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Two discoveries that will shape the 21st century
Deciphering the Human Genome
Lifebook.dat – the database required to make a human being
Production of Human Embryonic Stem Cell Lines
Formlife.exe – the executable program to make a human being
Cloning of Human Beings (a negative utopia)
Copy.exe – a possibility of pertuating ourselves?
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Cell
Nucleus
Chromosom
Gene
Gene-product: Protein
DNA
Blueprint of LifeDiakoniePublik 3/2001
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Informationsübertragung bei der zellteilung
Cell division: Transfer of Information!
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C in phosphate ester chain
C and N in bases
Base pairs
Sugar phosphatebackbone
Minorgroove
Majorgroove
H
O
P
5‘ 3‘
DNA as carrier of Information
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Human ß-Globin, Segment ... TAAGCCAGTG CCAGAAGAGC CAAGGACAGG TACGGCTGTC ATCACTTAGA CCTCACCCTG TGGAGCCACA CCCTAGGGTT GGCCAATCTA CTCCCAGGAG CAGGGAGGGC AGGAGCCAGG GCTGGGCATA AAAGTCAGGG CAGAGCCATC TATTGCTTAC ATTTGCTTCT GACACAACTG TGTTCACTAG CAACCTCAAA CAGACACCAT GGTGCACCTG ACTCCTGAGG AGAAGTCTGC CGTTACTGCC CTGTGGGGCA AGGTGAACGT GGATGAAGTT GGTGGTGAGG CCCTGGGCAG GTTGGTATCA AGGTTACAAG ACAGGTTTAA GGAGACCAAT AGAAACTGGG CATGTGGAGA CAGAGAAGAC TCTTGGGTTT CTGATAGGCA CTGACTCTCT CTGCCTATTG GTCTATTTTC CCACCCTTAG GCTGCTGGTG GTCTACCCTT GGACCCAGAG GTTCTTTGAG TCCTTTGGGG ATCTGTCCAC TCCTGATGCT GTTATGGGCA ACCCTAAGGT GAAGGCTCAT GGCAAGAAAG ...
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Human ß-Globin, Exon1, Segment ...GTG CAC CTG ACT CCT GAG GAG Val His Leu Thr Pro Glu Glu
AAG TCT GCC GTT ACT GCC CTG Lys Ser Ala Val Thr Ala Leu
TGG GGC AAG GTG AAC GTG ... Trp Gly Lys Val Asn Val + 126 further AS !
TGA Stop !!!
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Genomic Library of Mankind
• 46 Chromosomes 2 * 3,2 billion letters• 30 000 – 40 000 Genes• ca. 99 % not protein-coding (excess of void information)• Man/Chimpanzee 1-2% global text difference
(ca. 120 Mio Letters)
i.e. in every line of the lifebook about 1-2 „misprints“• enormous repetitive segments • Retroviral traces (hundreds of thousand items) –
the human genome is a museum of virus infections !
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Genomic Library of Individual Person
• ca. 2 Mio differences (SNPs)(between non-related persons)
• ca. 60 000 of them in coding regions• ca. 10 000 genetic defects
(each individual carries disposition for about 5 defects)
• every 500 -2000 letters a variation • (i.e. on every page of the life book a few „misprints“
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Evolutionary Traces in the Genome
• 25 % of the human genome are „deserts"
• ca. 50 % are repetitions
• among them ca. 45 % „jumping copies",
(silent since millions of years)
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Genomic Non-sensebut important identification tag!
Person 1 : CA CA CA CA CA CA CA 7 repeats no!!(Father ?) CA CA CA CA 4 repeats
Person 2: CA CA CA CA CA CA CA CA 8 repeats(Father ?) CA CA CA 3 repeats
Person 3: CA CA CA CA CA CA CA CA 8 repeats(Father ?) CA CA 2 repeats !!
Person 4: CA CA CA CA CA CA CA CA 8 repeats(Mother) CA CA CA CA CA CA CA 7 repeats !!
Person 5: CA CA CA CA CA CA CA 7 repeats (Child) CA CA 2 repeats
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Genetic prediction: Scope
It can establish a diagnosis
It can predict the future
It provides implied information on related individuals
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Genetic Diagnosis and Prediction: Scale
„Within the next decade genetic testing will be used widely for predictive testing in healthy people and for diagnosis and management of patients.“
Bell J (1998) „New Genetics in Clinical Practice“, Brit. Med. J. 316, 618-620
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Genetic Prediction: Upper Limit of Determination
Concordance of traits in monozygotic twins:
Rare mendelian diseases: up to 100%
Frequent complex diseases: 30 – 70%
Relevant prediction is in terms of probabilityrather than of certainty (maybe useful for the insurance company, but of limited use for the individual)
There is always considerable non-genetic variability!
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Genetic Diagnosis and Prediction: Tests of What ?
Non-inherited genetic traits: Chromosomal Aneuploidy e.g. Down syndroma, Klinefelter syndroma
Mendelian diseases: about 1500 out of 5000 may be diagnoseddominant mode of inheritance: in every generation of familyrecessive mode of inheritance: in one family “out of the blue“
Complex (multifactorial) diseases: about 40 genes may contribute (example of cardiovascular disease)
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Genetic Diagnosis and Prediction: Tests on Whom ?
• Partners• Embryo in vitro• Embryo in utero• Fetus before birth• Newborn• Child• Adult
Purposes (with example):
Prediction of disorder: HuntingtonSelection between alternatives: immunePrevention of disease: PKU
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Examples of Mendelian Diseases
Huntington (D)BRCA (breast cancer, D)Cystic fibrosisThrombophiliaPorphyriaHaemochromatosisMyotonic dystrophyDuchenne muscular dystrophy (sex-linked)PhenylketonuriaGalactosemiaThalassemiaCongenital hypothyrioidism
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Examples of Complex Diseases with Genetic Contribution
Diabetes type 1Diabetes type 2Breat cancerColon cancerProstate cancerAlzheimer´s dementia (early onset form)Multiple sclerosisBipolar disorderSchizophreniaAutismFamilial Parkinson disease
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Risk prediction of Complex Disease:GRR
Genotype Relative Risk (GRR) =
Frequency of disease in carriers of variant alleleFrequency of disease in carriers of normal allele
GRR> 50 single gene disorder with high penetrance
4-50 oligogenic disorder<4 polygenic factors (complex disease)
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Risk prediction of Complex Disease: Bad Test
Not even a high GRR guarantees a good test ifFrequency (of risk allele) > frequency (disease in population)
HLA-B27 other allele Sum
Healthy persons 985 8 898 9 983
Spondylitis ankylosans (Mb. Bekhterev) 15 2 17
All persons 1 000 9 000 10 000
Frequency of disease: 17 / 10 000 = 0.17%Frequency of gene variant: 1000 / 10 000 = 10%
GRR = 15/17 divided by 985/9983 = 8.9 Frequency of gene variant in disease: 15/17 = 88%Frequency of gene variant in healthy: 9845 / 9983 = 10%
Test prediction on risky gene : 15/1000 diseased persons = 1.5%Rate of false positives: 98.5% Rate of false negatives: 0.02%
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Is genetic prediction of disease possible?
Monogenic case , rare, high GRR, high penetrance: yes, if genotype is moderately specific
Polygenic case and multifactorial causation, low GRR: only statistical prediction in large populations samples
Population screening instead of individual diagnosis:
• Screening for heterozygotes for recessive disorder• Screening of fetuses or newborns for necessary therapy• Screening for predictive genotype in frequent disease (breast cancer)
• Any screening runs the following risks:
False positives, if genotype is not the specific causative factorFalse negatives, if genotype is not the only causative factor
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HDL2
IDL LDL
Chylo Chylo remnants
VLDL
HDL3
LDLRec
CETP/HL
CETP/HL
scavenger
SRB1 LCAT (LPL)
LPL
LPL
liver
intestine
periph. cholesterol
HL
discLCAT
nasc
surface remnants
surface remnants
HDLreccubulin
LRPHL
scavenger(on LPL def.)
(LRP&HSPG)
HLLDLRec
-
15/03/01
A C H B 48
A C E A C E
A C E A C E
E
B 100
B 48
B 100B 100
periph. cholesterol
Metabolic Network of Lipoproteins
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Cholesterol as risk factor
Heritability is 50% - even the best prediction can reduce the variation of individual values by 50%
Variation in more than 20 genes are responsible for the normal statusof cholesterol (clinical LDL/HDL ratio). Each can contribute around 2%
Individual prediction will be useless
Statistical prediction for groups will be possible provided that the complexity of genetic causation is not too high
Test makes sense only if there are genotypes with normal cholesterol levelsin young, but high levels at advanced age
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Risk and individual disease
Only part of all individuals with risk status will actually become ill
Every person belongs to several risk groups for a chronic disease with genetic component.
Thus in principle everybody should pay a risk surchargeFor all persons this will cancel
Provided that equity of information is established between insuranceand client!