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Author(s): David Ginsburg, 2009
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Learning Objectives
UNDERSTAND: • The basic anatomy of the human genome [eg. 3 X109 bp (haploid
genome); 1-2% coding sequence (~20,000 genes); types and extent of DNA sequence variation].
• Recombination and how it allows genes to be mapped • Genetic data for a pedigree, assigning phase, defining haplotypes• Linkage: Use of markers linked to a disease gene for genetic
diagnosis and to identify disease genes (positional cloning)• Distinction between a linked marker and the disease causing
mutation itself• Linkage disequilibrium and haplotype blocks• Genome wide association studies (GWAS) to identify gene variants
contributing to complex diseases/traits
DNA Sequence Variation
• DNA Sequence Variation:– Human to human: ~0.1% (1:1000 bp)
• Human genome = 3X109 bp X 0.1% =~3X106 DNA common variants
– Human to chimp: ~1-2%– More common in “junk” DNA: introns, intergenic regions
• poly·mor·phismPronunciation: "päl-i-'mor-"fiz-&mFunction: noun: the quality or state of existing in or assuming different forms: as a (1) : existence of a species in several forms independent of the variations of sex (2) : existence of a gene in several allelic forms (3) : existence of a molecule (as an enzyme) in several forms in a single species
IV
III
II
I
a/b b/b b/b a/b a/b b/b a/b a/b b/b
b/ba/aa/ba/a
a/b a/ba/b
b/bb/ba/ba/b
a/a
B.
Heteromorphismof chromosome 1
(one copy)
2 normal copiesof chromosome 1
a or b allele of Duffy blood group
Donahue, 1968
Gelehrter, Collins and Ginsburg: Principles of Medical Genetics 2E; Figure 9.1
I
II
III
B.
I
II
III
A.+ -
++ -
+ - -
-
+
- +
+ + -
-
1 2
1 2 3 4 5 6 7
1 2 3 4 5 6 7
1 2
1 2 3 4 5 6 7
1 2 3 4 5 6 7
Se/se se/se
Se/se Se/se se/se
se/se se/seSe/Seor
Se/se
se/se
Se/se
se/se
Se/se Se/se
Se/se se/se
se/se
= Myotonic Dystrophy
+ = Secretor Phenotype (Se/Se or Se/se)
Gelehrter, Collins and Ginsburg: Principles of Medical Genetics 2E; Figure 9.4
Gelehrter, Collins and Ginsburg: Principles of Medical Genetics 2E; Figure 9.4
A A
B B
a a
b b
A A
B B
a a
b b
A A
B B
a a
b b
A A a a
B b B b
LOCIFAR APART
A AB B
a ab b
B B b b
B Bb b
B b B b
LOCICLOSE TOGETHER
A A a a
A Aa a
A Aa a
RECOMBINANTS
MEIOSIS I
Linkage: A/a and B/b tend to be inherited together
the A and B loci are linked.
Key Concepts: Linkage and Recombination
Gelehrter, Collins and Ginsburg: Principles of Medical Genetics 2E; Figure 9.2
I
II
A
D N
a A A
N N
A
N
A
DN
a A
N N
a A
N
a
D
A
N N
a A
N
A
N
A
N
A
D
A
D
7654321
1 2
Marker= A or aDisease allele = DNormal allele = N
Linkage between Marker A/a and Disease D
Gelehrter, Collins and Ginsburg: Principles of Medical Genetics 2E; Figure 9.3
I
II
III
1 2
1 2 3
4.7 kb
3.0 kb
5 64 7 8 9
1 2 3 4 5 6 7 8 9
3.0 kb= NEUROFIBROMATOSIS (NF1)
1.7 kbEcoRI
*PROBE
EcoRI EcoRI
recombinant
Linkage between NF and RFLP marker
Gelehrter, Collins and Ginsburg: Principles of Medical Genetics 2E; Figure 9.5
3.5
3.0
2.5
2.0
1.5
1.0
0.5
00.05 0.10 0.15 0.20 0.25 0.30 0.35 0.40
=
LOD
0
0.05
3.16
0.15
2.86
0.20
2.57
0.3
1.82
0.4
0.89
0.10
3.08
Z
3.165
0.059
LOD
Gelehrter, Collins and Ginsburg: Principles of Medical Genetics 2E; Figure 9.6
DISEASE
FUNCTION
GENE
MAP
DISEASE
FUNCTION
GENE
MAP
FUNCTIONAL CLONING POSITIONAL CLONING
Gelehrter, Collins and Ginsburg: Principles of Medical Genetics 2E; Figure 9.15
I
II
III
IV
V
AD AA AA AA AB AA AC AB AB AB AB AA AA AA CD BC AC AC CD AA AA AA AB
ACAAACACACABACACCDACACACACACACACAACCCCCCCCACACCCACCCBCACBCACACABAAADAAAA
AA AC AC AB BC BC
HD linked to C allele: Single recombinant (IV1)
Gusella, et al. A polymorphic DNA marker genetically linked to Huntington's disease. Nature 306:234-238, 1983.
The Huntington's Disease Collaborative Research Group. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. Cell 72:971-983, 1993.
Gelehrter, Collins and Ginsburg: Principles of Medical Genetics 2E; Figure 9.26
Positional Cloning
GENETIC MARKERS
FAMILIES
MUTATION IDENTIFICATION
FINE GENETIC MAPPING
MUTATION SEARCH
PhysicalMapping
andCloning
YACs andBACs
TranscriptIdentification
CytogenicAbnormality
Positional CandidateApproach
Gelehrter, Collins and Ginsburg: Principles of Medical Genetics 2E; Figure 9.31
Positional Cloning Approach
Image of positional cloning
procedure removed
Gelehrter, Collins and Ginsburg: Principles of Medical Genetics 2E
Types of DNA Sequence Variation• RFLP: Restriction Fragment Length Polymorphism• VNTR: Variable Number of Tandem Repeats
– or minisatellite– ~10-100 bp core unit
• SSR : Simple Sequence Repeat – or STR (simple tandem repeat) – or microsatellite– ~1-5 bp core unit
• SNP: Single Nucleotide Polymorphism– Commonly used to also include rare variants
• Insertions or deletions– INDEL – small (few nucleotides) insertion or deletion
• Rearrangement (inversion, duplication, complex rearrangement)
• CNV: Copy Number Variation
SNP
• Most are “silent”• Intragenic• Promoters and other regulatory sequences• Introns• Exons
– 5’ and 3’ untranslated regions– Coding sequence (~1-2% of genome)
Allele 1Allele 1 A U G A A G U U U G G C G C A U U G A AC
Allele 2Allele 2 A U G A A G U U U G G U G C A U U G A AC
Adapted from ASCO teaching slides
Human Chromosome 4
2008
• 17,999,889 total entries in dbSNP
http://www.ncbi.nlm.nih.gov/projects/SNP/
• Chromosome 4– 1,183,767 SNPs
• ~1M SNP chip commercially available
1981 1991 1994 1996
3 markers 53 markers 393 markers 791 markersGelehrter, Collins and Ginsburg: Principles of Medical Genetics 2E; Figure 10.3
1 Mb
10 Mb
100 Mb
1 Gb
10 Gb
100 Gb
1000 Gb
1985 1990 1995 2000 2005 2010
Year
Bas
e P
airs
in G
enb
ank
Source Undetermined
Haploid Human Genome 3 X 109 bp, ~20,000 genes
1 Chromosome~1300 genes
Single Gene~1.5 Kb (Globin to
2 X 106 bp (Dystrophin)
H. Influenzae~1700 genes
S. Cerevisiae~6250 genes D. Melanogaster
~14000 genesC. Elegans
~18500 genesU.S. Federal Government (wikimedia)Andre Karwath (wikipedia)
Source Undetermined
Genomes
• >1000 viruses• >100 microbes• Plants (arabidopsis, oat, soybean,
barley, wheat, rice, tomato, corn)• Yeast, fly, worm, human, mouse, rat,
zebrafish, mosquito, malaria, ciona • Cow, pig, frog, chimp, gorilla, dog,
chicken, cat, bee
The Human Genome
23 pairs of chromosomes made of 3 billion base pairs
30%70%
~20,000 genes~20,000 genesExtragenic DNAExtragenic DNA
Repetitive Repetitive sequencessequences
Control regionsControl regions Spacer DNA Spacer DNA
between genesbetween genes Function mostly Function mostly
unknownunknown
Source Undetermined
Characteristics of the Human Genome Sequence
• 99% of euchromatin is covered, 2.85 Gb• Error rate: <<1:100,000 bp• <350 unclonable gaps• All data is freely accessible without restriction• Humans have fewer genes than expected
– ~20,000 from prev. estimates of 100,000)– ? human genes make more proteins
• ~1-2% of genome = coding sequences• ~1% = highly conserved noncoding sequences
Positional Cloning Approach
Image of positional cloning
procedure removed
Gelehrter, Collins and Ginsburg: Principles of Medical Genetics 2E
Family B
11338121
71432541
21431842
31353242
21431842
11338121
31353242
11338121
21353242
11338121
31353242
71432541
11338541
1133-121
11338121
1 2
0.67 0.57
1 2 3 4 5 6 7
0.06 0.02 0.63 0.60 0.97 0.45 0.64II
I
31431842
31184432
2135-242
D9S1776D9S1682D9S1863GL1-3GL2-1D9S164D9S1818D9S1826
D9S1776D9S1682D9S1863GL1-3GL2-1D9S164D9S1818D9S1826
33365423
31243333
43455244
33365423
23256423
31265423
43455244
23256423
1 2
1 2
I
II
Family D
0.53 0.51
0.06 0.48
D9S1776D9S1682D9S1863GL1-3GL2-1D9S164D9S1818D9S1826
D9S1776D9S1682D9S1863GL1-3GL2-1D9S164D9S1818D9S1826
64345712
Family C
23417546
63343
(6)31
23417546
63343631
23515115
23417546
23417545
1 2
1 2 3 4
0.07 0.55 0.55 0.62
23515115
54345
(7)12
0.58 0.59I
II
54345712
63343631
D9S1776D9S1682D9S1863GL1-3GL2-1D9S164D9S1818D9S1826
D9S1776D9S1682D9S1863GL1-3GL2-1D9S164D9S1818D9S1826
21345211
81345246
53473443
13657746
21652743
81345246
31233211
22157421
53473443
22157421
53473443
22157421
31233211
22157421
31233211
21345246
31233211
21654443
22345242
21654441
22345242
21456713
21654441
21652743
31233211
23657746
81345246
13657746
81345246
21654242
21654443
21345246
22345242
21345246
22345242
31233216
31233211
53473443
3234524[7
22325244]
22347]213]
2335[573[1
2234-21-
2232
(5)24-
21657441
83456712
1.02 0.610.80 1.04 0.63 0.90 0.92 1.090.97 1.04 0.53 0.65
0.64 0.05 0.05 0.57 1.01 0.63 0.65 0.06 0.98
0.68
1
1.16
21 3 4 6 7 8 9 10 11 13
1 2 3 4 5 6 7 8 9III
II
I
5 12
Family A
D9S1776D9S1682D9S1863GL1-3GL2-1D9S164D9S1818D9S1826
D9S1776D9S1682D9S1863GL1-3GL2-1D9S164D9S1818D9S1826
D9S1776D9S1682D9S1863GL1-3GL2-1D9S164D9S1818D9S1826
21345211
81345246
53473443
13657746
21652743
81345246
31233211
22157421
53473443
22157421
53473443
22157421
31233211
22157421
31233211
21345246
31233211
21654443
22345242
21654441
22345242
21456713
21654441
21652743
31233211
23657746
81345246
13657746
81345246
21654242
21654443
21345246
22345242
21345246
22345242
31233216
31233211
53473443
3234524[7
22325244]
22347]213]
2335[573[1
2234-21-
2232
(5)24-
21657441
83456712
1.02 0.610.80 1.04 0.63 0.90 0.92 1.090.97 1.04 0.53 0.65
0.64 0.05 0.05 0.57 1.01 0.63 0.65 0.06 0.98
0.68
1
1.16
21 3 4 6 7 8 9 10 11 13
1 2 3 4 5 6 7 8 9III
II
I
5 12
Family A
D9S1776D9S1682D9S1863GL1-3GL2-1D9S164D9S1818D9S1826
D9S1776D9S1682D9S1863GL1-3GL2-1D9S164D9S1818D9S1826
D9S1776D9S1682D9S1863GL1-3GL2-1D9S164D9S1818D9S1826
Levy, et al. Levy, et al. Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura. Nature 413:488-494, 2001.
Learning Objectives
UNDERSTAND: • The basic anatomy of the human genome [eg. 3 X109 bp (haploid
genome); 1-2% coding sequence (~20,000 genes); types and extent of DNA sequence variation].
• Recombination and how it allows genes to be mapped • Linkage: Use of markers linked to a disease gene for genetic
diagnosis and to identify disease genes (positional cloning)• Distinction between a linked marker and the disease causing
mutation itself• Genetic data for a pedigree, assigning phase, defining haplotypes• Linkage disequilibrium and haplotype blocks• Genome wide association studies (GWAS) to identify gene variants
contributing to complex diseases/traits
A A
B B
a a
b b
A A
B B
a a
b b
A A
B B
a a
b b
A A a a
B b B b
LOCIFAR APART
A AB B
a ab b
B B b b
B Bb b
B b B b
LOCICLOSE TOGETHER
A A a a
A Aa a
A Aa a
RECOMBINANTS
MEIOSIS I
Linkage: A/a and B/b tend to be inherited together
the A and B loci are linked.
Key Concepts: Linkage and Recombination
Gelehrter, Collins and Ginsburg: Principles of Medical Genetics 2E; Figure 9.2
DP DQ DRCYP21
C4B
CYP21P
C4A
C2 B C A
CLASS ICLASS II CLASS III
~4000 kb
TNFHFEBA
TELOMERECENTROMERE
The HLA (MHC) Locus
Gelehrter, Collins and Ginsburg: Principles of Medical Genetics 2E; Figure 9.12
A2, A24, B7, B35, DR1, DR13
A.
I.
II.
1 2
1 2 3 4 5
A1, A29, B7, B8, DR3, DR4
A2, A29, B7, B35,
DR4, DR13
A24, A29, B7,
DR1, DR4
A1, A24, B7, B8,
DR1, DR3
A2, A29, B7, B35,
DR4, DR13
A2, A29, B7, B35,
DR1, DR4
B.
I.
II.
1 2
1 2 3 4 5
A29, B7, DR4 A1, B8, DR3
A2, B35, DR13 A24, B7, DR1
A29, B7, DR4A2, B35, DR13
A1, B8, DR3 A24, B7, DR1
A29, B7, DR4 A2, B35, DR1
A29, B7, DR4 A24, B7, DR1
A29, B7, DR4 A2, B35, DR13
Assigning Phase
Gelehrter, Collins and Ginsburg: Principles of Medical Genetics 2E; Figure 9.13
A2HFE
HFEHFEA3
OTHER
A2
A3
A2
A1
A24
A11
A32
OTHERS
A1
A3
A11
A24
A32
A28
A26
A2
TIME
HEMOCHROMATOSIS CHROMOSOMES NORMAL CHROMOSOMES
10%
23%
14%
8%
5%
5%
39%
X
X
X
70%
30%
Linkage Disequilibrium
Gelehrter, Collins and Ginsburg: Principles of Medical Genetics 2E; Figure 9.14
These three SNPs could theoretically occur in 8 different haplotypes
…C…A…A…
…C…A…G…
…C…C…A…
…C…C…G…
…T…A…A…
…T…A…G…
…T…C…A…
…T…C…G…
But in practice, only two are observed
…C…A…A…
…C…A…G…
…C…C…A…
…C…C…G…
…T…A…A…
…T…A…G…
…T…C…A…
…T…C…G…
…C…A…A…
…C…A…G…
…C…C…A…
…C…C…G…
…T…A…A…
…T…A…G…
…T…C…A…
…T…C…G…
These three variants are said to be in linkage disequilibrium
A high frequency of a specific gene mutation in a A high frequency of a specific gene mutation in a population founded by a small ancestral grouppopulation founded by a small ancestral group
Founder Effect
Professor Marninalia (wikimedia)
Hb S only occurs on 4 haplotypes…only occurred 4 times in history
Could we use this approach to find human disease genes (identify specific haplotypes present more often in patients than in controls)?
Image of genetic make up of Benin,
Bantu, Senegal and Arab-India populations
removed
Complex Diseases
• Hypertension• Coronary artery disease• Diabetes• Obesity• Cancer• …
Difficult to map in large pedigrees by conventional linkage (multiple genes, variable effects)
• Candidate gene association study– Test a SNP (or SNPs) surrounding your favorite gene for
association with disease (more common in patients than controls)
• Publication bias
• Multiple observations
• Population substructure
• “looking under the streetlamp”
vs.
• Genome-wide association study (GWAS)– Unbiased– No prior assumptions
Human Chromosome 4
2008
• 17,999,889 total entries in dbSNP
http://www.ncbi.nlm.nih.gov/projects/SNP/
• Chromosome 4– 1,183,767 SNPs
• ~1M SNP chip commercially available
1981 1991 1994 1996
3 markers 53 markers 393 markers 791 markersGelehrter, Collins and Ginsburg: Principles of Medical Genetics 2E; Figure 10.3
Hybridization array: gene chipHybridization array: gene chip
DNA chip v6.0:
~1 million SNPs
RNA expression:
All ~ 20,000 genes
CGH:
Survey whole genome for large deletions, insertions, rearrangements
Ricardipus (flickr)
The Multiple observations problem
• Roll the dice once– Probability of rolling two 6’s = 2.8% (1:36=1/6 X 1/6)
• Roll the dice twice– Probability of rolling two 6’s at least once = 5.5%
• Roll the dice 100 times– Probability of rolling two 6’s at least once = 94%
Test 1 million SNPs, 100 phenotypes . . .
• Age-related macular degeneration (AMD)Age-related macular degeneration (AMD)
– > 10 million cases in the US> 10 million cases in the US– Leading cause of blindness among the elderlyLeading cause of blindness among the elderly
• Common variant in complement factor H (CFH) geneCommon variant in complement factor H (CFH) gene
– Tyr402HisTyr402His– His allele = 2-4 X increase risk of AMDHis allele = 2-4 X increase risk of AMD– Accounts for 20-50% of AMD riskAccounts for 20-50% of AMD risk
Nature Genetics, 2006, 38:320-323.
• Odds ratio 1.7• Replicated multiple times
Image of journal article on variant of
transcription factor 7 like 2 removed
How do we distinguish a disease causing mutation from a silent sequence variation?
• Obvious disruption of gene– large deletion or rearrangement– frameshift– nonsense mutation
• Functional analysis of gene product– expression of recombinant protein– transgenic mice
• New mutation by phenotype and genotype
• Computer predictions• Disease-specific mutation databases
– Same/similar mutation in other patients, not in controls
• Rare disease-causing mutation vs. private “polymorphism” (rare variant)
X
Other Genome Wide Association Studies (GWAS)
• Heart disease– MI, AF, QT prolongation, CAD, lipids
• Inflammatory bowel disease• Asthma• Neuropsychiatric disorders
– ALS, MS, Alzheimer, schizophrenia, bipolar disorder
• Rheumatologic disorders– RA, SLE
• Cancer risk– breast, prostate, colon
• Common traits– BMA, height, hair/eye/skin color
Lessons from GWAS
• Most (nearly all) previous “candidate” gene association studies are wrong
• Most common variants have only modest effects on risk (<< 2 fold)
• For type II diabetes, variants identified to date only account for ~5% of overall risk– NOT useful clinically (yet)
• Other diseases may be different– AMD– Thrombosis
• For the future:– ? More predictive, combinatorial analyses– ? Identify new drug targets
GWAS Lessons (continued)
• common alleles with small effects: – ? Clinical diagnostic utility– New biologic pathways- ?significance– New drug targets- ? value
• Should we be looking for large effect, rare variants instead?– Deep resequencing of extremes of the distribution– New technologies (massively parallel sequencing)
Personalized Medicine:Personalized Medicine:Potential Impact of GenomicsPotential Impact of Genomics
• Establish/confirm diagnosisEstablish/confirm diagnosis– SubclassificationSubclassification– prognosisprognosis
• Predisposition testing/preventionPredisposition testing/prevention
• Guiding therapy (pharmacogenomics)Guiding therapy (pharmacogenomics)
Gleevec™ – Specifically TargetsAn Abnormal Protein, Blocking Its Ability To Cause Chronic Myeloid Leukemia
Chromosome 9;22 translocation
CML
Bcr-Abl fusion protein
Gleevec™
Bcr-Abl fusion protein
Normal
Source Undetermined (All Images)
Pharmacogenomics today
• Thiopurine methyltransferase (TPMT)– 6-MP, azathioprine therapy dosing
• UGT1A1– irinotecan
• Dihydropyrimidine dehydrogenase– 5-FU
• Cytochrome P450– warfarin– Multiple other drugs:
• antidepressants, tamoxifen, PPIs
• VKORC1– warfarin
Pharmacogenomics for warfarin dosingPharmacogenomics for warfarin dosing
• Clinical value unprovenClinical value unproven• Practical limitations:Practical limitations:
– VKORC1/CYP2C9 genotype only accounts for ~30% of variance in VKORC1/CYP2C9 genotype only accounts for ~30% of variance in warfarin requirementwarfarin requirement
– Turnaround timeTurnaround time– pill sizepill size
Sconce et al., Sconce et al., Blood,Blood, 2005, 106: 2329-33 (Both Images) 2005, 106: 2329-33 (Both Images)
The Future…The Future…
• Will be differentWill be different– New/improved anticoagulantsNew/improved anticoagulants– Cheaper/faster DNA testing/sequencingCheaper/faster DNA testing/sequencing– Complex computational analysis- Complex computational analysis-
combinatorial risk factorscombinatorial risk factors– Much larger data sets– health system wideMuch larger data sets– health system wide– Data to support genotype-specific Data to support genotype-specific
therapy/prophylaxistherapy/prophylaxis
Slide 6: Gelehrter, Collins and Ginsburg: Principles of Medical Genetics 2E, Figure 9.1
Slide 7: Gelehrter, Collins and Ginsburg: Principles of Medical Genetics 2E, Figure 9.4
Slide 8: Gelehrter, Collins and Ginsburg: Principles of Medical Genetics 2E, Figure 9.2
Slide 9: Gelehrter, Collins and Ginsburg: Principles of Medical Genetics 2E, Figure 9.3
Slide 10: Gelehrter, Collins and Ginsburg: Principles of Medical Genetics 2E, Figure 9.5
Slide 11: Gelehrter, Collins and Ginsburg: Principles of Medical Genetics 2E, Figure 9.6
Slide 12: Gelehrter, Collins and Ginsburg: Principles of Medical Genetics 2E, Figure 9.15
Slide 13: Gelehrter, Collins and Ginsburg: Principles of Medical Genetics 2E, Figure 9.26
Slide 14: Gelehrter, Collins and Ginsburg: Principles of Medical Genetics 2E, Figure 9.31
Slide 16: Gelehrter, Collins and Ginsburg: Principles of Medical Genetics 2E
Slide 18: Gelehrter, Collins and Ginsburg: Principles of Medical Genetics 2E, Figure 5.22
Slide 19: Adapted from ASCO teaching slides
Slide 20: Gelehrter, Collins and Ginsburg: Principles of Medical Genetics 2E, Figure 10.3
Slide 21: Source Undetermined
Slide 22: Source Undetermined; Andre Karwath (wikipedia); U.S. Federal Government (wikimedia)
Slide 24: Source Undetermined
Slide 26: National Center for Biotechnology, http://www.ncbi.nlm.nih.gov/
Slide 27: Gelehrter, Collins and Ginsburg: Principles of Medical Genetics 2E
Slide 28: University Of California Santa Cruz, http://genome.ucsc.edu
Slide 29: Levy, et al. Levy, et al. Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura. Nature 413:488-494, 2001.
Slide 30: University Of California Santa Cruz, http://genome.ucsc.edu
Slide 31: National Center for Biotechnology, http://www.ncbi.nlm.nih.gov/Omim/mimstats.html
Slide 41: Regents of The University of Michigan
Slide 42: Regents of The University of Michigan
Slide 46: Gelehrter, Collins and Ginsburg: Principles of Medical Genetics 2E, Figure 10.3
Slide 47: Ricardipus, flickr, http://creativecommons.org/licenses/by-sa/2.0/deed.en
Additional Source Information for more information see: http://open.umich.edu/wiki/CitationPolicy