Recombination breakpoints Family Inheritance Me vs. my brother My dad (my Y)Mom’s dad (uncle’s Y) Human ancestry Disease risk Genomics: Regions  mechanisms  drugsSystems: genes  combinations  pathways What is possible with personal genotyping/sequencing Dad’s mom (his X) (my X)

Challenge: interpreting disease-associated variants CATGACTG CATGCCTG 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, motifs Compare 29 mammals Protein-codingNon-coding MicroRNA RNA structure Regulatory motifs Increased conservation pinpoints functional regions Distinct patterns of change distinguish different functions Mutations in conserved regions more likely disease-associated Disease SNP disrupts a conserved regulatory motif  disrupts binding X

Chromatin signatures reveal regulatory regions and networks 2. Histone modifications 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