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Genetics of Gene Expression

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?.

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Genetics of Gene Expression

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  1. Genetics of Gene Expression BIOS 691- 803 Statistics for Systems Biology Spring 2008

  2. 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?

  3. Aims – Disease Genetics • Many traits affected by levels of expression of genes • Anxiety and serotonin receptor • Risk of many diseases affected by predisposing traits

  4. 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

  5. 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

  6. 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

  7. 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

  8. Other Distal (‘Trans’) Effects • Signaling proteins • Scaffolding proteins • Enzymes

  9. Genetic Models • Dominant • AA = AB > BB • Recessive • AA > AB = BB • Additive • AA > AB > BB

  10. 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.

  11. QTL’s • Quantitative Trait Loci • Many genes affect quantitative trait • Height, blood pressure, etc. • Long history of mapping • Linkage Curve

  12. 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?

  13. 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?

  14. 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?

  15. 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

  16. 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

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