Molecular medicine - Szegedi...
Transcript of Molecular medicine - Szegedi...
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Introduction of forensic genetics
Molecular medicine -
Genetic analysis of molecular evidences
Pádár Zsolt
„Traces” - Death Valley, CA 2007 / 10 / 11
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… there are things in LIFE …
… and there are BAD things in LIFE …
… some we do …
… some other do to us …
… some, they suppose that we did …
… and there are EXTREMELY BAD things of
LIFE …
… and things, that we tought could only
happend to others …
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What a heck is the forensic genetics ?
Transmission geneticsMolecular geneticsPopulation geneticsEcological geneticsQuantitative geneticsNurture geneticsMedical geneticsCytogeneticsMitochondrial geneticsGenomics…
forward geneticsreverse geneticsevolution genetics molecular taxonomyepigeneticspharmacogeneticsforensic geneticspathogeneticsbioinformaticsgenetic engineering…
JurisprudenceJurisprudenceCriminalisticsCriminalisticsEthicsEthicsMedical Medical sciencessciencesVeterinary Veterinary sciencessciences
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2008. 11. 1. / 2009. 05. 04.
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Forensic geneticsGenetics and lawThe traits of the children are not only the sum of parent’s…„The science is only a method, but not the truth itself”
Applied scienceObjective examination of biological traces using methodo-
logy of molecular genetics regarding the given crimeTools for confirmation or rejection of criminal hypotheses
Bilateral relation to basic sciencesApplication and modification of methods in molecular
geneticsModification of requirements concerning basic sciencesProviding of new scientific resultsImpact on evolution of society and economy, effects to
community and peoples
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How does it work …?Human forensics
Crimeshomicide, robbery, rape …
Paternitygenealogy
Sudden deathsudden cardiac death (SCD)
sudden arrhythmic death syndrome
sudden infant death syndrome (SIDS)
Mass disastersvictim’s identification
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How does it work …
Nonhuman forensicsAnimal forensics
dog, cat, wildlife …cruelty, attack, poaching …
entomologytime, area
Forensic botany & fungileaves, seeds …pollens
Microorganismssoil identification
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Analysis of genetic polymorphismsTemperature sensitive expression of a recessive gene
TYR gene ► tyrosinase enzyme ► synthesis of melanineDefective tyrosinase ► loss of function at normal body temperature
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The first step - The crime scene …
„CSI University” ☺
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Complex analysis - „DNA investigation”
IdentificationDetermination of origin - where the result’s coming from?
Individualization – common source of identitynuclear DNA, mitochondrial DNA
Extension of the target materials and markersGenetic and technical variability and limitations
quantity – sensitivity, threshold, reproducibilityquality – degradation, contamination, assurancereaction complexity - stochasticsgenetic complexity - pigmentation
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Requirements …The forensic genetic investigation is not scientific research or experiment but examination using scientific methods…
Sensitivity, reliability, reproducibility, verification
Technology, methodologyScientific criteria, statisticsEthical criteria
ResponsibilityQuality assurance
… some, they suppose that we did …
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Milestones in forensic genetics …
LandsteinerJeffreysMullis
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Targets …Human and nonhuman DNA
Nuclear DNAAutosomes
Repetitive markers (VNTR’s, STR’s)Single nucleotide polymorphisms (SNP’s)
Sex chromosomesRepetitive markers (VNTR’s, STR’s)Single nucleotide polymorphisms (SNP’s)
Mitochondrial DNACytochrome(b)Control region (HVI, HVII, CR)SNP’s
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PCR
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Short Tandem Repeats (STRs)
AATG AATG AATGFluorescent
dye label
7 repeats
8 repeats
the repeat region is variable between samples while the flanking regions where PCR primers bind are constant
Homozygote = both alleles are the same length
Heterozygote = alleles differ and can be resolved from one another
Primer positions define PCR product size
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Principles of sample separation and detection
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Sample Detection
CCD Panel
ColorSeparation
Ar+ LASER (488 nm)
Fluorescence ABI Prism spectrograph
Capillary or Gel Lane
Size Separation
Labeled DNA fragments (PCR products)
Detection region
Principles of fluorerescent detection
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Laboratory process …
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Short Tandem Repeats (STRs)
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13 STR loci with chromosomal positions
CSF1PO
D5S818
D21S11
TH01
TPOX
D13S317
D7S820
D16S539 D18S51
D8S1179
D3S1358
FGAVWA
AMEL
AMEL
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amelogenin
D19
D3
D8
TH01
VWA D21FGA
D16D18 D2
amelogeninD19
D3D8 TH01
VWA D21
FGA
D16D18 D2
Two
diff
eren
tind
ivid
uals
DNA Size (base pairs)
Results obtained in less than 5 hours with a spot of blood the size of a pinhead
probability of a random match: ~1 in 3 trillion
Human identity testing with multiplex STRs
Simultaneous Analysis of 10 STRs and Gender ID
AmpFlSTR® SGM Plus™ kit
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Multiplex - 9 autosomal loci
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15 autosomal loci …
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… from a mosquito ?
Upps! Here I am !!!
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Increasing interest in the Y-chromosome…Increasing interest in the Y-chromosome…
STR MarkersDYS19
DYS389I/II
DYS390
DYS391
DYS392
DYS393
DYS385
YCAII
DYS437
DYS438
DYS439
Y
http
://w
ww
.ncb
i.nlm
.nih
.gov
/gen
ome/
guid
e/
Human Genome
1 2 3 4 5 6 7 8 9 10 11 12
13 14 15 16 17 18 19 20 21 22 X Y
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17 Y-chromosome loci - haplotype
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The talking envelope …the victim was brutally murdered…inconsistent confessions of suspects…
primitive personality…„but I didn’t do that …”less information, more doubts …
… but one envelope at crime scene …nuclear DNA analysis …
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The fingerprint…
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The fingerprint - resultsautosomal lociY-STR loci
inclusion
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Single Nucleotide Polymorphisms (SNP’s)
Millions of SNP in genomein every 500-1000 base pairspoint mutation in genes or/and regulator regions
Relation to phenotypeLineages of ancestry (Y-SNP’s)Diagnostics
multi-factorial polygene diseases
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T T C A A G Template
Primer
Primers - tailed different lengths
SNaPshotTM Multiplex Kit:one base extension
C G
Primer extensionand termination
TA
T
C
A
GA AT
GC
CG
G
T
C Colour = genotype
Length = lociElectrophoresis
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Automatic analysis
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The mitochondrial genomecircular DNACambridge Reference Sequence~ thousand copy / cellno histones associationhigh mutation rate
at D-loop during ~ 9000 year 1%susceptibility to free oxygen radicals
diseases, aging no excision repair system
no repair only selectionbottleneck effect
heteroplasmyrecombination within the same mitochondrion - no recombinant variance like nuclear DNA maternal inheritance - matrilineage
geographically determinedgeological segregation of the populations regarding fixed mutations at non coding regions and the maternal inheritance
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The control region
Control Region (CR) –D(isplacement)-loop
~1120 base pairsorigin of replication opens hypervariable regions
HV1, HV2 and HV3lower selection pressuresource of variations is the mutation
Sequence DatabasesEMPOP
Control Region (D-loop)
1/16569
cyt b
ND5ND6
ND4
ND4L
ND3
COIIIATP6
ATP8 COII
12S rRNS
16S rRNS
ND1
ND2
COI
OH
OL
HV1 HV216024 16365 73 340
16024 576
„16 569” bp
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Forensic point of viewThe mtDNA has lower discrimination power than nuDNA
The mtDNA identifies not individual but haplotype of maternal lineage
on the other handThe level of diversity fairly high it’s a high probable, that two randomly selected individual have different mtDNAhaplotype
this probability is usually over 95 % - independently of populationsThe 2/3 part of the detected haplotypes from new samples -are newThe common (frequency over 1%) haplotypes are rareThere are many thousands of haplotypes the relative frequencies of haplotypes are low
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Terminal (Sanger) sequencingdNTP and ddNTPdifferent fragment sizedye labelled primersordye labelled nucleotides
dideoxi inhibits !
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D-loop sequence - forensic tools of matrilineage identification
Assembling the sequence of the questionable sample to reference sequence CRS (e.g. 16071-16140)
Different nucleotides at same position provide the mtDNAhaplotype of the given sample
Evidence(Q)
16093C 16129A
Reference(R)
16093C 16129A
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mtDNA haplotypes
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Genealogy
3 AFRICAN - 9 EUROPEAN - 7 ASIAN MAIN HAPLOGROUPS
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Couple murdering …
2004 – a married couple is missing personal belongings, comb, toothbrush, cap, cup
2006 – NN male body murderedbroken piece of hair from a car
morphological similarity to hairs from comb2007 – cranium, mandible2008 – reference samples♀ child and ♂ brother
Whose are the cranium and the broken hair?
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Cranial remains
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Results of sequencingcombbonehairchildbrother
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Results
exclusion
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Cytochrome b gene
14747 → 15886 position(1140 base pairs)
Cytochrome b-c1 complex
Coding sequences:
- lower mutation rates,- synonym mutations
Genetic drift - sequence differences among species
Phylogenetic analyses
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Cytochrome b gene sequence – a forensictool of species identification
14747 → 15886 position (1140 basepair) PCR: 358 bp fragment
Standard deviation approx. 15-20%
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SNP a cytochrome b génben (Canis f.)
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The expert opinion …Answers and interpretations …
Population geneticsRepresentative populations
Statistical geneticsIndividualizationGenealogy, relationship
Errors …Technical reasons
Contaminations, incompatibilityPersonal reasons
Proficiency
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Hypothesis testing (Bayes)Hypothesis of prosecution (Hp):E.g.: The putative origin of bloodstain from crime scene is -
the suspect (XY)
Hypothesis of defense (Hd):E.g.: The putative origin of bloodstain from crime scene is -not the suspect, but unknown person (NN)
Bayesian-theory (test of probability)
Pr: probabilityE: evidenceI: informationH: hypothesisp: prosecutiond: defense
I)E,Pr(HI)E,Pr(H
I),HPr(EI),HPr(E
I)Pr(HI)Pr(H
d
p
d
p
d
p=×
priorprobability
(PrPR)
LikehoodRatio
(genetic evidence)
posterior
probability(PoPR)
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The Likehood RatioWhen the origin of biological trace is a given person and the analytical error is excluded, Pr(E|Hp,I)=1.
the Likehood Ratio (LR) is – in a simplified form –the reciprocal value of frequency of the given genetic profile
I),HPr(G1
I),H,GPr(G1
I),HPr(EI),HPr(E
LRdcdscd
p≈==
Matching Probability Frequency of genetic profile
Pr: probabilityE: evidenceG: genetic profileI: informationH: hypothesisp: prosecutiond: defensec: crime scenes: suspect
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Thank you for your attention!
„Genetically modified Christmas tree” - Amboy, CA