various
various disciplines disciplines
Simple brain physiology
Simple brain physiology
Concomitant rise in osmolarity and shrinkage of extraneuronal space reconciled
Østby, I., Øyehaug, L., Nagelhus, E., Zeuthen, T., Einevoll, G., Plahte, E., Ottersen, OP, Omholt, SW
Initially considered a passive bystander of neural activity, the astroglia now emerges as a key regulatory component of this activity. In addition to its role in the transport of water between brain and blood, the astrocyte cell is critically involved in removal,
metabolism, and release of neurotransmitters, maintenance of extracellular K+ and H+
levels, and supplying energy substrates for the neurons. Neuronal activity causes release of neurotransmittors and ions from the synaptic cleft which in turn causes a rise in the osmolarity of the extracellular space (ECS) between neurons and
surrounding astrocytes. Instead of causing a swelling of the ECS due to influx of water, the increase in osmolarity is followed by shrinkage of the ESC and a local swelling of the astrocyte. Despite having been acknowledged as a regulatory puzzle for two
decades, this inverse relationship of key importance to understanding astrocyte
function is still unresolved. Here we report that translation of available information on astrocyte membrane processes into a dynamic model describing the trafficking of ions and cotransporters across the membrane as a function of extracellular osmolarity, seems to provide a sufficient explanatory setting.
Mathematics of malign melanoma Mathematics of malign melanoma
Modelling of malign melanoma
Causally cohesive genotype
Causally cohesive genotype - - phenotype models phenotype models (cGP models)
(cGP models)
Mathematical models describing how complex Mathematical models describing how complex phenotypes arise from interactions of lower level phenotypes arise from interactions of lower level
systemic entities systemic entities
Articulated relation to the genotype Articulated relation to the genotype
genetic variation reflected in model parameters genetic variation reflected in model parameters
From regulatory principles to genetic descriptors From regulatory principles to genetic descriptors
feedback structure, dose- feedback structure, dose -response relationships response relationships
dominance, epistasis, genetic variance components dominance, epistasis, genetic variance components
Gene expression phenotypes Gene expression phenotypes
expression levels are complex genetic traits expression levels are complex genetic traits
Arne Gjuvsland
Merging genetics theory with the…
Peter Hunter
The mammalian heart model
The mammalian heart model – – a wild beast a wild beast
Recent achievement at University of Montreal
entire SGI Altix 4700 system
768 Intel Itanium 2 processors
1.2TB of shared memory
2 billion equations solved a dozen times
5 milliseconds of activation in a tissue block
One heart beat Æ two weeks
Yeast as experimental
test bed for development of a real quantitative
genetics theory
Development of a methane-based industrial scale in vitro production of meat
International consortium established at UMB June 15, 2007 (Norwa International consortium established at UMB June 15, 2007 (Norwa y, y, Netherlands, Germany, Portugal, Belgium, Israel, USA,
Netherlands, Germany, Portugal, Belgium, Israel, USA, …… …… .) .)
National funding, EU funding, National funding, EU funding, PhilantropicPhilantropicfundingfunding
Those who develop an in vitro production Those who develop an in vitro production technology will
technology will
by future generations be appraised for their by future generations be appraised for their foresightedness
foresightedness
guide the development of a sustainable future guide the development of a sustainable future
with regard to food production and other related commodities by
with regard to food production and other related commodities by use of use of biotechnology
biotechnology