Dit document omvat mijn samenvatting (info slides + notities) van Les 4 van het vak Neurogenetics gegeven door Rosa Rademakers. Ik heb dit voor elke les, buiten les 10. Daarvan heb ik wel notities bij de slides. Je mag me hiervoor ook altijd contacteren :))
Class 4
- Definitions and introduction to 3 methods to identify genetic modifiers
- Understand pro and cons of these methods
- Everything will come with reasons you can do it or not
- Paper;
o On average a healthy person have 4000 damaging mutations and 2 bona fide
disease-causing mutations --> we are still heathy -> genetic modifiers:
identification of these to find therapeutic interventions
- Another example
o 2 brothers with mutation in PSEN1 --> they followed the brothers
§ In beginning healthy
§ One gets sick--> dead
§ One gets no system
o Glucose PET scans
§ More green and blue --> problems
o Even more prominent with PiB
§ Blue = nothing
§ Red = not good
Definitions
Definition of genetic modifier
- Epistatis = eRect on the mutation is based on the genetic background
- Genetic modifier doesn’t do much, it works in the presence of the mutation ->
can lead to early onset, later onset
- Genetic modifiers are often found in a functionally similar pathway of the target
gene
Genetic modifier versus oligogenic disease
- Primary problem -> modifier comes in -> make changes
Approaches to identify genetic modifiers
- Availability of samples is important -> large collection of human samples are
diRicult
- Animal models provide ability to perform selected crosses to isolate modiefier
gene/variant
- You can only see what is present -> you need something that splits the population
in diRerent groups
Remember SMA caused by SMN1-loss function?
- Two copies of the SMN1 gene deleted
- SMN2 makes a little bit of protein
o But there is one mutation -> exon 7 is sipped, sometimes not and then you
have enough protein
- Most kids are severly eRect
, - Some people have more copies of SMN2 -> liver longer
- SMN1 is the primary eRect and SMN2 is the genetic modifier
Additional SMA genetic modifier
- 0 SMN1 & 2SMN2
o Very rare
o Sequencing SMN2 gene -> found variant in exon 7 -> makes new exonic
splicing enhancer -> people have more precent of SMN2
- Try small molecules and other therapeutics that cause this variant
- Hope for modifiers is to find something that you can convert to therapy
Huntington’s disease genetic modifiers (!!!!)
- Video
o Autosomal dominant disorder -> 50% change that you get
o Mid-life
o Symptoms in 3,4th or later decades
o Progressive whritin movement with cognitive and behavioral symptoms
o Characteristics brain pathology
o Defect: CAG repeat of the first exon of the HTT -> unstable from generation
to generation -> slightly diRerent CAG length than parent
o Genotype many alleles (from HT and normal population) -> about 90% of the
precent have an expanded repeat between 40-55 CAG, repeat below that
have a reduced penetrance, repeat > 55 CAG is rare
o Polyglutamine is longer than the CAG tract by 2 units
o Many years assumed that the polyglutamine aggregation was the driver of
the onset of the disease
o HD ages-onset is strongly correlated with CAG/polyglutamine length but
shows wide variation independent of this length
o Other genes also responsible for onset
o GWAS for identifying these genes: phenotype = deviation in observed age of
onset and the age of onset expected
§ You need a populations to be phenotypes
§ Large subject of genetic studies = GWAS participants
o Genotype and phenotype correlations are also important
§ HD is a true dominant
§ This argues against continuous dose-dependent damage at
physiological levels of expression
o GWAS reveals multiple loci that influence the age of onset of HD
§ Loci that are in red that are above the GWAS line (green) are involved in
DNA maintenance repair process. The three loci in black are not
involved in that mechanism -> involved in a two steps process
o Timing from birth to the onset of motor signs is driven by the length of the
expended pure CAG repeat, not by polyglutamine.
o Modifier genes can have multiple genetic versions with diRerent eRect on
the gene and opposing eRect on HD repeat. They require interaction with the
CAG repeat
o Conclusion
Les avantages d'acheter des résumés chez Stuvia:
Qualité garantie par les avis des clients
Les clients de Stuvia ont évalués plus de 700 000 résumés. C'est comme ça que vous savez que vous achetez les meilleurs documents.
L’achat facile et rapide
Vous pouvez payer rapidement avec iDeal, carte de crédit ou Stuvia-crédit pour les résumés. Il n'y a pas d'adhésion nécessaire.
Focus sur l’essentiel
Vos camarades écrivent eux-mêmes les notes d’étude, c’est pourquoi les documents sont toujours fiables et à jour. Cela garantit que vous arrivez rapidement au coeur du matériel.
Foire aux questions
Qu'est-ce que j'obtiens en achetant ce document ?
Vous obtenez un PDF, disponible immédiatement après votre achat. Le document acheté est accessible à tout moment, n'importe où et indéfiniment via votre profil.
Garantie de remboursement : comment ça marche ?
Notre garantie de satisfaction garantit que vous trouverez toujours un document d'étude qui vous convient. Vous remplissez un formulaire et notre équipe du service client s'occupe du reste.
Auprès de qui est-ce que j'achète ce résumé ?
Stuvia est une place de marché. Alors, vous n'achetez donc pas ce document chez nous, mais auprès du vendeur evagoormans. Stuvia facilite les paiements au vendeur.
Est-ce que j'aurai un abonnement?
Non, vous n'achetez ce résumé que pour €6,66. Vous n'êtes lié à rien après votre achat.
