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The Pathogenesis of Diseases from
Genetic and Genomic Point of View
I.
Oliver Rácz and František Ništiar
Institute of Pathological Physiology
Medical School, Šafárik University
2009 – 2016
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26th june 2000
is neither the beginning nor the end of
the way
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5 years before term (1990 - 2005)
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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Mendel, Watson, Crick & the medical
genetics of XIXth – XXth century
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Mendel‘s laws are valid also today
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Watson & Crick provided the material basis of
these laws (central dogma of molecular biology)
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Mendel‘s laws in medicine can be applied to
monogenic diseases – long list, relatively rare
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What is the genetics of diabetes, hypertension,
coronary heart disease, Alzheimer disease ?
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White flower from red
parents ???
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Quidditch ball for Harry Potter ?
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We discovered
the secret of
life, let’s have a
beer!
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Central dogma of molecular
biology (cca. 1965)
Replication
Transcription
Translation
Transformation
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Central dogma of molecular
biology? – not so simple
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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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Central dogma of molecular biology
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Central dogma of molecular
biology (now) – role of RNAs
Replication
Transcription
Translation
Transformation
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We and our relatives
Organism
Homo sapiens
Mus musculus
D. Melanogaster
C. Elegans
S. Cerevisiae
E. Coli
HIV virus
A.
Thaliana
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Genome size
3 000 000 000
2 600 000 000
137 000 000
97 000 000
12 100 000
4 600 000
9 700
100
000 000
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chromosomes/
genes
23/30 000
20/30 000
4/13 000
6/19 000
18/6 000
{1}3 200
9
?/25 000
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It is a little more complicated
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What is not “genetic”
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The number of human genes is as low as 30 000
 the small worm C. elegans has 20 000 genes
 the mouse has as many genes as we, also with very similar
function
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The mystery is in complexity and networking:
230000 >>>> 220000 (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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GENES AND THE ENVIRONMENT
GENOME
ENVIRONMENT
SEVERE MONOGENIC
DISEASES
NEGATIVE AND
POSITIVE
ENVIRONMENTAL
FACTORS
physical
chemical
biological
nutrition
life style
POLYMORPHISMS
GENETIC RISK
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GENES AND THE ENVIRONMENT
GENOME
ENVIRONMENT
SEVERE MONOGENIC
DISEASES
NEGATIVE AND
POSITIVE
ENVIRONMENTAL
FACTORS
physical
chemical
biological
nutrition
life style
LESS IMPORTANT MUTATIONS
GENETIC RISK
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Genes and diseases in practical
medicine
XIXth Century: symptom  diagnosis
sugar in urine = diabetes
XXth Century: symptom 
etiopatogenesis  diagnosis
autoimmune destruction of b cells = dm Type 1
XXIst Century: symptom 
genes and environment 
etiopatogenesis  diagnosis
susceptibility + overeating =
subtypes of dm Type 2
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Mutations
changes of genetic information
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THREE PRINCIPAL POSSIBILITIES
1. changes in genome not compatible with life
2. development and diversity
3. disease or increased risk fo disease*
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THE BASIC DIFFERENCE FOR HEREDITY:
–
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somatic and germ cell mutations
genome, chromosomal and gene mutations
no genes for diseases! – sickle cell, Alzheimer, diabetes...
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Everything is clear?
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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
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THE NONCODING SEQUENCES ?
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Everything is clear?
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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 100-300 bp,
– DIRT (PSEUDOGENES, FOREIGN GENES)
– TELOMERES (STABILISATION OF CHROMOSOMES)
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Gene mutations and SNPs*
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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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CLASSIC MONOGENIC DISASES
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Autosomal recessive (AR)
– Sickle cell disase, other Hbpathies, thalassemias
– Cystic fibrosis
– Inborn errors of metabolism
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Autosomal dominant (AD)
– Polydactylia
– Familial hypercholesterolemia
– Polycystic kidney disease
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X chromosome linked diseases
– Heamophilia A, B
– Daltonism
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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
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Autosomal dominant
–
–
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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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