ECON 546 Lecture Notes - Lecture 11: Box Plot, Wfs1, Brachydactyly
27 Jun 2018
School
Department
Course
Professor
BIOL 568 - Najafabadi L11: 13/2/18
L11: Regulatory variation and human diseases
Determinants of complex human traits:
oGenetic factor + Non-genetic factors (env) cell function & behaviour phenotype
Genetic determinants of traits:
oGWAS Crohn’s Disease – hit region on Chr 5.
oThere is a group of SNPs associated with the disease as opposed to just one due to linkage
disequilibrium. Only one SNP is actually causal.
oMajority of GWAS hits are not associated with protein change – very low proportions of SNPs
actually cause nonsynonymous substitutions.
oE.g. most of the SNPs that affect LDL cholesterol are synonymous – do not affect AA
sequence.
oInstead, affect regulatory sequences.
Genetic determinants of gene expression:
oGenetic variants affect gene regulation.
oLook at phenotype
oMacroscopic phenotype – can tell phenotype easily, visually or by clinical test.
oQTL for higher-order traits
oMicroscopic/molecular phenotypes – the expression of the gene
oeQTL (expression QTL) e.g. splicing
eQTLs (eQTL SNPs) affect various aspects of gene regulation:
oEpigenetic modifications
oTranscription initiation and elongation – binding of TF, recruitment of Pol II etc.
oPre-mRNA processing (e.g. alternative splicing)
oPost-transcriptional processing & mRNA stability
oPost-transcriptional processing & translation rate
Cis-eQTLs vs. trans-eQTLs:
oCis = SNP affects expression of gene that is close to the SNP
e.g. promoter, upstream enhancer
oTrans = SNP affects expression of gene that is distal to the
SNP, very far away on same chromosome or on a different
chromosome
oDifferent mechanisms of action
Cis-eQTLs:
oAffect binding of TF – sequence-specific
1
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Document Summary
Determinants of complex human traits: genetic factor + non-genetic factors (env) cell function & behaviour phenotype. Genetic determinants of traits: gwas crohn"s disease hit region on chr 5, there is a group of snps associated with the disease as opposed to just one due to linkage disequilibrium. Cis-eqtls vs. trans-eqtls: cis = snp affects expression of gene that is close to the snp e. g. promoter, upstream enhancer, trans = snp affects expression of gene that is distal to the. Snp, very far away on same chromosome or on a different chromosome: different mechanisms of action. Cis-eqtls: affect binding of tf sequence-specific. When c allele, tf can bind high expression of gene: when g allele, it cannot bind low expression of gene. Trans-eqtls: snp affects expression of tf, which in turn affects expression of other genes, snp in promoter of tf.
