genomics of host defense against infectious disease€¦ · genomics of host defense against ....
TRANSCRIPT
![Page 1: Genomics of Host Defense Against Infectious Disease€¦ · Genomics of Host Defense Against . Infectious Disease. Humans are genetically diverse. Genes influence disease susceptibility,](https://reader030.vdocuments.us/reader030/viewer/2022041105/5f0660f97e708231d417b2df/html5/thumbnails/1.jpg)
Genomics of Host Defense Against Infectious Disease
Humans are genetically diverse. Genes influence disease susceptibility, immune responses and responses to vaccines and therapy.
Evidence for the heritability of human immune response variation
Identification of genes responsible for immune response variationPrior to genome-wide association studiesUse of genome-wide association studies
Evolutionary biology of human host-pathogen interaction.
Personalized medicine infectious disease (not discussed)
Today’s Lecture:
![Page 2: Genomics of Host Defense Against Infectious Disease€¦ · Genomics of Host Defense Against . Infectious Disease. Humans are genetically diverse. Genes influence disease susceptibility,](https://reader030.vdocuments.us/reader030/viewer/2022041105/5f0660f97e708231d417b2df/html5/thumbnails/2.jpg)
Heritability of Human Immune Response Variation
![Page 3: Genomics of Host Defense Against Infectious Disease€¦ · Genomics of Host Defense Against . Infectious Disease. Humans are genetically diverse. Genes influence disease susceptibility,](https://reader030.vdocuments.us/reader030/viewer/2022041105/5f0660f97e708231d417b2df/html5/thumbnails/3.jpg)
Gregersen and Behrens (2006) Nat Rev Genetics 7: 917
Relative Risk of Autoimmune DiseasesAmong Siblings
![Page 4: Genomics of Host Defense Against Infectious Disease€¦ · Genomics of Host Defense Against . Infectious Disease. Humans are genetically diverse. Genes influence disease susceptibility,](https://reader030.vdocuments.us/reader030/viewer/2022041105/5f0660f97e708231d417b2df/html5/thumbnails/4.jpg)
Genetic Variability of Human Vaccine ResponseIdentical Twin Study
Variations in Antibody Response
Genetic Contribution to Variation
IdenticalNon-Identical
Tan, et al. (2001) Vaccine 19: 2434–2439
![Page 5: Genomics of Host Defense Against Infectious Disease€¦ · Genomics of Host Defense Against . Infectious Disease. Humans are genetically diverse. Genes influence disease susceptibility,](https://reader030.vdocuments.us/reader030/viewer/2022041105/5f0660f97e708231d417b2df/html5/thumbnails/5.jpg)
Do you think genetics plays a greater role in:
> your risk of dying of cancer OR
> your risk of dying of an infection?
What about Risk of Death by Infection?
![Page 6: Genomics of Host Defense Against Infectious Disease€¦ · Genomics of Host Defense Against . Infectious Disease. Humans are genetically diverse. Genes influence disease susceptibility,](https://reader030.vdocuments.us/reader030/viewer/2022041105/5f0660f97e708231d417b2df/html5/thumbnails/6.jpg)
Adoptee’s Relative Risk of Death by Same Cause as Biological Parent(Genetics)
Adoptee’s Relative Risk of Death by Same Cause as Adoptive Parent(Environment)
All Causes 1.71Infections 5.81Cardio- and Cerebrovascular 4.52Cancer 1.19
All Causes ~1.0Infections ~1.0Cardio- and Cerebrovascular 3.02Cancer 5.16
Strong Genetic Contribution to the Relative Risk of Death by Infection
Sørensen, et al. (1988) New Engl J Med 318:727
![Page 7: Genomics of Host Defense Against Infectious Disease€¦ · Genomics of Host Defense Against . Infectious Disease. Humans are genetically diverse. Genes influence disease susceptibility,](https://reader030.vdocuments.us/reader030/viewer/2022041105/5f0660f97e708231d417b2df/html5/thumbnails/7.jpg)
Identification of genes responsible for
immune response variation
![Page 8: Genomics of Host Defense Against Infectious Disease€¦ · Genomics of Host Defense Against . Infectious Disease. Humans are genetically diverse. Genes influence disease susceptibility,](https://reader030.vdocuments.us/reader030/viewer/2022041105/5f0660f97e708231d417b2df/html5/thumbnails/8.jpg)
Manolio, et al. (2008) J Clin Invest 118: 1590
Genetic and Environmental Contributions toMonogenic and Complex Disorders
Major Genetic Determinant Minor Genetic Determinants
Environmental Determinants
![Page 9: Genomics of Host Defense Against Infectious Disease€¦ · Genomics of Host Defense Against . Infectious Disease. Humans are genetically diverse. Genes influence disease susceptibility,](https://reader030.vdocuments.us/reader030/viewer/2022041105/5f0660f97e708231d417b2df/html5/thumbnails/9.jpg)
Mendelian and non-Mendelian diseases
• Geneticists have been very successful in discovering the variations due to Mendelian disorders. These are characterized by in that they follow the Mendelian rules of inheritance.
• The study of particular families using linkage studies has been successful for the Mendelian diseases.
• However, the more common complex (i.e. non-Mendelian) disorders have been much more difficult to investigate, even when there are clear genetic components of the disease. Genes contributing to complex traits may be identified by association studies.
![Page 10: Genomics of Host Defense Against Infectious Disease€¦ · Genomics of Host Defense Against . Infectious Disease. Humans are genetically diverse. Genes influence disease susceptibility,](https://reader030.vdocuments.us/reader030/viewer/2022041105/5f0660f97e708231d417b2df/html5/thumbnails/10.jpg)
Simple Sequence Repeats (SSR): Stretches of 1-6nucleotides repeated in tandem. Slippage of DNApolymerase generates variation in repeat number
Microsatellite: Short tandem repeats that vary innumber among individuals
Common Markers used in Molecular GeneticsCommon Markers used in Molecular Genetics
Single nucleotide polymorphism (SNP): Single basepair differences present in at least 1% of the population
![Page 11: Genomics of Host Defense Against Infectious Disease€¦ · Genomics of Host Defense Against . Infectious Disease. Humans are genetically diverse. Genes influence disease susceptibility,](https://reader030.vdocuments.us/reader030/viewer/2022041105/5f0660f97e708231d417b2df/html5/thumbnails/11.jpg)
Candidate GeneTrial and error
Genome Wide GenotypingNo prior assumptions
Gene-Marker Relationship
![Page 12: Genomics of Host Defense Against Infectious Disease€¦ · Genomics of Host Defense Against . Infectious Disease. Humans are genetically diverse. Genes influence disease susceptibility,](https://reader030.vdocuments.us/reader030/viewer/2022041105/5f0660f97e708231d417b2df/html5/thumbnails/12.jpg)
Poland, et al. (2007) Clin Pharm Therap 82: 653
Interplay between Innate and AcquiredImmune Responses to Measles
![Page 13: Genomics of Host Defense Against Infectious Disease€¦ · Genomics of Host Defense Against . Infectious Disease. Humans are genetically diverse. Genes influence disease susceptibility,](https://reader030.vdocuments.us/reader030/viewer/2022041105/5f0660f97e708231d417b2df/html5/thumbnails/13.jpg)
Examples of Genes Affecting Infectious DiseaseSusceptibility and Resistance
TLR Polymorphisms
Genes Associated with HIV Susceptibility and Progression
HLA and Viral Disease Susceptibility
![Page 14: Genomics of Host Defense Against Infectious Disease€¦ · Genomics of Host Defense Against . Infectious Disease. Humans are genetically diverse. Genes influence disease susceptibility,](https://reader030.vdocuments.us/reader030/viewer/2022041105/5f0660f97e708231d417b2df/html5/thumbnails/14.jpg)
LPS, LipopolysaccharideLTA, Lipoteichoic Acid, LTAPG, Peptidoglycan, PGTLRs, Toll Like ReceptorsNLRs, Nucleotide Binding
Oligomerization Like ReceptorsMyD88, Myeloid Differentiation
Antigen 88, MyD88
Toll Like Receptor Signaling
Boc
hud,
P-Y
., et
al.
(200
7) L
ance
t Inf
ect D
is 7
: 531
-542
![Page 15: Genomics of Host Defense Against Infectious Disease€¦ · Genomics of Host Defense Against . Infectious Disease. Humans are genetically diverse. Genes influence disease susceptibility,](https://reader030.vdocuments.us/reader030/viewer/2022041105/5f0660f97e708231d417b2df/html5/thumbnails/15.jpg)
Bochud, P-Y., et al. (2007) Lancet Infect Dis 7: 531-542
Mutations Affecting Innate Immunity
![Page 16: Genomics of Host Defense Against Infectious Disease€¦ · Genomics of Host Defense Against . Infectious Disease. Humans are genetically diverse. Genes influence disease susceptibility,](https://reader030.vdocuments.us/reader030/viewer/2022041105/5f0660f97e708231d417b2df/html5/thumbnails/16.jpg)
TLR Polymorphisms and Disease
Misch and Hawn (2008) Clinical Science 114: 347-360
![Page 17: Genomics of Host Defense Against Infectious Disease€¦ · Genomics of Host Defense Against . Infectious Disease. Humans are genetically diverse. Genes influence disease susceptibility,](https://reader030.vdocuments.us/reader030/viewer/2022041105/5f0660f97e708231d417b2df/html5/thumbnails/17.jpg)
Genetic Influences on HIV Susceptibility and Progression
Tele
ntia
nd U
. M. Z
ange
r Ann
u. R
ev. P
harm
acol
. Tox
icol
. 200
8. 4
8:22
7-25
6
![Page 18: Genomics of Host Defense Against Infectious Disease€¦ · Genomics of Host Defense Against . Infectious Disease. Humans are genetically diverse. Genes influence disease susceptibility,](https://reader030.vdocuments.us/reader030/viewer/2022041105/5f0660f97e708231d417b2df/html5/thumbnails/18.jpg)
HLA Associations with Viral Infections
Martin and Carrington (2005) Current Opinion in Immunology 17: 510516
A, B & C, Class I, Cytotoxic T cellsD, Class II, Helper T cells
![Page 19: Genomics of Host Defense Against Infectious Disease€¦ · Genomics of Host Defense Against . Infectious Disease. Humans are genetically diverse. Genes influence disease susceptibility,](https://reader030.vdocuments.us/reader030/viewer/2022041105/5f0660f97e708231d417b2df/html5/thumbnails/19.jpg)
Mapping Genetic TraitsBy Genome-Wide Association
Requires:
- Large numbers of genetic markers to cover genome
- Methods to extensively genotype large numbers of people
![Page 20: Genomics of Host Defense Against Infectious Disease€¦ · Genomics of Host Defense Against . Infectious Disease. Humans are genetically diverse. Genes influence disease susceptibility,](https://reader030.vdocuments.us/reader030/viewer/2022041105/5f0660f97e708231d417b2df/html5/thumbnails/20.jpg)
Genetic Linkage and Association
Bochud, P-Y., et al. (2007) Lancet Infect Dis 7: 531-542
![Page 21: Genomics of Host Defense Against Infectious Disease€¦ · Genomics of Host Defense Against . Infectious Disease. Humans are genetically diverse. Genes influence disease susceptibility,](https://reader030.vdocuments.us/reader030/viewer/2022041105/5f0660f97e708231d417b2df/html5/thumbnails/21.jpg)
How many SNPs?
Nickerson and Kruglyak, Nature Genetics, 2001
~ 10 million common SNPs (> 1- 5% MAF) - 1/300 bp
![Page 22: Genomics of Host Defense Against Infectious Disease€¦ · Genomics of Host Defense Against . Infectious Disease. Humans are genetically diverse. Genes influence disease susceptibility,](https://reader030.vdocuments.us/reader030/viewer/2022041105/5f0660f97e708231d417b2df/html5/thumbnails/22.jpg)
Common Genotyping Strategies
Bochud, P-Y., et al. (2007) Lancet Infect Dis 7: 531-542
![Page 23: Genomics of Host Defense Against Infectious Disease€¦ · Genomics of Host Defense Against . Infectious Disease. Humans are genetically diverse. Genes influence disease susceptibility,](https://reader030.vdocuments.us/reader030/viewer/2022041105/5f0660f97e708231d417b2df/html5/thumbnails/23.jpg)
Golden Gate Genotyping (Ilumina, Inc.)Golden Gate Genotyping (Ilumina, Inc.)
Allele-Specific Ligation….Primer Hybridization
to Amplified Genomic DNA
Allows Amplification with One of Two Universal Fluorescent Primer Pairs
Gene-Specific Tags
Direct HybridizationTo Gene-Specific Spots
On Microarray Beads
![Page 24: Genomics of Host Defense Against Infectious Disease€¦ · Genomics of Host Defense Against . Infectious Disease. Humans are genetically diverse. Genes influence disease susceptibility,](https://reader030.vdocuments.us/reader030/viewer/2022041105/5f0660f97e708231d417b2df/html5/thumbnails/24.jpg)
International HapMap project
Feb 2001 - 1.42 million (1/1900 bp)Nov 2003 - 2.0 million (1/1500 bp)Feb 2004 - 3.3 million (1/900 bp)Mar 2005 - 5.0 million (validated - 1/600 bp)
• Provide a collection of millions of SNPs spanning the genome, and serving as genetic markers.
• Study correlations in the inheritance of SNPs (linkage disequilibrium, LD)
• Characterize haplotype blocks• Provide a guide for whole genome association studies
![Page 25: Genomics of Host Defense Against Infectious Disease€¦ · Genomics of Host Defense Against . Infectious Disease. Humans are genetically diverse. Genes influence disease susceptibility,](https://reader030.vdocuments.us/reader030/viewer/2022041105/5f0660f97e708231d417b2df/html5/thumbnails/25.jpg)
Haplotypes and Tag SNPs
In theroy, 6 SNPs would distinguish 26 = 64 different haplotypes, if each is inherited independently of the others. However in this example, just 4 haplotypes comprise 90% of the observed chromosomes. This indicates the presence of linkage disequilibrium.
The SNPs fall into 2 groups (SNPs 1, 2 & 3 and SNPs 4, 5 & 6) such that by knowing nucleotide of any one of the SNPs (known as a Tag SNP) one can predict the sequences of the other SNPs in the group. The use of Tag SNPs and linkage disequilibrium reduces the number of SNPs required for genome-wide association mapping studies.
![Page 26: Genomics of Host Defense Against Infectious Disease€¦ · Genomics of Host Defense Against . Infectious Disease. Humans are genetically diverse. Genes influence disease susceptibility,](https://reader030.vdocuments.us/reader030/viewer/2022041105/5f0660f97e708231d417b2df/html5/thumbnails/26.jpg)
Linkage equilibrium: Loci Aa and Bb are in equilibriumif their transmission probabilities πA and πB are independent
Linkage disequilibrium: Loci linked in transmission, i.e. that are inherited together.
πAB πA πB=
r 2 =(πAB - πA πB )πA πB πa πb
Linkage DisequilibriumLinkage Disequilibrium
![Page 27: Genomics of Host Defense Against Infectious Disease€¦ · Genomics of Host Defense Against . Infectious Disease. Humans are genetically diverse. Genes influence disease susceptibility,](https://reader030.vdocuments.us/reader030/viewer/2022041105/5f0660f97e708231d417b2df/html5/thumbnails/27.jpg)
Haplotype Blocks
![Page 28: Genomics of Host Defense Against Infectious Disease€¦ · Genomics of Host Defense Against . Infectious Disease. Humans are genetically diverse. Genes influence disease susceptibility,](https://reader030.vdocuments.us/reader030/viewer/2022041105/5f0660f97e708231d417b2df/html5/thumbnails/28.jpg)
Recombination Hotspots are Widespread and Account for LD Structure
Recombination Hot SpotsSNPs
![Page 29: Genomics of Host Defense Against Infectious Disease€¦ · Genomics of Host Defense Against . Infectious Disease. Humans are genetically diverse. Genes influence disease susceptibility,](https://reader030.vdocuments.us/reader030/viewer/2022041105/5f0660f97e708231d417b2df/html5/thumbnails/29.jpg)
Ancestral DNA
Non-ancestral DNA
Loss of Linkage (Linkage Disequilibrium) Around a Mutation
Low LD
High LD
![Page 30: Genomics of Host Defense Against Infectious Disease€¦ · Genomics of Host Defense Against . Infectious Disease. Humans are genetically diverse. Genes influence disease susceptibility,](https://reader030.vdocuments.us/reader030/viewer/2022041105/5f0660f97e708231d417b2df/html5/thumbnails/30.jpg)
Distance kB
R2
LD Usually does not Extend Beyond 100 kB
![Page 31: Genomics of Host Defense Against Infectious Disease€¦ · Genomics of Host Defense Against . Infectious Disease. Humans are genetically diverse. Genes influence disease susceptibility,](https://reader030.vdocuments.us/reader030/viewer/2022041105/5f0660f97e708231d417b2df/html5/thumbnails/31.jpg)
Genome-Wide Scan for Allele Frequency Differences Between 2 Control Groups
P values SNP allele frequencies
Test Statistics
Wel
lcom
e Tr
ust C
ase
Con
trol C
onso
rtium
(200
7) N
atur
e 44
7: 6
61
![Page 32: Genomics of Host Defense Against Infectious Disease€¦ · Genomics of Host Defense Against . Infectious Disease. Humans are genetically diverse. Genes influence disease susceptibility,](https://reader030.vdocuments.us/reader030/viewer/2022041105/5f0660f97e708231d417b2df/html5/thumbnails/32.jpg)
Genome-Wide Scan for Allele Frequency Differences By Geographic Region
Wellcome Trust Case Control Consortium (2007) Nature 447: 661
Illustrates Stratification
![Page 33: Genomics of Host Defense Against Infectious Disease€¦ · Genomics of Host Defense Against . Infectious Disease. Humans are genetically diverse. Genes influence disease susceptibility,](https://reader030.vdocuments.us/reader030/viewer/2022041105/5f0660f97e708231d417b2df/html5/thumbnails/33.jpg)
Example of Chromosome Region withStrong Evidence of Geographic Association
Wellcome Trust Case Control Consortium (2007) Nature 447: 661
Geographic Bias may Still be Interesting
![Page 34: Genomics of Host Defense Against Infectious Disease€¦ · Genomics of Host Defense Against . Infectious Disease. Humans are genetically diverse. Genes influence disease susceptibility,](https://reader030.vdocuments.us/reader030/viewer/2022041105/5f0660f97e708231d417b2df/html5/thumbnails/34.jpg)
Genome-Wide Scan for Allele Frequency Differences Associated with Seven Diseases
Wel
lcom
e Tr
ust C
ase
Con
trol C
onso
rtium
(200
7) N
atur
e 44
7: 6
61
![Page 35: Genomics of Host Defense Against Infectious Disease€¦ · Genomics of Host Defense Against . Infectious Disease. Humans are genetically diverse. Genes influence disease susceptibility,](https://reader030.vdocuments.us/reader030/viewer/2022041105/5f0660f97e708231d417b2df/html5/thumbnails/35.jpg)
Examples of Chromosome Regions withStrong Evidence of Disease Association
Note effect of recombination on SNP associationWellcome Trust Case Control Consortium (2007) Nature 447: 661
![Page 36: Genomics of Host Defense Against Infectious Disease€¦ · Genomics of Host Defense Against . Infectious Disease. Humans are genetically diverse. Genes influence disease susceptibility,](https://reader030.vdocuments.us/reader030/viewer/2022041105/5f0660f97e708231d417b2df/html5/thumbnails/36.jpg)
Genome Regions with Strongest Disease AssociationsOdds Ratio
Wellcome Trust Case Control Consortium (2007) Nature 447: 661
![Page 37: Genomics of Host Defense Against Infectious Disease€¦ · Genomics of Host Defense Against . Infectious Disease. Humans are genetically diverse. Genes influence disease susceptibility,](https://reader030.vdocuments.us/reader030/viewer/2022041105/5f0660f97e708231d417b2df/html5/thumbnails/37.jpg)
GW Association: AdmixureH
afle
r and
Dej
ager
(200
5) N
at R
ev Im
mun
ol 5
: 83
![Page 38: Genomics of Host Defense Against Infectious Disease€¦ · Genomics of Host Defense Against . Infectious Disease. Humans are genetically diverse. Genes influence disease susceptibility,](https://reader030.vdocuments.us/reader030/viewer/2022041105/5f0660f97e708231d417b2df/html5/thumbnails/38.jpg)
Genome-Wide SNP Associations with Gene Expression Variation
Genes frequently display variations in expression levels among individuals
Much of the variation is linked to statistically significant associations with SNPs
Most associated SNPs are linked to the differentially expressed gene itself (cis-effects)
Modest differences in gene expression (20%) can be associated with individual SNP alleles.
R2 values for single allele effects on gene expression range from 0.2 to 0.6.
Variations in gene expression also results from sequence copy number variation as assessed by comparative genomic hybridization.
Stranger et al., (2005) Plos Genetics 1: e78
Stranger et al. (2007); Science 315: 848.
Cheung et al. (2005); Nature 437: 1365.
![Page 39: Genomics of Host Defense Against Infectious Disease€¦ · Genomics of Host Defense Against . Infectious Disease. Humans are genetically diverse. Genes influence disease susceptibility,](https://reader030.vdocuments.us/reader030/viewer/2022041105/5f0660f97e708231d417b2df/html5/thumbnails/39.jpg)
SNP Mapping of Gene Expression Variation
Genome AnnotationGene modelsSequence elementsChIP on Chip (Histone Acetyl., etc)
Haplotype Block
Expression
![Page 40: Genomics of Host Defense Against Infectious Disease€¦ · Genomics of Host Defense Against . Infectious Disease. Humans are genetically diverse. Genes influence disease susceptibility,](https://reader030.vdocuments.us/reader030/viewer/2022041105/5f0660f97e708231d417b2df/html5/thumbnails/40.jpg)
Evolutionary Genomics
![Page 41: Genomics of Host Defense Against Infectious Disease€¦ · Genomics of Host Defense Against . Infectious Disease. Humans are genetically diverse. Genes influence disease susceptibility,](https://reader030.vdocuments.us/reader030/viewer/2022041105/5f0660f97e708231d417b2df/html5/thumbnails/41.jpg)
Epidemic Disease inNew World Following
European ContactMortality from infectious disease (e.g. smallpox, measles, influenza, etc.) contributing to declines of 80-95% among indigenous peoples.
The concept of innate susceptibility is controversial due to complex interplay among genetic, epidemiologic, and socio-environmental factors and difficulties estimating pre-contact population sizes. Academic jealousies, politics and turf wars add to the fun.
Innate susceptibility implies rapid evolution between the time of common ancestry and renewed contact (10- 20,000 years).
Brazilian Shaman, 1578. Noble David Cook. Born to Die. Cambridge University Press, 1998, page 119.
![Page 42: Genomics of Host Defense Against Infectious Disease€¦ · Genomics of Host Defense Against . Infectious Disease. Humans are genetically diverse. Genes influence disease susceptibility,](https://reader030.vdocuments.us/reader030/viewer/2022041105/5f0660f97e708231d417b2df/html5/thumbnails/42.jpg)
Recent Acceleration of HumanAdaptive Evolution
High Linkage DisequilibriumAround Selected Alleles
Age Distribution of Ascertained Selected Alleles
Wang E. T. et.al. PNAS 2006;103:135-140 Hawks J. et.al. PNAS 2007;104: 2053-2058
![Page 43: Genomics of Host Defense Against Infectious Disease€¦ · Genomics of Host Defense Against . Infectious Disease. Humans are genetically diverse. Genes influence disease susceptibility,](https://reader030.vdocuments.us/reader030/viewer/2022041105/5f0660f97e708231d417b2df/html5/thumbnails/43.jpg)
Lethal Response to 1918 Flu
Loo and Gale (2007) Nature 445: 267
In such cases, strong selectionagainst immune responses