Family Inheritance Me vs my brother My dad my Y Moms dad uncles Y Human ancestry Disease risk Genomics Regions mechanisms drugs Systems genes combinations pathways ID: 474953
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Slide1
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
drugs
Systems
: genes
combinations pathways
What is possible with personal genotyping/sequencing
Dad’s
mom (his X)
(
my X)Slide2
Challenge: interpreting disease-associated variants
CATGACTG
CATG
C
CTG
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-specificityThe targets: regulators
enhancers/promoters motifs target genesThe grammars: Interplay of multiple TFs prediction of gene expression
The parts list = Building blocks of gene regulatory networks
Requires:
Systematic understanding of human genomeSlide3
Evolutionary signatures reveal genes, RNAs, motifs
Compare 29 mammals
Protein-coding
Non-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
XSlide4
Chromatin signatures reveal regulatory regions and networks
2. Histone
modifications
3. DNA accessibility
1. DNA methylation
Epigenomic maps
Correlated
activity: predict linksSlide5
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