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Istraživanja genoma čoveka
I. Novaković
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Nasledna osnova čoveka
• Podeljena je u 23 para hromozoma– + DNK u mitohondrijama
99.9995%0.0005%
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Organizacija humanog genoma
g en i u jedn o j ili p ar ko p ijan p r.: za h orm on rasta,
in su lin , d istrofin
clano vi u tan dem sko m n izun p r.: za rRNK, tRNK
sn RNK, h iston e
clano vi rasu ti u g eno m un p r.: g en i za g lob in ske lan ce,
im u n og lob u lin e, kolag en
fam ilije g ena
kod irajuca DNK(~10% )
p seu d og en ifrag m en ti g en ain tron i, sekven ce kojese n e p revod e itd .
n eko d iraju ca DNK(~90% )
geni i s rodne sekvenc e(~30% )
jed in stven e sekven ceili m ali b roj kop ija
(~80% )
tan d em ska il i n etan d em ska p on avljan jarasu ti p on ovci
sred n je d o visoko rep etitivn esekven ce
(~20% )
DNK van gena(~70% )
GENOM J EDR A3000 Mb
oko 30.000 g en a
13 g en a za i RNK22 g en a za tRNK2 g en a za rRNK
M IT OHONDR IJ A L N I GENOM16,6 Mb37 g en a
HU M A N I GENOM
Jedinstvene ili srednjerepetitivne sekvence
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Humani genom:
3x109 parova svaki 1000. nukleotid
nukleotida je polimorfan
Razlike u nukleotidnom sastavu tj. gradji DNK koje se sreću u populaciji zdravih ljudi f alela > 1%, hetrozigoti > 2% Genetički markeri, DNK profil, predispozicija za
bolest...
3x109 bp
Genetički-DNK polimorfizam
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Tipovi DNK polimorfizma
Polimorfizam pojedinačnih nukleotida (SNP)
Različiti broj uzastopnih
ponovaka (VNTR, CNV)
Deleciono/insercione varijante
(CA)10 = ALEL 2(CA)15 = ALEL 3
(CA)5 = ALEL 1
(CA)20 = ALEL 4(CA)25 = ALEL 5
AAGGT C ili T GTTC
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Izvori DNK za analizu
Biološki materijal u kome su
ćelije sa jedrom: krv horionske resice, amnionska tečnost, krv iz pupčanika bris bukalne sluzokože trag telesne tečnosti koren dlake ...
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PCR – lančana reakcija polimerizacijemolekula DNK
PCR (
umnožavanje odredjenog segmenta DNK pomoćuenzima Taq polimeraze
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Real-time PCR
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Sekvenciranje DNK
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“Genski čip”- test hibridizacije na mikroploči
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“Genski čip”- test hibridizacije na mikroploči
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Genetička osnova bolesti
• Hromozomske aberacije
• Monogenske bolesti– AD, AR– X vezano– preko mtDNK
• Poligenske bolesti
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monogenskeforme
poligenske/multifaktorske forme
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Rodoslovna stabla
muškarac
žena
nepoznat pol
brak
aficirana osoba
mrtva osoba
prenosilac X-vezanerecesivne osobine
brak u srodstvu
dvojajčani blizanci
jednojajčani blizanci
bez potomstva
heterozigot zamutaciju koja seprenosi autozomima
proband
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Mutacije gena
– Delecije = gubitak dela ili celog gena– Duplikacije/insercije = “višak” dela gena– Supstitucije (point mutacije) = zamena jednog
para baza drugim parom– Povećanje broja ponovaka u genu
Rezultat: Protein za koji je gen zadužen je
IZMENJEN ili ODSUTAN
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Segregaciona analiza
• Na koji način se svojstvo-bolest prenosi u porodici?
• Da li način prenošenja odgovara nekom od Mendelskih načina nasleđivanja:
•AR, AD•XR, XD•Y
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Mapiranje gena = određivanje mesta tj. pozicije u genomu
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METODE MAPIRANJA GENA
funkcionalno poziciono
protein
RNK
DNK
1,2 2,3
1,3 1,4 3,4
1,4
2,4
Lod skor > 3
Linkage analiza
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Linkage analiza –analiza vezanosti
• Zajedničko nasleđivanje dve (ili više) osobina– Osobina + osobina
• Osobina + bolest• Bolest + bolest
Odgovorni geni se nalaze na istom
hromozomu
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Analiza vezanosti = Analiza polimorfnih DNK markera u genomu
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Lod skor
• Lod > 3 verovatnoća vezanosti lokusa
= 103 : 1 = 1.000 : 1 (
• Lod < -2 verovatnoća vezanosti lokusa
= 10-2 : 1 = 0,01 : 1
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Fahrov sindromIdiopatska kalcifikacija bazalnih
ganglija
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Am. J. Hum. Genet. 65:764–772, 1999
Identification of a Locus on Chromosome 14q for Idiopathic Basal Ganglia Calcification (Fahr Disease)Daniel H. Geschwind,1,2 Maxim Loginov,1,2 John M. Stern21Neurogenetics Program and 2Department of Neurology, UCLA School of Medicine, Los Angeles
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III-15a 73 60 Parkinsonizam, distonijaIII-18 76 70 ParkinsonizamIII-26 70 58 disfagija, ParkinsonizamIV-7 50 23 psihoza, ParkinsonizamIV-25 52 37 fokalna distonija, tremor, napadi panikeIV-27 58 * grčevi, jerkingIV-32 43 36 ataksija, tremorIV-45 46 37 fokalna distonija, disfagijaIV-49 41 40 ParkinsonizamIV-51 40 18 tremor pri pisanju, fokalna distonija, horeaV-4 38 * fokalna distonija, grčeviV-74b 29 12 fokalna distonija, tremorV-75b 28 13 Tremor, disfagijaV-83 10 6 disfagija, fokalna distonijaV-84 9 5 Tremor, distonija
*početak ne (10–20 years, by history).a Pozitivan CT, poznata klinička slika, ali nije ispitivan(deceased).b Verovatno aficiran (negativan CT, <30 god.)
starost početak glavni simptomi
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Mapiranje gena = određivanje mesta tj. pozicije u genomu
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Mapiranje gena = određivanje mesta tj. pozicije u genomu
14q13-21
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Genomics 84 (2004) 577–586
Cloning, genomic structure, and expression profiles of TULIP1(GARNL1), a brain-expressed candidate gene for 14q13-linkedneurological phenotypes, and its murine homologue
Thomas Schwarzbraun,a John B. Vincent,b Axel Schumacher,b Daniel H. Geschwind,c Joao Oliveira,c Christian Windpassinger,a Lisa Ofner,a Michael K. Ledinegg,a Peter M. Kroisel,a Klaus Wagner,a and Erwin Peteka,*
a Institute of Medical Biology and Human Genetics, Medical University of Graz, Harrachgasse 21/8, A-8010 Graz, AustriabNeurogenetics Section, Centre for Addiction and Mental Health, Clarke Division, 250 College Street, Toronto, ON M5T 1R8, Canadac Department of Neurology and Neurogenetics Program, David Geffen School of Medicine, University of California at Los Angeles,Los Angeles, CA 90095, USA
Gen kandidat….
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Ali...
American Journal of Medical Genetics Part B (Neuropsychiatric Genetics) 147B:1319–1322 (2008)Brief Research Communication
Exclusion of Linkage to Chromosome 14q in aLarge South Tyrolean Family With IdiopathicBasal Ganglia Calcification (IBGC)
Claudia Be´u Volpato,1* Alessandro De Grandi,1 Ebba Buffone,2 Irene Pichler,1 Uwe Gebert,3 Gunther Schifferle,4Rudolf Scho¨nhuber,2 and Peter P. Pramstaller1,2,51Institute of Genetic Medicine, European Academy, Bolzano, Italy2Department of Neurology, Central Hospital, Bolzano, Italy3Department of Radiology, Marienklinik, Bolzano, Italy4Department of Radiology, Central Hospital, Bolzano, Italy5Department of Neurology, University of Lubeck, Lubeck, Germany
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J Mol Neurosci (2009) 39:346–353
2q37 as a Susceptibility Locus for Idiopathic Basal GangliaCalcification (IBGC) in a Large South Tyrolean Family
Claudia Béu Volpato, Alessandro De Grandi, Ebba Buffone, Maurizio Facheris,Uwe Gebert, Günther Schifferle, Rudolf Schönhuber, Andrew Hicks &Peter P. Pramstaller
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Mapiranje gena za ICBG
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FS 9 FS 7 FS 5 FS 3 FS 4
FS 1 FS 8
FS 2 FS 6
2 42 21 21 31 12 1
FS4
D14s596 2 4D14s1014 1 2
D14s75 1 2D14s306 3 3D14s288 3 1D14s259 2 1
FS15 24 25 11 12 11 2
FS8
2 51 41 53 13 22 1
FS32 33 31 32 23 11 1
FS5
3 53 43 52 11 21 1
FS62 21 31 13 23 32 1
FS2
2 12 31 43 32 22 1
FS74 22 41 11 23 31 1
FS9
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Analiza vezanosti u porodici iz Srbije
= 0.00
D14s596 -3.36
D14s1014 -2.998
D14s75 -3.132
D14s306 -6.573
D14s288 -3.345
D14s259 -5.876
haplotip -5.706
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Kostić Vladimir, M. Lukić-Ječmenica, I. Novaković, V. Dobričić, L. Brajković, M. Krajinović, C. Klein, A. Pavlović: Exclusion of linkage to chromosomes
14q, 2q37 and 8p21.1-q11.23 in a Serbian family with idiopathic basal ganglia calcification. J Neurol. 2011;258(9):1637-42.
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Wang C, Li Y, Shi L, Ren J, Patti M, Wang T, de Oliveira JR, Sobrido MJ, Quintáns B,
Baquero M, Cui X, Zhang XY, Wang L, Xu H, Wang J, Yao J, Dai X, Liu J, Zhang L, Ma H, Gao Y, Ma X, Feng S,
Liu M, Wang QK, Forster IC, Zhang X, Liu JY
"Mutations in SLC20A2 link familial idiopathic basal ganglia calcification with phosphate homeostasis". Nat Genet 44 (February 2012).
Sodium-dependent phosphate transporter 2 PIT-2, inorganic phosphate transporter
8p12-p11
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Mutations in SLC20A2 are a Major Cause of Familial Idiopathic Basal Ganglia Calcification
Neurogenetics, November 2012
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F5 Family c.583_584delGT
F1 Family c.508delT
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ICBG porodica iz Srbije
• Nema mutacije u SLC20A2 genu!
• GENETIČKA HETEROGENOST!
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NATURE METHODS, VOL.5 NO.1, JANUARY 2008
Next-generation sequencing transforms today’s biologyStephan C Schuster
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Poligenske bolesti
Genetička osnova
(više parova gena)
Faktori sredine
fenotip
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Studije asocijacije
Udruženost genskih polimorfizama sa nekom od poligenskih bolesti.
Sklonost tj. podložnost!
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Pristupi u izučavanju multifaktorske osnove bolesti
• Studije asocijacije
Geni kandidati
Čitav genom
bolesni zdravi
Učestalost polimorfizma:
:
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Izbor gena-kandidata
– Na osnovu poznavanja etio-patogenetskih činilaca
– Geni identifikovani u analizama vezanosti
– Geni identifikovani kod animalnih modela
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Alzheimer-ova demencija
– ApoE polimorfizam4 alel PREDISPOZICIJA!
– ranije obolevanje (4/4, 4/3) !– 50-75% heterozig. NE OBOLEVA!– drugi geni, faktori sredine...
genotip AD Kontr. AD Kontr.
4/4, 4/3, 4/2 64% 31% 47% 17%
3/3, 2/3, 2/2 36% 69% 53% 83%
S A D Japan
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Studije asocijacije u čitavom genomu(Genome Wide Association Studies, GWAS)
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Studije asocijacije čitavog genoma(Genome Wide Association Studies, GWAS)
• Simultana analiza >10.000 SNP
• Microarray tehnologija
(genski čip)
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GWAS i Alzheimerova bolest
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GWAS i Alzheimerova bolest
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GWAS i Alzheimerova bolest
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GWAS i Alzheimerova bolest
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GWAS i Alzheimerova bolest
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GWAS i Alzheimerova bolest
• Meta analiza 12 GWAS studija
• + 5,043 ispitanika sa Mayo klinike
(2,455 AB : 2,588 K)
“Investigation of 15 of the top candidate genes for late-onset Alzheimer’s disease” Belbin et al, 2011
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GWAS i Alzheimerova bolest
• BIN1, bridging integrator-1 • CLU, clusterin ili complement lysis inhibitor (CLI) • CR1,complement receptor
• EXOC3L2, exocyst complex component 3-like 2 • PICALM phosphatidylinositol binding clathrin assembly protein
imunomodulacija
unutraćelijski transport
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GWAS i Alzheimerova bolest
• TNK1, tyrosine kinase, non-receptor, 1 • GAB2, GRB2-associated-binding protein 2 (adapter,
aktivator fosfatidil inozitol kinaze 3)
• LOC651924 • GWA_14q32.13,
• PGBD1, piggyBac transposable element derived 1
• EBF3, early B-cell factor 3 Regulator ćelijskog ciklusa, TSG
PSEUDOGEN, sličan sa Ubiquitin-like 1-activating enzyme E1B
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“A genome-wide survey of human short-term memory”
• 909.622 lokusa
• Faza 1: Švajcarska (333 ispitanika)– Faza 2: Švajcarska (254 ispitanika)– Faza 3: Nemačka (922 ispitanika)– Faza 4: Srbija (523 ispitanika)
A Papassotiropoulos etal, 2010
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“A genome-wide survey of human short-term memory”
rs6731900rs565348
rs10930201
rs2278729
rs11235714
rs225344
Hromozom 2 11 21
Gen SCN1A (sodium channel, voltage-gated, type I, alpha subunit)
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SCN1A (rs10930201) genotip:
AC AA
…Funkcionalna NMR
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"A genome-wide survey and functional brain imaging study identify CTNNBL1 as a memory-
related gene"
• CTNNBL1 = Beta catenin like protein 1• Hromozom 20
A Papassotiropoulos etal, , 2011.
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Problemi kod studija asocijacije
• Nekonzistentnost rezultata usled:
– Različite brojnosti ispitivanih populacija
– Geografskih/etničkih specifičnosti
– Razlika između polova
– Sadejstva gen-gen i gen-sredina
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“Missing heritability”
B. Maher, Nature, 2008
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Moguća objašnjenja
• Rešenje nam je “pred nosom”
• Odgovorne su retke varijante SNPs, koje GWAS ne analiziraju
• Ključne su CNV (copy number variations) a ne SNP
• U pitanju je vrlo složena interakcija gena i sredine, kroz generacije...
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Sinteza proteina:transkripcija i translacija
DNK
RNK
obrada
translacija
G* AAAAAA
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Era OMIKS-a
• Genom– Egzom (sve kodirajuće sekvence)
• Transkriptom
• Proteom
• Metabolom
• Interaktom
• ….