Upload
christopher-norton
View
217
Download
0
Tags:
Embed Size (px)
Citation preview
Recombination breakpointsFa
mily
Inhe
ritan
ce
Me vs. my brother
My dad (my Y) Mom’s dad(uncle’s Y)
Hum
an a
nces
try
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