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HANNIE KREMER KNO & ANTROPOGENETICA. ANTROPOGENETICA – HUMAN GENETICS. Things we do Map diseases to chromosomes (position) - monogenic and complex disorders Interpret DNA variation – monogenic and complex disorders - PowerPoint PPT Presentation
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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. Therapy98% Identical 99,8% identical
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
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
Human Genetics Nijmegen
max = 6.47 = 0D9S1842
Chromosoom 9q21-q22.3D9S1842
D9S1781
D9S197
D9S1816
D9S280
D9S1851
D9S287
D9S176
2.8
ROR2
1.6
0
1.4
0.1
0.6
2.1
cM
Linkage interval Robinow syndroom
Human Genetics Nijmegen
Robinow syndrome Ror2 null mouse
From DeChiara et al. Nature Genetics March 2000
Genotyping Single Nucleotide Polymorphisms (SNPs)
…cctcctagggttgcaaagcctccttggctatg……cctcctagggttgcatagcctccttggctatg…
Person B:Person A: …cctcctagggttgcatagcctccttggctatg……cctcctagggttgcatagcctccttggctatg…
Allel 1
Allel 2
~ 1,000,000 SNPs
> 1 SNP per >3 kb
500,000 SNPs
arrays
Whole genome association studies
Diabetes type 1
Obesity
ADHD
2000 cases 4000 controls
SNPs indicate genes involved
Gene 1Gene 2Gene 3Gene 4
……Gene 30.000
Case control design
500,000 SNPs
arrays
Whole genome association study
Obesitas
9000 cases 30000 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: 889-894, 2007.
35% +0 kg50% +1.5 kg
15% +3.0 kg
FTO gene
500.000 SNPs
arrays
Whole genome association study
Obesitas9000 cases 30000 controls
BMI > 30
FTO gene
INTERPRET GENETIC VARIATION
• Sequence variation at a specific nucleotide• Copy number variations (CNV)
Ins A
p63 gene mutations in EEC syndrome
V202M S272N
R279C (3)R279H (12)R279Q
C306RR304W (8)R304Q (14)R304P
R204W (10)R204Q (7)R204L R280C (6)
R280H (2)R280S
R227Q (8)
C308SC308Y
P309S
D312HD312N
C269Y
TA SAMDNA binding IsoTA-p63
Y192C (3)
L162PY163C
29 Mutations in 90 families28 missense1 frameshift
A315ER313G
L248C
276 copy number abnormalities in 100 patients with Mental Retardation
3
20
23 23
21
5
1
3
01
0
5
10
15
20
25
Perc
enta
ge o
f pat
ient
s
0 1 2 3 4 5 6 7 8 90
5
10
15
20
25
0 1 2 3 4 5 6 7 8 90
5
10
15
20
25
DNA copy number alterations identified per patient
0 1 2 3 4 5 6 7 8 9
How do we differentiate normal variation from causal changes?
Chromosome 15
Chromosome 15
Mother
Father Chromosome 1
Chromosome 1
Chromosome 1
Paient 1 Chromosome 15
de novo inherited variation
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
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?
1.) Sequence Capture
2.) Sequencing
3.) Mapping
mapped reads
formed contigstargeted exon(s)
4.) Mutation detection
Can we look at the all EXons of the genOME?EXOME sequencing!
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
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
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, MartaZ 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 VeltmanNature Genetics
Alex Hoischen Christian GillisenBregje van Bon
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
RPGRIP1
NPHP2inversin
NPHP5IQCB1
nephrocystin-3
NPHP3
RPGRIP1L
NPHP4nephrocystin-4
PDE-δ
Arl3 RP2 β-tubulin
NPHP1nephrocystin-1
RPGR
Photoreceptor cilium protein complex
CEP290
Dynein
lebercilin *
CC2D2A
RPGRIP1
NPHP2inversin
NPHP5IQCB1
nephrocystin-3
NPHP3
RPGRIP1L
NPHP4nephrocystin-4
PDE-δ
Arl3 RP2 β-tubulin
NPHP1nephrocystin-1
RPGR
Photoreceptor cilium protein complex
Senior Loken
RP
LCA / Joubert / Meckel
Joubert / Meckel
CEP290
Dynein
lebercilin *LCA
LCA
Nephron- ophthisis
CC2D2A
Joubert
Joubert
AANGEBOREN GEHOORVERLIES
~ 1 in 900 children has congenital hearing impairment >20 dB in one or more frequencies
50 % inherited 50% environmental
70% Nonsyndromic 30% Syndromic
~%77AR
~%22 AD
~%1 X-linked
<%1 Mitochondrial
• Usher• Alport• Pendred• Norrie• Waardenburg• Branchio-Oto-Renal• Jervell and Lange-
Nielsen
• Ototoxic drugs
• Acustic trauma
• Infections~%77AR
~%22 AD
Known Genes
21 6 166
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
DFNB63 LOCUS
TECTA
MYO7A
USH1C
DFNA32
DFNB20
DFNB24
DFNB51
DFNB63
D11S2371
D11S1337
D11S4179
D11S1291
D11S916
D11S1314
D11S4139
D11S4136
D11S4113
D11S987
~5.2
9 M
b
15.515.415.315.215.114.314.214.1131211.211.1211.111112.112.212.313.113.213.313.413.514.114.214.32122.122.222.323.123.2
23.3
24.124.224.325
FGF3DFN
B63
TR57
26 bekende of voorspelde genen
FT1A-G PKDF702
DFN
B63
DFN
B63
DFN
B63
FT2
1.03 Mb
EFFECT VAN MUTATIES
E110KA29SfsX54 (c.358+4G>A)
W105RR81Q
A215AG163VfsX4 (c.358+4G>A)3’ UTR3’ UTR
Catechol-O-methyltransferase domein
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.