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
- 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
