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Genetics of Gene Expression
BIOS 691- 803
Statistics for Systems Biology
Spring 2008
Kinds of Questions
• What kinds of sequence changes cause
effects?
• Are most genetic changes affecting nearby
genes or distal genes?
• How much variation is there?
• How robust is regulation overall?
Aims – Disease Genetics
• Many traits affected by levels of
expression of genes
– Anxiety and serotonin receptor
• Risk of many diseases affected by
predisposing traits
Aims - Discovery
• Most gene regulatory roles unknown
• A gene whose variants affect levels of a
variety of other genes in a function
regulates that process
Tags and Causes
• Variants that have arisen recently in
(evolutionary) history have not had time to
become independent of many of their
neighbors through recombination
– Linkage disequilibrium (LD)
• SNP assays usually report only a fraction
of all variants
• Often the SNP that causes an effect is in
LD with a tagged SNP
Local (‘Cis’) Effects
• Variants in DNA nearby a gene correlate
with that gene’s expression levels
• Usually promoter region
– Transcription factor binding sites
• Sometimes
– 3’ UTR – stability
– Synonymous codon - translation
– Exon splicing junction
Distal (‘Trans’) Effects of TF’s
• Transcription factor mutations:
– DNA binding site – lose binding or change
specificity
– Activation sites – lose activation or change
interacting partners
– Regulatory sites –
• Many downstream genes affected
Other Distal (‘Trans’) Effects
• Signaling proteins
• Scaffolding proteins
• Enzymes
Genetic Models
• Dominant
– AA = AB > BB
• Recessive
– AA > AB = BB
• Additive
– AA > AB > BB
Power and Models
• A test based on an additive model has
moderate power to detect both recessive
and dominant model
• A test based on a dominant model is
extremely weak for a recessive and v.v.
QTL’s
• Quantitative Trait Loci
• Many genes affect quantitative trait
– Height, blood pressure, etc.
• Long history of mapping
• Linkage Curve
Brem & Kruglyak: Questions about
Genetic Complexity
• Are traits for offspring ‘in-between’ or
outside the range of parent values?
• How often do several loci influence a trait
in a natural population?
–
• Are epistatic interactions in natural
variants common?
–
–
Brem & Kruglyak: Questions
• Are traits for offspring ‘in-between’ or
outside the range of parent values?
• How often do several loci influence a trait
in a natural population?
– How hard will it be to find these loci?
• Are epistatic interactions in natural
variants common?
–
–
Brem & Kruglyak: Questions
• Are traits for offspring ‘in-between’ or
outside the range of parent values?
• How often do several loci influence a trait
in a natural population?
– How hard will it be to find these loci?
• Are epistatic interactions in natural
variants common?
– Will there be masked variation?
– Epistatic interactions cause variant offspring?
Brem & Kruglyak: Study Design
• Why eQTL’s?
– Many phenotypes depend on expression
levels
– Expression measures are cheap
• Model
– Yeast genetics easy
• Haploid strains can be propagated
• Markers as surrogates for genotype
– Recombination infrequent in each segregant
Brem & Kruglyak: Data
• 112 ‘inbred’ strains of yeast from mating of
two parent strains
• 5,727 gene expression values by array
• 2,957 markers for parental strain