08.22.08: The Human Genome

Author(s): David Ginsburg, 2009License: Unless otherwise noted, this material is made available under the terms ofthe Creative Commons Attribution–Non-commercial–Share Alike 3.0 License:http://creativecommons.org/licenses/by-nc-sa/3.0/ We have reviewed this material in accordance with U.S. Copyright Law and have tried to maximize your ability to use, share, and adapt it. The citation key on the following slide provides information about how you may share and adapt this material. Copyright holders of content included in this material should contact open.michigan@umich.edu with any questions, corrections, or clarification regarding the use of content. For more information about how to cite these materials visit http://open.umich.edu/education/about/terms-of-use. Any medical information in this material is intended to inform and educate and is not a tool for self-diagnosis or a replacement for medical evaluation, advice, diagnosis or treatment by a healthcare professional. Please speak to your physician if you have questions about your medical condition. Viewer discretion is advised: Some medical content is graphic and may not be suitable for all viewers.

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The Human Genome M1 Patients and Populations David Ginsburg, MD August 22, 2008Fall 2008

Learning ObjectivesUNDERSTAND:•  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·phism Pronunciation: "päl-i-mor-"fiz-&m Function: 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

Heteromorphism 2 normal copies of chromosome 1 of chromosome 1 (one copy)B. Donahue, 1968I a or b allele of Duffy blood groupII a/b b/b b/b a/b a/b b/b a/b a/b b/bIII a/b a/b b/b b/b a/a a/b a/a b/bIV a/a a/b a/b a/b Gelehrter, Collins and Ginsburg: Principles of Medical Genetics 2E; Figure 9.1

A. + - I 1 2 + + - - - + - II 1 2 3 4 5 6 7 + - - + + + - = Myotonic Dystrophy III 1 2 3 4 5 6 7+ = Secretor Phenotype Gelehrter, Collins and Ginsburg: Principles of Medical Genetics 2E; Figure 9.4 (Se/Se or Se/se) B. I 1 2 Se/se se/se II 1 2 3 4 5 6 7 Se/se Se/se se/se se/se se/se Se/se se/se III 1 2 3 4 5 6 7 Se/Se se/se se/se Se/se Se/se Se/se se/se or Se/se Gelehrter, Collins and Ginsburg: Principles of Medical Genetics 2E; Figure 9.4

Key Concepts: Linkage and Recombination LOCI LOCI FAR APART CLOSE TOGETHER A Aa a A Aa a B Bb b B Bb b A A a a A A a a B B b b B B b b Linkage: A/a and B/b tend to be inherited together the A and B loci are linked. A A a a A a A a B b B b B b B b MEIOSIS I A A a a A a A a B b B b B b B b RECOMBINANTS Gelehrter, Collins and Ginsburg: Principles of Medical Genetics 2E; Figure 9.2

Linkage between Marker A/a and Disease D I 1 2 A a A A D N N N II 1 2 3 4 5 6 7 a A A A a A a A a A A A A A N N D N N N D N N N D N D N Gelehrter, Collins and Ginsburg: Principles of Medical Genetics 2E; Figure 9.3Marker= A or aDisease allele = DNormal allele = N

Linkage between NF and RFLP marker I 1 2 recombinant II 1 2 3 4 5 6 7 8 9 III 1 2 3 4 5 6 7 8 94.7 kb3.0 kb EcoRI 3.0 kb EcoRI 1.7 kb EcoRI = NEUROFIBROMATOSIS (NF1) PROBE * Gelehrter, Collins and Ginsburg: Principles of Medical Genetics 2E; Figure 9.5

3.5 3.0 2.5 2.0LOD 1.5 1.0 0.5 0 0.05 0.10 0.15 0.20 0.25 0.30 0.35 0.40 θ θ= 0 0.05 0.10 0.15 0.20 0.3 0.4 Z θ LOD ∞ 3.16 3.08 2.86 2.57 1.82 0.89 3.165 0.059 Gelehrter, Collins and Ginsburg: Principles of Medical Genetics 2E; Figure 9.6

DISEASE DISEASEMAP FUNCTION MAP FUNCTION GENE GENE FUNCTIONAL CLONING POSITIONAL CLONINGGelehrter, Collins and Ginsburg: Principles of Medical Genetics 2E; Figure 9.15

HD linked to C allele: Single recombinant (IV1) I II III AD AA AA AA AB AA AC AB AB AB AB AA AA AA CD BC AC AC CD AA AA AA AB IV AA AA AD AA AB AC AC BC AC BC CC AC CC AC AC CC CC CC CC AA AC AC AC AC AC AC AC CD AC AC AB AC AC AC AA AC V AA AC AC AB BC BC Gelehrter, Collins and Ginsburg: Principles of Medical Genetics 2E; Figure 9.26 Gusella, et al. A polymorphic DNA marker genetically linkedto Huntingtons disease. Nature 306:234-238, 1983.The Huntingtons Disease Collaborative Research Group. A novel genecontaining a trinucleotide repeat that is expanded and unstable onHuntingtons disease chromosomes. Cell 72:971-983, 1993.

Positional Cloning Cytogenic Abnormality Physical Mapping and Cloning FAMILIES FINE GENETIC MUTATION Transcript MAPPING SEARCH Identification GENETIC MUTATION MARKERS YACs and IDENTIFICATION BACs Positional Candidate ApproachGelehrter, Collins and Ginsburg: Principles of Medical Genetics 2E; Figure 9.31

Image ofCystic Fibrosis carrier screeningadvertisement removed

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

STRGelehrter, Collins and Ginsburg: Principles ofMedical Genetics 2E; Figure 5.22

SNPAllele 1 A U G A A G U U U G G C G C A U U G C A AAllele 2 A U G A A G U U U G G U G C A U U G C A A Adapted from ASCO teaching slides •  Most are silent •  Intragenic •  Promoters and other regulatory sequences •  Introns •  Exons –  5 and 3 untranslated regions –  Coding sequence (~1-2% of genome)

Human Chromosome 4 1981 1991 1994 1996 2008 •  17,999,889 total entries in dbSNP http:// www.ncbi.nlm.nih.go v/projects/SNP/ •  Chromosome 4 –  1,183,767 SNPs •  ~1M SNP chip commercially available 3 markers 53 markers 393 markers 791 markers Gelehrter, Collins and Ginsburg: Principles of Medical Genetics 2E; Figure 10.3

1000 GbBase Pairs in Genbank 100 Gb 10 Gb 1 Gb 100 Mb 10 Mb 1 Mb 1985 1990 1995 2000 2005 2010 Source Undetermined Year

Haploid Human Genome 3 X 109 bp, ~20,000 genes Source Undetermined 1 Chromosome ~1300 genes Single Gene ~1.5 Kb (Globin to 2 X 106 bp (Dystrophin) H. Influenzae ~1700 genesS. Cerevisiae~6250 genes D. Melanogaster C. Elegans ~14000 genes ~18500 genes Andre Karwath (wikipedia) U.S. Federal Government (wikimedia)

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 Genome23 pairs of chromosomes made of 3 billion base pairs Extragenic DNA ~20,000 genes l  Repetitive sequences l  Control regions l  Spacer DNA between genes 70% 30% l  Function mostly unknown 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

National Center for Biotechnology

Positional Cloning Approach Image of positional cloning procedure removed Gelehrter, Collins and Ginsburg: Principles of Medical Genetics 2E

University Of California Santa Cruz

1 2 1 Family BFamily A I I 1.16 0.67 0.57 D9S1776 35 D9S1682 13 D9S1776 23 17 D9S1863 24 D9S1682 11 11 GL1-3 37 GL2-1 33 D9S1863 43 34 D9S164 24 GL1-3 35 33 D9S1818 14 D9S1826 13 GL2-1 13 82 D9S164 82 15 II 1 2 3 4 5 6 7 8 9 10 11 12 13 D9S1818 44 24 D9S1826 22 11 1.02 0.80 1.04 0.61 0.63 0.90 0.92 0.97 1.09 1.04 0.53 0.65 0.68 D9S1776 28 22 2 2 2 2 23 23 23 25 25 12 83 8 5 22 D9S1682 13 12 1 1 1 2 11 21 21 23 23 31 11 1 3 22 1 2 3 4 5 6 7 D9S1863 64 63 6 4 6 3 12 12 14 14 66 32 3 4 GL1-3 55 54 5 5 5 4 32 43 53 53 57 57 55 43 4 7 33 42 II 76 73 72 53 0.97 0.45 0.64 GL2-1 D9S164 47 45 4 6 4 5 42 4 7 4 2 53 22 73 42 73 42 73 44 44 77 22 5 3 2 4 - (5) 22 0.06 0.02 0.63 0.60 D9S1818 D9S1826 41 12 44 4 1 4 4 41 21 21 11 24 13 24 44 13 63 41 61 4 4 14 D9S1776 21 31 31 21 37 31 21 12 1 3 3 2 61 11 6 3 - - D9S1682 11 11 11 11 11 11 11 1 2 3 4 5 6 7 8 9 D9S1863 43 13 33 33 34 43 33 III GL1-3 33 83 53 53 53 33 53 0.64 0.05 0.05 0.57 1.01 0.63 0.65 0.06 0.98 GL2-1 18 48 38 38 32 18 - - D9S1776 D9S1682 2 2 1 1 22 21 22 23 2 3 2 8 1 8 3 2 2 2 2 2 3 2 D9S164 81 41 21 21 25 85 21 11 21 1 1 3 1 3 1 D9S1863 6 3 33 63 32 6 2 6 3 6 3 3 3 3 3 D9S1818 42 32 42 42 44 44 42 GL1-3 GL2-1 5 4 4 5 44 55 54 43 5 3 5 4 5 4 4 2 5 4 5 5 [5 7] D9S1826 21 21 21 21 21 21 21 45 53 2 3 7 5 7 5 D9S164 4 2 22 22 22 7 2 7 2 7 2 2 2 7 2 D9S1818 4 4 41 44 41 4 1 4 4 4 4 4 4 3 1 D9S1826 3 6 21 26 26 3 1 6 6 6 6 [7 4] [1 3] Family C 1 2 Family D 1 2 I I 0.58 0.59 0.53 0.51 D9S1776 2 2 5 6 D9S1776 42 33 D9S1682 3 3 4 3 D9S1682 33 31 D9S1863 4 5 3 3 D9S1863 42 32 GL1-3 1 1 4 4 GL1-3 55 64 GL2-1 7 5 5 3 GL2-1 56 53 D9S164 5 1 (7)(6) D9S164 24 43 D9S1818 4 1 1 3 D9S1818 42 23 D9S1826 6 5 2 1 D9S1826 43 33 1 2 3 4 1 2 II II 0.07 0.55 0.55 0.62 0.06 0.48 D9S1776 26 2 6 2 5 2 6 4 3 2 3 D9S1682 33 3 3 3 4 D9S1776 3 4 D9S1682 3 3 3 1 D9S1863 43 5 3 4 3 4 3 4 3 2 2 GL1-3 14 1 4 1 4 D9S1863 1 4 GL1-3 5 6 5 6 GL2-1 73 5 3 7 5 7 5 5 5 6 5 5 7 GL2-1 Levy, et al. Mutations in a member of the ADAMTS gene family D9S164 56 1 6 5 7 D9S164 2 4 4 4 D9S1818 43 1 3 4 1 4 1 4 2 2 2 cause thrombotic thrombocytopenic purpura. Nature 6 2 D9S1818 D9S1826 61 5 1 5 2 D9S1826 4 3 3 3 413:488-494, 2001.

University Of California Santa Cruz

National Center for Biotechnology

Learning ObjectivesUNDERSTAND:•  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

Key Concepts: Linkage and Recombination LOCI LOCI FAR APART CLOSE TOGETHER A Aa a A Aa a B Bb b B Bb b A A a a A A a a B B b b B B b b Linkage: A/a and B/b tend to be inherited together A A a a the A and B loci are linked. A a A a B b B b B b B b MEIOSIS I A A a a A a A a B b B b B b B b RECOMBINANTS Gelehrter, Collins and Ginsburg: Principles of Medical Genetics 2E; Figure 9.2

The HLA (MHC) LocusCENTROMERE TELOMERE CYP21 CYP21P TNF DP DQ DR C2 A B B C A HFE C4B C4A CLASS II CLASS III CLASS I ~4000 kb Gelehrter, Collins and Ginsburg: Principles of Medical Genetics 2E; Figure 9.12

Assigning PhaseA. I. 1 A2, A24, 2 B35, DR1, DR13 B7, A1, A29, B7, B8, DR3, DR4 II. 1 2 3 4 5 A2, A29, A24, A29, A1, A24, A2, A29, A2, A29, B7, B35, B7, B7, B8, B7, B35, B7, B35, DR4, DR13 DR1, DR4 DR1, DR3 DR4, DR13 DR1, DR4B. I. 1 2 A29, B7, DR4 A2, B35, DR13 A1, B8, DR3 A24, B7, DR1 II. 1 2 3 4 5 A29, B7, DR4 A1, B8, DR3 A29, B7, DR4 A2, B35, DR13 A24, B7, DR1 A2, B35,DR1 A29, B7, DR4 A29, B7, DR4 A24, B7, DR1 A2, B35, DR13 Gelehrter, Collins and Ginsburg: Principles of Medical Genetics 2E; Figure 9.13

Linkage Disequilibrium HFE A2 A2 A1 A3 X A11 A24 A32 A28 A26 A2 TIMEHEMOCHROMATOSIS CHROMOSOMES NORMAL CHROMOSOMES HFE HFE A3 A3 X 70% 10% OTHER A2 X 30% 23% A1 14% A24 8% A11 5% A32 5% OTHERS 39% 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…

These three variants are said to be in linkage disequilibrium …C…A…A… …C…A…G… …C…C…A… …C…C…G… …T…A…A… …T…A…G… …T…C…A… …T…C…G…

Founder EffectA high frequency of a specific gene mutation in a population founded by a small ancestral group Professor Marninalia (wikimedia)

Regents of The University of Michigan

Image of genetic make up of Benin, Bantu, Senegal and Arab-India populations removed Hb S only occurs on 4 haplotypes…only occurred 4 times in historyCould we use this approach to find human disease genes (identify specific haplotypes present more often in patients than in controls)?

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 streetlampvs.•  Genome-wide association study (GWAS) –  Unbiased –  No prior assumptions

Human Chromosome 4 1981 1991 1994 1996 2008 •  17,999,889 total entries in dbSNP http:// www.ncbi.nlm.nih.go v/projects/SNP/ •  Chromosome 4 –  1,183,767 SNPs •  ~1M SNP chip commercially available 3 markers 53 markers 393 markers 791 markers Gelehrter, Collins and Ginsburg: Principles of Medical Genetics 2E; Figure 10.3

Hybridization array: gene chip DNA chip v6.0: ~1 million SNPs RNA expression: All ~ 20,000 genes CGH: Ricardipus (flickr) Survey whole genome for large deletions, insertions, rearrangements

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) –  > 10 million cases in the US –  Leading cause of blindness among the elderly•  Common variant in complement factor H (CFH) gene –  Tyr402His –  His allele = 2-4 X increase risk of AMD –  Accounts for 20-50% of AMD risk

Image of journal article on variant of transcription factor 7 like 2 removed Nature Genetics, 2006, 38:320-323.•  Odds ratio 1.7•  Replicated multiple times

Images of journal articles about genome-wideassociation studies removed

Source Undetermined

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 X•  Rare disease-causing mutation vs. private polymorphism (rare variant)

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: Potential Impact of Genomics•  Establish/confirm diagnosis –  Subclassification –  prognosis•  Predisposition testing/prevention•  Guiding therapy (pharmacogenomics)

Image ofdecodme.com homepage removed

Image ofDNAdirect.com homepage removed

Image of23andme.com homepage removed

Gleevec™ – Specifically TargetsAn Abnormal Protein, BlockingIts Ability To Cause Chronic Myeloid Leukemia Chromosome 9;22 translocation Bcr-Abl fusion protein Bcr-Abl fusion protein Gleevec™CML 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

Image of Warfarin mechanism of action removed Sadler, Nature 427:493, 2004.

Pharmacogenomics for warfarin dosing Sconce et al., Blood, 2005, 106: 2329-33 (Both Images)•  Clinical value unproven•  Practical limitations: –  VKORC1/CYP2C9 genotype only accounts for ~30% of variance in warfarin requirement –  Turnaround time –  pill size

The Future…•  Will be different –  New/improved anticoagulants –  Cheaper/faster DNA testing/sequencing –  Complex computational analysis- combinatorial risk factors –  Much larger data sets– health system wide –  Data to support genotype-specific therapy/ prophylaxis

New Sequencing TechnologiesSource Undetermined

Additional Source Information for more information see: http://open.umich.edu/wiki/CitationPolicy 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. 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

Sconce et al., Blood, 2005, 106: 2329-33 (Both Images)Slide 66: Source UndeterminedSlide 50: Nature Genetics, 2006, 38:320-323.Slide 52: Source UndeterminedSlide 61: Source Undetermined (All Images)

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