Inhoudsopgave
Week 1...................................................................................................................................................3
LE Introduction...................................................................................................................................3
LE Genome Architecture.....................................................................................................................3
The human genome........................................................................................................................3
Functional DNA:..............................................................................................................................3
‘Junk’ DNA......................................................................................................................................5
The epigenome...............................................................................................................................5
LE Genome Variation & Chromosomal Abnormalities........................................................................6
Genome variations.........................................................................................................................6
Chromosomal abnormalities..........................................................................................................9
Week 2.................................................................................................................................................14
LE Determination of variation...........................................................................................................14
Genome-wide determination of variation....................................................................................14
Local determination of variation..................................................................................................15
LE Mendelian inheritance & SNVs....................................................................................................16
Inheritance patterns.....................................................................................................................16
Coding variants: protein level.......................................................................................................17
Coding variants: nonsense mediated mRNA decay (NMD)...........................................................18
Mitochondrial inheritance............................................................................................................19
Week 3.................................................................................................................................................21
LE Microsatellite instability: diagnostics & mechanisms...................................................................21
Molecular mechanisms of microsatellite instability.....................................................................25
LE Microsatellite instability: disease mechanisms............................................................................29
Missplicing, nuclear foci and RAN translation...............................................................................30
Week 4.................................................................................................................................................32
LE Microsatellite instability: Molecular therapy...............................................................................32
Exam Preparation: microsatellite instability Q&A.............................................................................34
LE The needle in the haystack: Mendelian inheritance....................................................................35
Exome and genome sequences....................................................................................................35
Analysis of exome and genome sequences..................................................................................37
Week 5.................................................................................................................................................38
LE Multifactorial traits......................................................................................................................38
Week 6.................................................................................................................................................38
LE Non-invasive prenatal DNA & pre-implantation diagnostics........................................................38
, Fetal DNA in maternal blood........................................................................................................39
NIPT..............................................................................................................................................40
Numerical chromosomal abnormalities........................................................................................41
CNVs.............................................................................................................................................42
SNVs..............................................................................................................................................43
Pre-implantation genetic testing (PGT).........................................................................................44
Week 7.................................................................................................................................................46
LE The importance of model organisms in humans..........................................................................46
LE Drosophila as a model to study neurodevelopment/ Crash course in genome editing in retinal
diseases............................................................................................................................................46
LE Genome editing therapies for USH2A..........................................................................................48
LE Prime Editing: a novel CRISPR/Cas0-based...................................................................................48
Q&A......................................................................................................................................................49
,Week 1
LE Introduction
Waiting time for final diagnosis is very long. Many patients need to see multiple doctors before
getting their diagnosis
SSA more important than lectures
Only the red line & nociception are obligatory
The work groups (not bold) is also exam material
Genetic dominant disorders often skip a generation. And the phenotype can develop later on in life.
LE Genome Architecture
The human genome
~20.000 genes and ~25.000 non-coding genes in 22 pair autosomes and 2 sex chromosomes
Multiple deletions in a row =
GC have 3 hydrogen bonds, AT have 2
The first exons are often GC rich which are difficult to translate because the ribosome binds
Functional DNA:
- Protein coding genes
o Intergenic and intronic sequences
o Exon is coding, intron is spliced out
, o
o Genes have different isoforms that get expressed in different environments
- Non-coding genes
o Long non-coding or small non-coding RNAs
o Small non-coding RNAs: long gene is cut into smaller pieces (200 nt)
piRNAs: gene splicing of transposons to make sure transposons don’t jump
(Transposon, class of genetic elements that can “jump” to different locations
within a genome. Although these elements are frequently called “jumping
genes,” they are always maintained in an integrated site in the genome. In
addition, most transposons eventually become inactive and no longer move.)
miRNAs (microRNA) target coding genes. Regulate gene expression by base-
pairing with mRNAs.
Always in hairpin formation. They are transported, RICS complex is
formed and it can
o Inhibit translation
o Inhibit elongation
o Or mRNA deadenylation (shortening of mRNA poly A tail
Deletion of a miRNA gene or part of, can cause diseases
siRNAs (small interfering RNA): about 21 nt, gets into hairpin-RNA or dsRNA
bind to mRNA -> degradation -> interfering with translation. Target
transposons and exogenous genes
o Long non-coding RNAs: RNAs of 200+ nt
Week 1...................................................................................................................................................3
LE Introduction...................................................................................................................................3
LE Genome Architecture.....................................................................................................................3
The human genome........................................................................................................................3
Functional DNA:..............................................................................................................................3
‘Junk’ DNA......................................................................................................................................5
The epigenome...............................................................................................................................5
LE Genome Variation & Chromosomal Abnormalities........................................................................6
Genome variations.........................................................................................................................6
Chromosomal abnormalities..........................................................................................................9
Week 2.................................................................................................................................................14
LE Determination of variation...........................................................................................................14
Genome-wide determination of variation....................................................................................14
Local determination of variation..................................................................................................15
LE Mendelian inheritance & SNVs....................................................................................................16
Inheritance patterns.....................................................................................................................16
Coding variants: protein level.......................................................................................................17
Coding variants: nonsense mediated mRNA decay (NMD)...........................................................18
Mitochondrial inheritance............................................................................................................19
Week 3.................................................................................................................................................21
LE Microsatellite instability: diagnostics & mechanisms...................................................................21
Molecular mechanisms of microsatellite instability.....................................................................25
LE Microsatellite instability: disease mechanisms............................................................................29
Missplicing, nuclear foci and RAN translation...............................................................................30
Week 4.................................................................................................................................................32
LE Microsatellite instability: Molecular therapy...............................................................................32
Exam Preparation: microsatellite instability Q&A.............................................................................34
LE The needle in the haystack: Mendelian inheritance....................................................................35
Exome and genome sequences....................................................................................................35
Analysis of exome and genome sequences..................................................................................37
Week 5.................................................................................................................................................38
LE Multifactorial traits......................................................................................................................38
Week 6.................................................................................................................................................38
LE Non-invasive prenatal DNA & pre-implantation diagnostics........................................................38
, Fetal DNA in maternal blood........................................................................................................39
NIPT..............................................................................................................................................40
Numerical chromosomal abnormalities........................................................................................41
CNVs.............................................................................................................................................42
SNVs..............................................................................................................................................43
Pre-implantation genetic testing (PGT).........................................................................................44
Week 7.................................................................................................................................................46
LE The importance of model organisms in humans..........................................................................46
LE Drosophila as a model to study neurodevelopment/ Crash course in genome editing in retinal
diseases............................................................................................................................................46
LE Genome editing therapies for USH2A..........................................................................................48
LE Prime Editing: a novel CRISPR/Cas0-based...................................................................................48
Q&A......................................................................................................................................................49
,Week 1
LE Introduction
Waiting time for final diagnosis is very long. Many patients need to see multiple doctors before
getting their diagnosis
SSA more important than lectures
Only the red line & nociception are obligatory
The work groups (not bold) is also exam material
Genetic dominant disorders often skip a generation. And the phenotype can develop later on in life.
LE Genome Architecture
The human genome
~20.000 genes and ~25.000 non-coding genes in 22 pair autosomes and 2 sex chromosomes
Multiple deletions in a row =
GC have 3 hydrogen bonds, AT have 2
The first exons are often GC rich which are difficult to translate because the ribosome binds
Functional DNA:
- Protein coding genes
o Intergenic and intronic sequences
o Exon is coding, intron is spliced out
, o
o Genes have different isoforms that get expressed in different environments
- Non-coding genes
o Long non-coding or small non-coding RNAs
o Small non-coding RNAs: long gene is cut into smaller pieces (200 nt)
piRNAs: gene splicing of transposons to make sure transposons don’t jump
(Transposon, class of genetic elements that can “jump” to different locations
within a genome. Although these elements are frequently called “jumping
genes,” they are always maintained in an integrated site in the genome. In
addition, most transposons eventually become inactive and no longer move.)
miRNAs (microRNA) target coding genes. Regulate gene expression by base-
pairing with mRNAs.
Always in hairpin formation. They are transported, RICS complex is
formed and it can
o Inhibit translation
o Inhibit elongation
o Or mRNA deadenylation (shortening of mRNA poly A tail
Deletion of a miRNA gene or part of, can cause diseases
siRNAs (small interfering RNA): about 21 nt, gets into hairpin-RNA or dsRNA
bind to mRNA -> degradation -> interfering with translation. Target
transposons and exogenous genes
o Long non-coding RNAs: RNAs of 200+ nt
