Chromatin States: A quantitative genetics perspectivetommy/I-CORE-0115/Gat-Viks -...
Transcript of Chromatin States: A quantitative genetics perspectivetommy/I-CORE-0115/Gat-Viks -...
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Chromatin States:
A quantitative genetics perspective
Irit Gat-ViksDepartment of Cell research and Immunology
Life Sciences, Tel-Aviv University
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Finding genes influencing a disease
The genetic basis of disease
Natural Polymorphisms
... ATGATCGATACTCGATAACCCGA ...
... ATGATCGATACGCGATAACCCGA ...
Experimental Perturbations
Knockdown mice
Phenotype SNP
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Genetic variantGenetic variant Complex phenotypeComplex phenotypeGenome-wide association
studies (GWAS)
Exploit natural polymorphisms to understand disease
mechanisms
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NHGRI GWA Catalog
www.genome.gov/GWAStudies
Before 2012 Today:
>1900 GWAS publications
> 1000 susceptibility loci
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Association study for a quantitative trait
individuals
Trait
Association
score
Genomic position
Genomic position
Haplotype b
Haplotype B
Predicted variant
(QTL)
Individuals
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AA GA
phen
oty
pe
QTL analysis: Standard linear models
t-test
genotype
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QTL analysis: Standard linear models
1.ANOVA model
- Phenotype of j-th individual of marker genotype i
- Effect of marker i
- Residual error: the deviation of the jth individual from the expected value of the ith marker, E(eij)=0. Var(eij)=σ2
The presence of a linked QTL is indicated by a significant between-marker variance
ijiij ex += µijx
iµije
2. Multiple regression model
- Phenotype of jth individual
- Indicator variables (one for each marker genotype)
- Residual error
The presence of a linked QTL is indicated by a significant fraction of character variance accounted for by the marker genotype
jij
n
i
ij egbx ++= ∑=1
µ
jx
ijg
je
=otherwise0
i genotypemarker has j individual if1ijg
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Manhatten plot
Risk Alleles for Multiple Sclerosis
MHC region
N Engl J Med 2007
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A quantitative genetics perspective
Histone
marks
Gene
expressionChromatin
accessibility
genetics
TF-DNA
binding
Physiological
phenotype &
disease
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Constructing regulatory elements maps using
epigenomic profiling
For example, revealing enhancers:
• The locations of enhancer elements coincide with DNase I
hypersensitive regions of open chromatin flanked by
nucleosomes marked with H3K4me1/2.
• H3K27ac and H4K16ac are associated with active chromatin.
• H3K27me3 and H3K9me3 are associated with repressed
chromatin.
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Genetic risk variants Regulatory elements maps
Epigenomic profiling
Phenotyping + Genotyping
GWAS
• Loci with enhancer features (H3K4me1, H3K27ac) are
highly enriched for risk variants
• Risk variants preferentially map to enhancers specific to
disease-relevant cell types (e.g., colon cancer predisposition
variants)
Interpreting susceptibility loci using epigenomic profiling
Corradin et al. genome medicine 2014
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Enrichment of genome-wide association study variants
in putative enhancer elements
The challenge: what is the role of non-coding variants in
gene expression?
Corradin et al. genome medicine 2014
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Non-coding
variant
Non-coding
variantComplex
phenotype
Complex
phenotype
Genome-wide association
studies (GWAS)
Understand the role of non-coding variants in
gene expression
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Gene
expression
Gene
expressionGWASNon-coding
variant
Non-coding
variantComplex
phenotype
Complex
phenotype
Understand the role of non-coding variants in
gene expression
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Gene
expression
Gene
expressionGWASNon-coding
variant
Non-coding
variant
Understand the role of non-coding variants in
gene expression
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individuals
Gene expression
trait
Association
score
Genomic position
Genomic position
Haplotype b
Haplotype B
Predicted variant
(QTL)
Individuals
expression QTL (eQTL)
Understand the role of non-coding variants in
gene expression
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Gene
expression
Gene
expressionGWASNon-coding
variant
Non-coding
variant
Understand the role of non-coding variants in
gene expression
Mechanism
?
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Understanding the role of variants in gene expression
based on their genomic positions
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Understanding the role of variants in gene expression
based on their genomic positions
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Cis-acting eQTL Trans-acting eQTL
Understanding the role of variants in gene expression
based on their genomic positions
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Gene
expression
Gene
expression
Cis - eQTLs
The challenge: eQTL analysis cannot reveal the
complete functional mechanism by which non-coding
variants influence gene expression
Non-coding
variant
Non-coding
variantTrans - eQTLs
Determine the mechanisms by which regulatory
variants affect gene expression
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Determine the mechanisms by which regulatory
variants affect gene expression
Gene
expression
Gene
expression
TF binding,
Non-coding
variant
Non-coding
variantMolecular
phenotypes
Molecular
phenotypes
Histone marks,
DNase I sensitivity
Cis-eQTL
Trans-eQTL
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Association study for a quantitative trait
individuals
Association
score
Genomic position
Genomic position
Haplotype b
Haplotype B
Predicted variant
(QTL)
Individuals
Traits
• Gene expression traits
• Open chromatin traits
• Histone modification traits
• Cis-association
• Trans-association
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Example 1: Genetic landscape of open chromatin in
yeast
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Example 1: Genetic landscape of open chromatin in
yeast
FAIRE-seq
Identify open chromatin peaks (OCRs)
For each peak: QTL analysis of OCR traits
OCR Trait = density of peak
Lee et al. PLOS Genetics 2013
Broader peaks of naked
DNA compared to DHS-seq
and ATAC-seq
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Association study for an open chromatin trait
individuals
Trait
Association
score
Genomic position
Genomic position
Haplotype b
Haplotype B
Predicted variant
(QTL)
Individuals
OCR Trait = density of
open chromatin peak
Lee et al. PLOS Genetics 2013
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Characterization of cis-associations
Lee et al. PLOS Genetics 2013
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Characterization of trans-associations
Lee et al. PLOS Genetics 2013
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Example 2:
Integrate genetics + histone marks + expression traits
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Gene
expressionHaplotypeHistone mark
Integrate genetics + histone marks + expression traits
Johannes et al. Nature Reviews Genetics 2008
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Integrate genetics + histone marks + expression traits
Johannes et al. Nature Reviews Genetics 2008
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Sequence
dependent
Sequence
independent
Integrate genetics + histone marks + expression traits
Relationships between
histone marks and gene
expression
Johannes et al. Nature Reviews Genetics 2008
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SNP expr
SNP
expr
SNP exprEpi-
variant
Epi-
variant
Epi-
variant
Sequence
dependent
Integrate genetics + histone marks + expression traits
Johannes et al. Nature Reviews Genetics 2008
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Inferring causal relations
L R C L C R L
C
R
M1 M2 M3
L - SNP
R – epi-variant
C – expression
Schadt et al. Nature Genetics 2005
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The likelihood for each model over all individuals in
the population of interest are given by:
)|();( MdatapMLfunctionlikelihood θθ ==
)|()|()()|,,( 11 iiiii
n
iM RCPLRPLPCRLP ⋅⋅∏= =θ
)|()|()()|,,( 12 iiiii
n
iM CRPLCPLPCRLP ⋅⋅∏= =θ
)|()|()()|,,( 11 iiiii
n
iM LCPLRPLPCRLP ⋅⋅∏= =θ
SNP expr
SNP
expr
SNP exprEpi-
variant
Epi-
variant
Epi-
variant
Schadt et al. Nature Genetics 2005
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Rintish et al. 2014; 30 Rat BXH/BXB strains, liver and heart
• 18.1% and 14.5% of all H3K4me3 and H3K27me3 QTLs were also eQTL.
• 20% of all eQTL were also QTL for a histone mark.
Degner et al. (2012), 70 Yoruba lymphoblastoid cell lines
•16% of DNase I sensitivity QTL (dsQTL) were also eQTL
•23% of eQTL were also dsQTL
Integrate genetics + histone marks + expression traits
SNP expr
Epi-
variant
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Genetic landscape of histone modifications in
rat liver and heart
Rintisch et al. Genome research 2014
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Rintisch et al. Genome research 2014
Cbln1 Pparg
Integrate genetics + histone marks + expression traits
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Rintisch et al. Genome research 2014
Dpysl5
Integrate genetics + histone marks + expression traits
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Example 3: Revealing functionally linked modifications
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McVicker et al. (Pritchard & Gilad labs) Science 2013
Coordinated change in histone marks along ~2kb regions
Lymphoblastoid cell lines (LCLs)
from 70 Yoruba (Nigeria)
individuals
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Revealing functionally linked modifications,
depending on the same genetic element
Correlation in allelic imbalance between histone marks at
DNase I sensitive QTL sites (dsQTLs)
McVicker et al. Science 2013
1 individual
1 active region
∆2∆1
∆2
∆1Allelic
imbalance
@marker 1
Allelic imbalance
@marker 2
1 individual
1 active region
1 individual
1 regionmarker 2marker 1
<2kb
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McVicker et al. Science 2013
Allelic imbalance across DNase I sensitivity QTLs and eQTLs
>5kb
DNase I
sensitivity QTL
Possibly
reflecting the 3D
organization of
the chromatin
Coordinated change in histone marks between
distal (>5kb) regions
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McVicker et al. Science 2013
Coordinated change in histone marks between
distal (>5kb) regions
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Coordinated change in histone marks between
distal regions
McVicker et al. Science 2013
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Coordinated change in histone marks between
distal regions
McVicker et al. Science 2013
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Example 4: Reveal the function of chromatin states
in complex physiological traits
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Gene
expression
Gene
expression
TF binding,
Non-coding
variant
Non-coding
variantMolecular
phenotypes
Molecular
phenotypes
Histone marks,
Chromatin state
Example 4: Reveal the function of chromatin states
in complex physiological traits
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Gene
expression
Gene
expression
TF binding,
Non-coding
variant
Non-coding
variantMolecular
phenotypes
Molecular
phenotypes
Histone marks,
Chromatin state
Complex
phenotype
Complex
phenotype
Example 4: Reveal the function of chromatin states
in complex physiological traits
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•Genetic variants linked to eight genes in humans are
significantly associated with blond hair color in Europeans.
•Some variants alter the coding regions of genes known to
be involved in pigmentation.
•Some variants map outside the protein-coding regions of
pigmentation genes.
A molecular basis for classic blond hair color in
Europeans
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• Encodes a secreted ligand for the KIT receptor tyrosine kinase
and has an essential role in the development, differentiation
and pigmentation.
The Human KITLG gene (mouse Kitl)
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Guenther et al. Nature Genetics 2014
• A noncoding SNP (rs12821256) located over 350 kb upstream of
KITLG is significantly associated with blond hair color in Iceland and
The Netherlands.
• The blond-associated A>G substitution at this position is prevalent
in northern European populations but virtually absent in African and
Asian populations
The Human KITLG gene (mouse Kitl)
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Guenther et al. Nature Genetics 2014
Large inversion
Displacement of a single copy of the distant upstream
regulatory sequences for Kitl is sufficient to reduce Kitl
expression and lighten hair color.
An inversion spanning the noncoding SNP
rs12821256
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Guenther et al. Nature Genetics 2014
Searching for the functional enhancer
Five human fragments were cloned upstream of a lacZ reporter
gene and tested for in vivo enhancer activity in transgenic mice.
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Guenther et al. Nature Genetics 2014
rs12821256 alters a TCF/LEF binding site and
reduces LEF responsiveness in keratinocytes
TCF ChIP-Seq
reads from the
ENCODE project
The sequence surrounding
rs12821256 resembles a
consensus TCF/LEF
binding motif
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Guenther et al. Nature Genetics 2014
rs12821256 alters a TCF/LEF binding site and
reduces LEF responsiveness in keratinocytes
(consensus)(A)(G)
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Mouse lines differing at a single base-pair position in
the KITLG enhancer show differences in hair color
Guenther et al. Nature Genetics 2014
Matched lines of
site-specific
integration in
transgenic mice
Small (20%) quantitative changes in enhancer activity were
sufficient to alter hair color in vivo
no enhancer blond-
variant
ancestral -
variant
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The molecular basis of disease
Histone
marks
Gene
expressionChromatin
conformation
genetics
TF-DNA
binding
Physiological
phenotype &
disease
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Utilizing genetics to understand
transcriptional circuitry and the regulatory conformation
of the genome
- Interpreting susceptibility loci using epigenomic profiling
- Revealing susceptibility loci that impact the chromatin landscape: Which genetic variants determine histonemarks, open chromatin and TF binding?
- Reveal functionally linked histone marks between nearby or distal regions
- Reveal chromatin regulators
- Reveal the function of chromatin states in common disease
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Thank you!