Genetics of Gene Expression BIOS 691 803 Statistics
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 e. QTL’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
- Slides: 16