1. The Pathogenesis of Diseases from Genetic and Genomic Point of View
Oliver Rácz and František Ništiar
Institute of Pathological Physiology
Medical School, Šafárik University
2009 – 2016
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2. 26th june 2000 is neither the beginning nor the end of the way
5 years before term ( )
The race is over, victory for Craig Venter.
The genome is mapped* - now what ?
Not a discovery!
A very important technological result and competition is always useful.
all is based on Mendel‘s and Watson‘s & Crick‘s discoveries in XIXth XXth century
*3*109 letters
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3. Mendel, Watson, Crick & the medical genetics of XIXth – XXth century
Mendel‘s laws are valid also today
Watson & Crick provided the material basis of these laws (central dogma of molecular biology)
Mendel‘s laws in medicine can be applied to monogenic diseases – long list, relatively rare
What is the genetics of diabetes, hypertension, coronary heart disease, Alzheimer disease ?
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4. White flower from red parents ???
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5.
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6. Quidditch ball for Harry Potter ?
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7. We discovered the secret of life, let’s have a beer!
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8.
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9. Central dogma of molecular biology (cca. 1965)
Replication
Transcription
Translation
Transformation
DNA DNA
RNA
PROTEIN A B
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10.
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11. Central dogma of molecular biology? – not so simple
DNA DNA
RNA
PROTEIN A B
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12. Central dogma of molecular biology? Epigenetics ? Role of RNA?
Regulation of transcription
Transcription factors, etc.
Methylation, acetylation…
Regulation of RNA editing
Alternative splicing
Regulation of RNA transport
Regulation of translation
siRNA, tRNA modifications
Postsynthetic modifications
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13. Central dogma of molecular biology
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14. Central dogma of molecular biology (now) – role of RNAs
Replication
Transcription
Translation
Transformation
DNA DNA
RNA
PROTEIN A B
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15. We and our relatives Organism Genome size chromosomes/ genes
Homo sapiens
23/30 000
Mus musculus
20/30 000
D. Melanogaster
4/13 000
C. Elegans
6/19 000
S. Cerevisiae
18/6 000
E. Coli
{1}3 200
HIV virus
9 700 9
A. Thaliana
?/25 000
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16. It is a little more complicated
DNA DNA
RNA
PROTEIN A B
DNA DNA
RNA
PROTEIN A B
DNA DNA
RNA
PROTEIN A B
DNA DNA
RNA
PROTEIN A B
DNA DNA
RNA
PROTEIN A B
DNA DNA
RNA
PROTEIN A B
DNA DNA
RNA
PROTEIN A B
DNA DNA
RNA
PROTEIN A B
DNA DNA
RNA
PROTEIN A B
DNA DNA
RNA
PROTEIN A B
DNA DNA
RNA
PROTEIN A B
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17. What is not “genetic” The number of human genes is as low as 30 000
the small worm C. elegans has genes
the mouse has as many genes as we, also with very similar function
The mystery is in complexity and networking: >>>> (possible on/off states)
And a number of surprises around transcription and translation (miRNA, tRNA modifications)
It is mapped but do we understand it?
GENETICS = HEREDITY
GENOMICS = EVERYTHING
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18. GENES AND THE ENVIRONMENT
GENOME
ENVIRONMENT A
SEVERE MONOGENIC
DISEASES
NEGATIVE AND
POSITIVE
ENVIRONMENTAL
FACTORS
physical
chemical
biological
nutrition
life style B
POLYMORPHISMS C
GENETIC RISK
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19. GENES AND THE ENVIRONMENT
GENOME
ENVIRONMENT A
THE DNA IS A DEAD MOLECULE
COMMUNICATES WITH THE ENVIRONMENT
THROUGH EPIGENETIC MECHANISMS
DNA methylation
Histone modification
siRNA
SEVERE MONOGENIC
DISEASES
NEGATIVE AND
POSITIVE
ENVIRONMENTAL
FACTORS
physical
chemical
biological
nutrition
life style B
LESS IMPORTANT MUTATIONS C
GENETIC RISK
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20. Genes and diseases in practical medicine
XIXth Century: symptom Þ diagnosis
sugar in urine = diabetes
XXth Century: symptom ß
etiopatogenesis Þ diagnosis
autoimmune destruction of b cells = dm Type 1
XXIst Century: symptom ß
genes and environment ß
susceptibility + overeating =
subtypes of dm Type 2
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21. Mutations changes of genetic information
THREE PRINCIPAL POSSIBILITIES
changes in genome not compatible with life
development and diversity
disease or increased risk fo disease*
THE BASIC DIFFERENCE FOR HEREDITY:
somatic and germ cell mutations
genome, chromosomal and gene mutations
no genes for diseases! – sickle cell, Alzheimer, diabetes...
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22. Everything is clear? CTT ACT GCC GGT TCG..........TGA
EACH AMINOACID IS CODED BY THREE CONSECUTIVE NUCLEOTIDES (TRIPLETS, CODONS)
CTT ACT GCC GGT TCG TGA
Leu Thr Ala Gly Ser STOP
OK, silent, missense, nonsense, frameshift
AND THE NONCODING SEQUENCES ?
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23. Everything is clear? BUT
CTT ACT GCC GGT TCG TGA
Leu Thr Ala Gly Ser STOP
BUT
IN THE GENOME THERE IS MORE NONCODING (REALLY NONCODING?!) SEQUENCES AS CODING
INTRONS IN THE GENES
REGULATION (SWITHCES)
REPETITIVE SEQENCES (IN MAN UP TO 50 % )
LINE 6000 bp,
SINE bp,
DIRT (PSEUDOGENES, FOREIGN GENES)
TELOMERES (STABILISATION OF CHROMOSOMES)
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24. Gene mutations and SNPs*
Point mutations in exons
Frameshift mutation in exons (1,2,4,5...)
Small deletion of triplets (3,6...)
Bigger deletions – transition to chromosomal aberrations
Mutations or polymorphisms in regulatory parts, introns, genes for r-tRNA = SNP, 10*more than the classic mutations
Variability of repeated sequences - markers
Dynamic mutations – triple repeat mutations
*SINGLE NUCLEOTID POLYMORPHISM
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25. CLASSIC MONOGENIC DISASES
Autosomal recessive (AR)
Sickle cell disase, other Hbpathies, thalassemias
Cystic fibrosis
Inborn errors of metabolism
Autosomal dominant (AD)
Polydactylia
Familial hypercholesterolemia
Polycystic kidney disease
X chromosome linked diseases
Heamophilia A, B
Daltonism
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26. Autosomal recessive (AR)
Two healthy (carrier heterozygotes) hidden in the population
Probability of ill (homozygote) children 1:4 (25%)
High number of relatively rare diseases, often fatal
Autosomal dominant
One ill heterozygote parent
Probablity of transfer to next generation 50%
Survival is better – “low penetration and expression”
2 * why
X chromosome linked diseases
Healthy heterozygote mother
Probablity of ill sons 50 % (Charles, William, George)
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