selection regulation epigenomics disease Manolis Kellis MIT Computer Science amp Artificial Intelligence Laboratory Broad Institute of MIT and Harvard Goal A systemslevel understanding of genomes and gene regulation ID: 781156
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Slide1
Computational personal genomics: selection, regulation, epigenomics, disease
Manolis Kellis
MIT Computer Science & Artificial Intelligence Laboratory
Broad Institute of MIT and Harvard
Slide2Goal: A systems-level understanding of genomes and gene regulation:
The regulators
: Transcription factors, microRNAs, sequence specificities
The regions
: enhancers, promoters, and their tissue-specificity
The targets: TFstargets,
regulators
enhancers, enhancersgenes
The grammars
: Interplay of multiple TFs
prediction of gene expression The parts list = Building blocks of gene regulatory networks
CATGACTG
CATG
C
CTG
Disease-associatedvariant (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)
Understanding human variation and human disease
Challenge: from loci to mechanism, pathways, drug targets
Slide3Compare 29 mammals: Reveal constrained positionsReveal individual transcription factor binding sitesWithin motif instances reveal position-specific biasMore species: motif consensus directly revealed
NRSF
motif
Slide4Chromatin state dynamics across nine cell typesSingle annotation track for each cell typeSummarize cell-type activity at a glanceCan study 9-cell activity pattern across
Correlated
activity
Predicted
linking
Slide5xx
Disease-associated SNPs enriched for enhancers in relevant cell typesE.g. lupus SNP in
GM enhancer disrupts Ets1 predicted activator
Revisiting disease-
associated variants
Slide6HaploReg: Automate search for any disease study(compbio.mit.edu/HaploReg)
Start with any list of SNPs or select a GWA studyMine publically available ENCODE data for significant hitsHundreds of assays, dozens of cells, conservation, motifs
Report significant overlaps and link to info/browser
Slide7Experimental dissection of regulatory motifsfor 10,000s of human enhancers
54000+ measurements (x2 cells, 2x repl)
Slide8Example activator: conserved HNF4 motif match
WT expression
specific to HepG2
Non-disruptive changes maintain expression
Motif match disruptions reduce expression to background
Random changes depend on effect to motif match
Slide9Allele-specific chromatin marks: cis-vs-trans effectsMaternal and paternal GM12878 genomes sequencedMap reads to phased genome, handle SNPs indelsCorrelate activity changes with sequence differences
Slide10Brain methylation in 750 Alzheimer patients/controls
500,000
methylation
probes
750 individuals
10+ years of cognitive evaluations, post-mortem brains
93% of functional epigenomic variation is genotype driven!
Global repression in 7,000 enhancers, brain-specific targets
Phil de Jager, Roadmap disease epigenomics
Brad Bernstein
REMC mapping
Genome
Epigenome
meQTL
Phenotype
Epigenome
Classification
MWAS
1
2
Slide11Global hyper-methylation in 1000s of AD-associated loci
Alzheimer’s-associated probes are hypermethylated
480,000 probes, ranked by Alzheimer’s association
P-value
Methylation
Top 7000 probes
Global effect across 1000s of probes
Rank all probes by Alzheimer’s association
7000 probes increase methylation (repressed)
Enriched in brain-specific enhancers
Near motifs of brain-specific regulators
Complex disease: genome-wide effects
Slide12Covers computational challenges associated with personal genomics:- genotype phasing and
haplotype reconstruction resolve mom/dad chromosomes- exploiting
linkage for variant imputation co-inheritance patterns in human population
- ancestry painting for admixed genomes result of human migration patterns
- predicting likely causal variants
using functional genomics from regions to mechanism- comparative genomics annotation of coding/non-coding elements
gene regulation- relating regulatory variation to gene expression or
chromatin quantitative trait loci- measuring recent evolution and human selection
selective pressure shaped our genome
- using
systems/network information to decipher weak contributions combinatorics- challenge of complex multi-genic traits: height, diabetes, Alzheimer's
1000s of genes
Slide13Recombination breakpoints
Family Inheritance
Me vs.
my brother
My dad
Dad’s mom
Mom’s dad
Human ancestry
Disease risk
Genomics:
Regions
mechanisms
drugs
Systems
: genes
combinations pathways
Personal genomics today: 23 and We
Slide14Personal genomics tomorrow: Already 100,000s of complete genomesHealth, disease, quantitative traits: Genomics regions
disease mechanism, drug targetsProtein-coding cracking regulatory code, variation
Single genes systems, gene interactions, pathwaysHuman ancestry: Resolve all of human ancestral relationships
Complete history of all migrations, selective eventsResolve common inheritance vs. trait associationWhat’s missing is the computationNew algorithms, machine learning, dimensionality reduction
Individualized treatment from 1000s genes, genomeUnderstand missing heritability
Reveal co-evolution between genes/elementsCorrect for modulating effects in GWAS
Slide15Collaborators and AcknowledgementsChromatin state dynamicsBrad Bernstein, ENCODE consortiumMethylation in Alzheimer’s diseasePhil de Jager, Brad Bernstein, Epigenome Roadmap
Mammalian comparative genomicsKerstin Lindblad-Toh, Eric Lander, 29 mammals consortium
Massively parallel enhancer reporter assaysTarjei Mikkelsen, Broad InstituteFunding
NHGRI, NIH, NSFSloan Foundation
Slide16Daniel
Marbach
Mike Lin
Jason
Ernst
Jessica
Wu
Rachel
Sealfon
Pouya
Kheradpour
Manolis
Kellis
Chris
Bristow
Loyal
Goff
Irwin
Jungreis
MIT Computational Biology group
Compbio.mit.edu
SushmitaRoy
Luke WardStata4
Stata3Louisa
DiStefanoDave
Hendrix
Angela
Yen
Ben
Holmes
Soheil
Feizi
Mukul
Bansal
Bob
Altshuler
Stefan
Washietl
Matt
Eaton
Slide17Human constraint outside conserved regionsNon-conserved regions: ENCODE-active regions show reduced diversity Lineage-specific constraint in biochemically-active regions
Conserved regions:
Non-ENCODE regions show increased diversity
Loss of constraint in human when biochemically-inactive
Average
diversity
(heterozygosity)
Aggregate over
the genome
Active regions
Ward and Kellis,
Science 2012