Translational genomics
Medical biology Master
Lecture 1: Introduction & the red line
The near future:
- genome sequencing at birth
- Monogenetic diseases immediately diagnosed
- Use of genome data in personalized treatment protocols
- Predictive profiles (+ health advice) for late-onset diseases
- DNA-food/DNA-dating/ DNA-jobs/ DNA-insurance/ DNA-discrimination
Personalized medicine:
Do the assessment of
the risk at the baseline
risk. This is what we are
going to look at. Also, a
bit of preclinical
progression is part of
this course.
Personal health plan
based on the baseline
risk. That is the idea of
personalized medicine.
What do we want?
- Personal
diagnosis:
mutation or
something else
- Personal prognosis: what will happen in … years.
- Personal disease management: how to deal with the disease, e.g.
hearing aid for hearing loss. It does not treat the disease. Aid for the
symptoms. Symptoms are tackled
- Personal treatment: actually, dealing with the disease, so the
disease will be treated. Act against the cause of the disease.
Which mode of inheritance is most likely in the pedigree below?
Disease inheritance: autosomal dominant, can be late onset disease
(reduced penetrance).
Too many people for autosomal recessive.
Mitochondrial cannot be the case because we see a male transmitting the
disease
Can also be x-linked dominant: however, its rare There are not many X-linked dominant
diseases
1
, Translational genomics
Medical biology Master
Lecture 2: Genome architecture
The human genome:
DNA in the nucleus + DNA in mitochondria
The nucleus:
- 22 pairs autosomes
- 2 sex chromosomes (XX or XY)
- 20.000 coding genes
- 25.000 non-coding genes
Base pairs: Purines (A + G) and pyrimidines (T + C +
(U (in RNA only)))
Between A + T 2 hydrogen bonds
Between G + C 3 hydrogen bonds
Functional DNA:
- Protein-coding genes
- Non coding genes
- Regulatory elements
Protein coding genes:
Ribosome binds at 5’ UTR, here a lot of C and
G’s are located. Red sequences are the
coding regions.
Gene = functional unit without promoter
region.
UTR = untranslated region
Genes are differently spliced in different tissues
different isoforms.
Small blue box = 3’ UTR on the right.
5’UTR on the left.
Promotor region= place where transcription
factors can bind.
Bars are exons, everything in between are introns
Non-coding genes:
Long non coding RNAs (lncdRNAs)
Small non coding RNAs (siRNAs + miRNAs + piRNAs)
2
, Translational genomics
Medical biology Master
Small ncRNA: mechanism of action
Small RNA precursors turn into mature small RNAs, they are then incorporated into the
human RISC complexes and then they target the genes. RNA protein complex (small RNA +
RISC) looks for targets and the miRNA guide the protein to the target genes.
Micro RNAs (miRNAs):
Immature miRNA (pre-miRNA) is transported outside of the nucleus, and is recognized by
RISC complex (a lot of proteins including Dicer protein).
Then, either miRNAs can result in:
- Inhibition of translation initiation
- Inhibition of translation elongation
- mRNA deadenylation (remove the poly-A tail)
all leading to negative regulation of translation.
RNA binds to protein and brings to position in DNA
miRNAs can result in diseases.
Feingold syndrome 2: miR-17 -92 deletion
- Short hands, thumb is almost gone, syndactyly
3
, Translational genomics
Medical biology Master
Long non-coding RNA: types They can be:
- Intronic lncRNA
- Intergenic lncRNA
- Natural antisense transcript (NAT)
lncRNA can:
- Bind the protein they can then guide the protein for storage etc.
- Bind the DNA if it binds the promotor, the gene will not get expressed anymore
(to regulate gene expression)
- Bind the RNA also in this way you can regulate gene expression
NATs: mechanism of action
a. RNA pol II you get transcription of the genes. However, the other strand cannot be
translated, because the RNA pol II is on the upper gene. So basically, the other one cannot
be translated anymore. it hinders (physical hindrance due to the big RNA polymerase
complex) the transcription of the other gene (of the gene it regulates) (this happens on DNA
level)
b. On RNA level: Binds to splice site, and splice site will not be recognized anymore. E.g.
when NATs bind to exon 3 splice site not recognized by splicing machinery products
only consists of exon 1 and 2.
c. NAT can bind to RNA and do RNA editing recruit proteins for RNA editing e.g. A>T
nuclear retention
4
Medical biology Master
Lecture 1: Introduction & the red line
The near future:
- genome sequencing at birth
- Monogenetic diseases immediately diagnosed
- Use of genome data in personalized treatment protocols
- Predictive profiles (+ health advice) for late-onset diseases
- DNA-food/DNA-dating/ DNA-jobs/ DNA-insurance/ DNA-discrimination
Personalized medicine:
Do the assessment of
the risk at the baseline
risk. This is what we are
going to look at. Also, a
bit of preclinical
progression is part of
this course.
Personal health plan
based on the baseline
risk. That is the idea of
personalized medicine.
What do we want?
- Personal
diagnosis:
mutation or
something else
- Personal prognosis: what will happen in … years.
- Personal disease management: how to deal with the disease, e.g.
hearing aid for hearing loss. It does not treat the disease. Aid for the
symptoms. Symptoms are tackled
- Personal treatment: actually, dealing with the disease, so the
disease will be treated. Act against the cause of the disease.
Which mode of inheritance is most likely in the pedigree below?
Disease inheritance: autosomal dominant, can be late onset disease
(reduced penetrance).
Too many people for autosomal recessive.
Mitochondrial cannot be the case because we see a male transmitting the
disease
Can also be x-linked dominant: however, its rare There are not many X-linked dominant
diseases
1
, Translational genomics
Medical biology Master
Lecture 2: Genome architecture
The human genome:
DNA in the nucleus + DNA in mitochondria
The nucleus:
- 22 pairs autosomes
- 2 sex chromosomes (XX or XY)
- 20.000 coding genes
- 25.000 non-coding genes
Base pairs: Purines (A + G) and pyrimidines (T + C +
(U (in RNA only)))
Between A + T 2 hydrogen bonds
Between G + C 3 hydrogen bonds
Functional DNA:
- Protein-coding genes
- Non coding genes
- Regulatory elements
Protein coding genes:
Ribosome binds at 5’ UTR, here a lot of C and
G’s are located. Red sequences are the
coding regions.
Gene = functional unit without promoter
region.
UTR = untranslated region
Genes are differently spliced in different tissues
different isoforms.
Small blue box = 3’ UTR on the right.
5’UTR on the left.
Promotor region= place where transcription
factors can bind.
Bars are exons, everything in between are introns
Non-coding genes:
Long non coding RNAs (lncdRNAs)
Small non coding RNAs (siRNAs + miRNAs + piRNAs)
2
, Translational genomics
Medical biology Master
Small ncRNA: mechanism of action
Small RNA precursors turn into mature small RNAs, they are then incorporated into the
human RISC complexes and then they target the genes. RNA protein complex (small RNA +
RISC) looks for targets and the miRNA guide the protein to the target genes.
Micro RNAs (miRNAs):
Immature miRNA (pre-miRNA) is transported outside of the nucleus, and is recognized by
RISC complex (a lot of proteins including Dicer protein).
Then, either miRNAs can result in:
- Inhibition of translation initiation
- Inhibition of translation elongation
- mRNA deadenylation (remove the poly-A tail)
all leading to negative regulation of translation.
RNA binds to protein and brings to position in DNA
miRNAs can result in diseases.
Feingold syndrome 2: miR-17 -92 deletion
- Short hands, thumb is almost gone, syndactyly
3
, Translational genomics
Medical biology Master
Long non-coding RNA: types They can be:
- Intronic lncRNA
- Intergenic lncRNA
- Natural antisense transcript (NAT)
lncRNA can:
- Bind the protein they can then guide the protein for storage etc.
- Bind the DNA if it binds the promotor, the gene will not get expressed anymore
(to regulate gene expression)
- Bind the RNA also in this way you can regulate gene expression
NATs: mechanism of action
a. RNA pol II you get transcription of the genes. However, the other strand cannot be
translated, because the RNA pol II is on the upper gene. So basically, the other one cannot
be translated anymore. it hinders (physical hindrance due to the big RNA polymerase
complex) the transcription of the other gene (of the gene it regulates) (this happens on DNA
level)
b. On RNA level: Binds to splice site, and splice site will not be recognized anymore. E.g.
when NATs bind to exon 3 splice site not recognized by splicing machinery products
only consists of exon 1 and 2.
c. NAT can bind to RNA and do RNA editing recruit proteins for RNA editing e.g. A>T
nuclear retention
4
