The Central Dogma

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The Central Dogma Data
DNA
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Structure of Integrative Genomics
Concepts
Models Networks
Hidden Structures/ Processes
Evolution
Data Models Inference
Analysis
Functional Explanation
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G Genomes
Key challenge Making a single molecule
observable!!
Classical Solution (70s) Many
De Novo Sequencing Halted extensions or
degradation
80s From one to many PCR Polymerase Chain
Reaction
00s Re-sequencing Hybridisation to complete
genomes
Future Solution One is enough!!
Observing the behavior of the polymerase
Passing DNA through millipores registering
changes in current
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G Assembly and Hybridisation
Contigs and Contig Sizes as function of Genome
Size (G), Read Size (L) and overlap (Ø)
Lander Waterman, 1988 Statistical Analysis of
Random Clone Fingerprinting
Complementary or almost complementary strings
allow interrogation.
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T - Transcriptomics
Measures transcript levels averaging of a set of
cells.
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P Proteomics, M Metabonomics F -
Phenomics
P uses Mass Spectrometry and 2D gel
electrophoresis of degraded peptides and Protein
Arrays using immuno-recognition of complete
proteins
M uses Mass Spectrometry and 2D gel
electrophoresis of metabolites
F The set of all phenotypes. Hard to
define Focus on Clinical Traits Behavioural
Traits hard to observe
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Concepts
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G?F

• Mechanistically predicting relationships
  between different data types is very difficult

• Empirical mappings are important

• Functions from Genome to Phenotype stands out
  in importance
• G is the most abundant data form -
  heritable and precise. F is of greatest interest.

Zero-knowledge mapping dominance, recessive,
interactions, penetrance, QTL,.
Mapping with knowledge weighting interactions
according to co-occurence in pathways.
Model based mapping genome?system?phenotype
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The General Problem is Enormous
Set of Genotypes

• In 1 individual, 3 107 positions could
  segregate.
• In the complete human population 5108 might
  segregate.
• Thus there could be 2500.000.00 possible
  genotypes

Partial Solution Only consider functions
dependent on few positions
Classical Definitions

• Multiple Loci

Epistasis The effect of one locus depends on the
state of another
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Genotype and Phenotype Covariation Gene Mapping
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Pedigree Analysis Association Mapping
Adapted from McVean and others
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Heritability Inheritance in bags, not strings.
The Phenotype is the sum of a series of factors,
simplest independently genetic and environmental
factors F G E
This allows calculation of relative effect of
genetics and environment
Has been been defined for 2 characters
simultaneously to define common factors
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PIN based model of Interactions Emily et al, 2009
Rhzetsky et al.
33 table
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Summary of this lecture