08.22.08: The Human Genome

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The Human Genome

David Ginsburg, MD August 22, 2008

M1 Patients and Populations

Fall 2008

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·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

IV

III

II

I

a/b b/b b/b a/b a/b b/b a/b a/b b/b

b/b a/a a/b a/a

a/b a/b a/b

b/b b/b a/b a/b

a/a

B.

Heteromorphism of chromosome 1

(one copy)

2 normal copies of 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/se Se/Se or

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)



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

LOCI FAR APART

A A B B a a

b b

B B b b

B B b b

B b B b

LOCI CLOSE TOGETHER

A A a a

A A a a

A A a 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


I

II

A D N

a A A N N

A N

A D N

a A N N

a A N

a D

A N N

a A N

A N

A N

A D

A D

7 6 5 4 3 2 1

1 2

Marker= A or a Disease allele = D Normal allele = N

Linkage between Marker A/a and Disease D


I II III

1 2

1 2 3

4.7 kb 3.0 kb

5 6 4 7 8 9 1 2 3 4 5 6 7 8 9

3.0 kb = NEUROFIBROMATOSIS (NF1) 1.7 kb EcoRI

* PROBE EcoRI EcoRI

recombinant

Linkage between NF and RFLP marker


3.5 3.0 2.5 2.0 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 = 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

θ 0.059

LOD


DISEASE

FUNCTION

GENE

MAP

DISEASE

FUNCTION

GENE

MAP

FUNCTIONAL CLONING POSITIONAL CLONING


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

AC AA AC AC AC AB AC AC CD AC AC AC AC AC AC AC AA CC CC CC CC AC AC CC AC CC BC AC BC AC AC AB AA AD AA AA

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.


Positional Cloning

GENETIC MARKERS

FAMILIES

MUTATION IDENTIFICATION

FINE GENETIC MAPPING

MUTATION SEARCH

Physical Mapping

and Cloning

YACs and BACs

Transcript Identification

Cytogenic Abnormality

Positional Candidate Approach


Image of Cystic Fibrosis

carrier screening

advertisement 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

STR


SNP

•  Most are “silent” •  Intragenic •  Promoters and other regulatory sequences •  Introns •  Exons

–  5’ and 3’ untranslated regions –  Coding sequence (~1-2% of genome)

Allele 1 A U G A A G U U U G G C G C A U U G A A C

Allele 2 A U G A A G U U U G G U G C A U U G A A C 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 markers Gelehrter, 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 Pa

irs in

Gen

bank

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 genes C. Elegans

~18500 genes U.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 Extragenic DNA

l  Repetitive sequences

l  Control regions l  Spacer DNA

between genes 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

Family B

1 1 3 3 8 1 2 1

7 1 4 3 2 5 4 1

2 1 4 3 1 8 4 2

3 1 3 5 3 2 4 2

2 1 4 3 1 8 4 2

1 1 3 3 8 1 2 1

3 1 3 5 3 2 4 2

1 1 3 3 8 1 2 1

2 1 3 5 3 2 4 2

1 1 3 3 8 1 2 1

3 1 3 5 3 2 4 2

7 1 4 3 2 5 4 1

1 1 3 3 8 5 4 1

1 1 3 3 - 1 2 1

1 1 3 3 8 1 2 1

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 0.64 II

I

3 1 4 3 1 8 4 2

31184432

2 1 3 5 - 2 4 2

D9S1776 D9S1682 D9S1863 GL1-3 GL2-1 D9S164 D9S1818 D9S1826


3 3 3 6 5 4 2 3

3 1 2 4 3 3 3 3

4 3 4 5 5 2 4 4

3 3 3 6 5 4 2 3

2 3 2 5 6 4 2 3

3 1 2 6 5 4 2 3

4 3 4 5 5 2 4 4

2 3 2 5 6 4 2 3

1 2

1 2

I

II

Family D

0.53 0.51

0.06 0.48



6 4 3 4 5 7 1 2

Family C

2 3 4 1 7 5 4 6

6 3 3 4 3

(6) 3 1

2 3 4 1 7 5 4 6

6 3 3 4 3 6 3 1

2 3 5 1 5 1 1 5

2 3 4 1 7 5 4 6

2 3 4 1 7 5 4 5

1 2

1 2 3 4

0.07 0.55 0.55 0.62

2 3 5 1 5 1 1 5

5 4 3 4 5

(7) 1 2

0.58 0.59 I

II

5 4 3 4 5 7 1 2

6 3 3 4 3 6 3 1



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



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




Levy, et al. Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura. Nature 413:488-494, 2001.

University Of California Santa Cruz

National Center for Biotechnology

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

LOCI FAR APART

A A B B a a

b b

B B b b

B B b b

B b B b

LOCI CLOSE TOGETHER

A A a a

A A a a

A A a 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


DP DQ DR CYP21

C4B

CYP21P

C4A C2 B C A

CLASS I CLASS II CLASS III ~4000 kb

TNF HFE B A

TELOMERE CENTROMERE

The HLA (MHC) Locus


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, DR4 A2, 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


A2 HFE

HFE HFE A3

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


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



These three variants are said to be in linkage disequilibrium

A high frequency of a specific gene mutation in a population founded by a small ancestral group

Founder Effect

Professor Marninalia (wikimedia)

Regents of The University of Michigan

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 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: 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)

–  > 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

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

Images of journal articles about genome-wide

association 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

•  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: Potential Impact of Genomics

•  Establish/confirm diagnosis – Subclassification – prognosis

•  Predisposition testing/prevention •  Guiding therapy (pharmacogenomics)

Image of decodme.com

homepage removed

Image of DNAdirect.com

homepage removed

Image of 23andme.com

homepage removed

Gleevec™ – Specifically Targets An 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

Sadler, Nature 427:493, 2004.

Image of Warfarin mechanism of action removed

Pharmacogenomics for warfarin dosing

•  Clinical value unproven •  Practical limitations:

–  VKORC1/CYP2C9 genotype only accounts for ~30% of variance in warfarin requirement

–  Turnaround time –  pill size

Sconce et al., Blood, 2005, 106: 2329-33 (Both Images)

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 Technologies

Source Undetermined

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

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

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

08.22.08: The Human Genome

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