Recombination breakpointsFa

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Me vs. my brother

My dad (my Y) Mom’s dad(uncle’s Y)

Hum

an a

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Dis

ease

risk

Genomics: Regions mechanisms drugs Systems: genes combinations pathways

What is possible with personal genotyping/sequencing

Dad’s mom (his X) (my X)

Challenge: interpreting disease-associated variants

CATGACTGCATGCCTG

Disease-associated

variant (SNP/CNV/…)

Gene annotation

(Coding, 5’/3’UTR, RNAs) Evolutionary signatures

Non-coding annotation

Chromatin signatures

Roles in gene/chromatin regulation

Activator/repressor signatures

Other evidence of function

Signatures of selection (sp/pop)

Ability to predict causal effect of every nucleotide mutation in context• The regulators: Transcription factors, microRNAs, sequence specificities• The regions: enhancers, promoters, and their tissue-specificity• The targets: regulators enhancers/promoters motifs target genes• The grammars: Interplay of multiple TFs prediction of gene expression

The parts list = Building blocks of gene regulatory networks

Requires: Systematic understanding of human genome

Evolutionary signatures reveal genes, RNAs, motifsCompare 29 mammals

Protein-coding Non-coding

MicroRNA

RNA structure

Regulatory motifs

Increased conservation pinpoints functional regions

Distinct patterns of changedistinguish different functions

Mutations in conserved regionsmore likely disease-associated

Disease SNP disrupts a conservedregulatory motif disrupts binding

X

Chromatin signatures reveal regulatory regions and networks

2. Histonemodifications

3. DNA accessibility

1. DNA methylation

Epigenomic maps

Correlated activity: predict links

xx

• Disease-associated SNPs enriched for enhancers in relevant cell types• E.g. lupus SNP in GM enhancer disrupts Ets1 predicted activator

Revisiting disease- associated variants