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HANNIE KREMER KNO & ANTROPOGENETICA. ANTROPOGENETICA – HUMAN GENETICS.

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Presentation on theme: "HANNIE KREMER KNO & ANTROPOGENETICA. ANTROPOGENETICA – HUMAN GENETICS."— Presentation transcript:

1 HANNIE KREMER KNO & ANTROPOGENETICA

2 ANTROPOGENETICA – HUMAN GENETICS

3 Things we do 1.Map diseases to chromosomes (position) - monogenic and complex disorders 2. Interpret DNA variation – monogenic and complex disorders 3.Understand the function of genes - pathogenesis 4.Therapy 98% Identical 99,8% identical

4 Things we do 1.Map diseases to chromosomes (position) - monogenic disorders 2. Interpret DNA variation – monogenic and complex disorders 3.Understand the function of genes - pathogenesis 4.Therapy

5 MAP DISEASES TO CHROMOSOMES MONOGENIC DISORDERS

6 A n * B n B * Linkage: If a gene and a marker are on the same chromosome they will segregate together UNLESS They are separated by recombination A

7 A n* BA n* B A * n B B n* A

8 Robinow syndrome Short stature Wide-spaced eyes Short nose Small penis

9 Human Genetics Nijmegen  max = 6.47  = 0 D9S1842 Chromosoom 9q21-q22.3 D9S1842 D9S1781 D9S197 D9S1816 D9S280 D9S1851 D9S287 D9S ROR cM Linkage interval Robinow syndroom

10 Human Genetics Nijmegen Robinow syndrome Ror2 null mouse From DeChiara et al. Nature Genetics March 2000

11 COMPLEX DISORDERS MAP DISEASES TO CHROMOSOMES

12 Genotyping Single Nucleotide Polymorphisms (SNPs) … cctcctagggttgca a agcctccttggctatg… … cctcctagggttgca t agcctccttggctatg… Person B : Person A : … cctcctagggttgca t agcctccttggctatg… Allel 1 Allel 2 ~ 1,000,000 SNPs > 1 SNP per >3 kb

13 500,000 SNPs arrays Whole genome association studies Diabetes type 1 Obesity ADHD 2000 cases4000 controls SNPs indicate genes involved Gene 1 Gene 2 Gene 3 Gene 4 …… Gene Case control design

14 500,000 SNPs arrays Whole genome association study Obesitas 9000 cases30000 controls BMI > 30 FTO gene Case control design Frayling et al. A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science 316: , 2007.

15 35% +0 kg 50%+1.5 kg 15%+3.0 kg FTO gene SNPs arrays Whole genome association study Obesitas 9000 cases30000 controls BMI > 30 FTO gene

16 INTERPRET GENETIC VARIATION Sequence variation at a specific nucleotide Copy number variations (CNV)

17 Ins A p63 gene mutations in EEC syndrome V202M S272N R279C (3) R279H (12) R279Q C306R R304W (8) R304Q (14) R304P R204W (10) R204Q (7) R204L R280C (6) R280H (2) R280S R227Q (8) C308S C308Y P309S D312H D312N C269Y TA SAM DNA bindingIso TA-p63  Y192C (3) L162P Y163C 29 Mutations in 90 families 28 missense 1 frameshift A315E R313G L248C

18 Structure model of p63 DNA binding domain

19 276 copy number abnormalities in 100 patients with Mental Retardation How do we differentiate normal variation from causal changes?

20 Patient 1 Genomic profile obtained 250K SNP array Log 2 Patient/Control

21 Chromosome 15 Mother Father Chromosome 1 Paient 1 Chromosome 15 de novoinherited variation

22 Alex HoischenChristian Gillisen Next Generation sequencing

23 The complete genome of an individual by massively parallel DNA sequencing. Wheeler et al. Nature, April 2008 Here we report the DNA sequence of a diploid genome of a single individual, James D. Watson, sequenced to 7.4-fold redundancy in two months using massively parallel sequencing 1953

24 Question of the year 2007 Nature genetics The sequencing of the equivalent of an entire human genome for $1,000 has been announced as a goal for the genetics community What would you do if this sequencing capacity were available immediately?

25 1.) Sequence Capture 2.) Sequencing 3.) Mapping mapped reads formed contigs targeted exon(s) 4.) Mutation detection Can we look at the all EXons of the genOME? EXOME sequencing!

26 ABI SOLID 600 million map-able 50bp reads  30Gb Roche million map-able 500bp reads  500Mb

27 To understand human health and disease we have to understand all types of genomic variation: ~4,000,000 variants ~3,000,000 SNP variants* ~10,000 non-synonymous coding variants* ~1,000,000 CNVs* * Per individual genome

28 Focus on de novo disease 4 DNAs from patients with Schinzel-Giedion syndrome patient samples n=14 4 human exomes: 2.5Gb output per sample

29

30 De novo mutations of SETBP1 cause Schinzel-Giedion syndrome in 13 patients Alexander Hoischen*, Bregje WM van Bon*, Christian Gilissen*, Peer Arts, Bart van Lier, Marloes Steehouwer, Petra de Vries, Rick de Reuver, Geert Mortier, Koen Devriendt, Marta Z Amorim, Nicole Revencu, Alexa Kidd, Mafalda Barbosa, Anne Turner, Janine Smith, Christina Oley, Alex Henderson, Ian M Hayes, Elizabeth M Thompson, Han G Brunner, Bert BA de Vries, Joris A Veltman Nature Genetics Alex Hoischen Christian Gillisen Bregje van Bon

31 Things we do 1.Map diseases to chromosomes (position) - monogenic disorders 2. Interpret DNA variation – monogenic and complex disorders 3.Understand the function of genes - pathogenesis 4.Therapy

32 RPGR Photoreceptor cilium protein complex Retinitis Pigmentosa

33 RPGRIP1 NPHP2 inversin NPHP5 IQCB1 nephrocystin-3 NPHP3 RPGRIP1L NPHP4 nephrocystin-4 PDE-δ Arl3 RP2 β-tubulin NPHP1 nephrocystin-1 RPGR Photoreceptor cilium protein complex CEP290 Dynein lebercilin * CC2D2A

34 RPGRIP1 NPHP2 inversin NPHP5 IQCB1 nephrocystin-3 NPHP3 RPGRIP1L NPHP4 nephrocystin-4 PDE-δ Arl3 RP2 β-tubulin NPHP1 nephrocystin-1 RPGR Photoreceptor cilium protein complex Senior Loken RP LCA / Joubert / Meckel Joubert / Meckel CEP290 Dynein lebercilin * LCA Nephron - ophthisis CC2D2A Joubert

35 GENETICA VAN GEHOORVERLIES ROL VAN BIOINFORMATICA

36 AANGEBOREN GEHOORVERLIES ~ 1 in 900 children has congenital hearing impairment >20 dB in one or more frequencies 50 % inherited 50% environmental 70% Nonsyndromic30% Syndromic ~%77 AR ~%22 AD ~%1 X-linked <%1 Mitochondrial Usher Alport Pendred Norrie Waardenburg Branchio-Oto-Renal Jervell and Lange-Nielsen Ototoxic drugs Acustic trauma Infections ~%77 AR ~%22 AD Known Genes

37 WAAROM IS HET OPHELDEREN VAN OORZAKEN VAN ERFELIJKE ZIEKTEN BELANGRIJK?  Vraag van patiënt naar de oorzaak beantwoorden: is het erfelijk - erfelijkheidsadvies  Vroege diagnostiek van familieleden – goede begeleiding  Inzicht in genen/eiwitten die essentieel zijn voor ontwikkeling en functie van het binnenoor  Handvaten voor therapie

38 FAMILIE TR57

39 DFNB63 LOCUS TECTA MYO7A USH1C DFNA32 DFNB20 DFNB24 DFNB51 DFNB63 D11S2371 D11S1337 D11S4179 D11S1291 D11S916 D11S1314 D11S4139 D11S4136 D11S4113 D11S987 ~5.29 Mb FGF3 DFNB63 TR57 26 bekende of voorspelde genen FT1A-GPKDF702 DFNB63 FT Mb

40 LRTOMT KARAKTERISATIE Genome browser build 36.1 LRTOMT1 LRTOMT2

41 EFFECT VAN MUTATIES E110K A29SfsX54 (c.358+4G>A) W105R R81Q A215A G163VfsX4 (c.358+4G>A) 3’ UTR Catechol-O-methyltransferase domein

42 MOLECULAR MODELING

43 EFFECT VAN MISSENSE MUTATIES

44 HET BINNENOOR

45 SAMENVATTING  Bioinformatica is essentieel voor verschillende stappen in studies naar ziektegenen  De structuur en functie van het humane genoom en genen zijn nog lang niet in kaart gebracht  De oorzaak van DFNB63 is gelegen in defecten in het LRTOMT gen. Het precieze effect van mutaties in dit gen op de functie van het binnenoor is nog niet duidelijk.


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