sdl45

Sdl 4 – Huntington disease
Features
- personality changes, restless, fidgety
- abnormal movements (athetoid)
- chorea (dance-like movements) in > 90% of cases
- striking emaciation despite appetite
- psychiatric signs e.g. dementia, depression

Position cloning should be understood by you all

HD gene (IT15) near end of chromosome 4p
Difficulty finding markers, close to telomeres
Triplet-repeat diseases, autosomal dominant

Under coding triplet repeat disease category
CAG triplet repeats encoding for long polyglutamine tract, kainate acting on receptors to cause lesion of caudate nucleus

premutation (state/condition that confers genetic instability but not enough to cause the disease phenotype) ~35
threshold (the minimum state of condition required to manifest disease) – 36, normally > 40

Coding vs non-coding triplet repeat diseases
non-coding
- non-coding regions
- usually multi-system disorders
- size of triplet repeats and variation much greater than coding-repeats since outside coding region, more space)
-phenotypic variability, somatic heterogeneity more prominent than coding repeat
- many ass. with silent premutations b4 expanding to full mutation aft germline transmission

eg. Fragile X (5' UTR - FMR1 gene), Friedreich ataxia (intron1), myotonic dystrophy

FRAXA i.e. CGG repeats
Friedriech i.e. GAA repeats

coding
- coding regions
- all ass. with CAG repeat expansions translated into long polyglutamine tract
- typically progressive neurodegen diseases, neuronal loss
- intergenerational instability more pronounced in paternal transmission
(severity greater in child if father has the mutation rather than mother, transmitted to child causes earlier onset and greater severity than tat of mother)
- confers gain-of-function which usually ameriolates disease by presence of protein aggregates or nuclear inclusions in nucleus

eg. Huntington's, spinocerebellar ataxia type 1

Huntington gene
methods to isolate this shit~
synthesise oligonucleotide primers that are used to amplify this region by PCR
determine the no. of CAG repeats by polyacrylamide gel electrophoresis

For huntington’s, significance of phenotypic variation despite mapping to single locus due to paternal trans? no. triplet repeats (single-gene heterogeneity)

Sdl 5 – Alcoholism
Factors leading to alcoholism risk:
alcohol metabolism, acetaldehyde metabolism, drug euphoriant potency, anti-depressant effects
“risk-taking” behaviour, dependency, withdrawal severity

Qualitative traits (Mendelian traits)
Ass. with ‘either or’ expression pattern in a population and are generally mediated by a single gene

Quantitative traits
Traits that continuously vary across the populatin and usually involve a constellation of multiple genetic and environmental influences

Additive means combined effects from several genes leading to gradation of phenotypic effects
Epistasis/multiplicative is the quantitative interaction between genes; a particular phenotype will not emerge until an individual possess a certain combination at genes

Human DRD2 receptor found as roles in mediating alcohol susceptibility as well as also equal no. of studies conflicting against this by evidence.

Complexities of quantitative traits (eg. alcoholism)
occur due to population stratification (population), additive and multiplicative effects, environment effects or pleitrophy* (individuals)
Pleitrophy simply a single gene having multiple phenotypes

Dependence also has multiple definitions, but is not as commonly used as abuse outside of the medical profession. Physical medicine considers dependence to be the body's physical adaptation to the persistent presence of alcohol. Psychological medicine considers dependence to be a person's mental reliance upon something to maintain their mental status quo.

Heavy drinkers might drink a lot but may be subjected to effects a lot too!

Quantitative traits are usually analysed by QTLs
QTLs (quantitative trait locus) is a region of chromosome that has been shown by genetic mapping to contain one or more genes that contribute to phenotypic differences

Some experiments to conduct QTL analysis:
1) Large population ass. studies
Identifies candidate genes by comparing genes of groups of ppl i.e. that of alcoholics vs control subjects, need large cohorts
May be false positives eg candidate gene might NOT be true causative gene e.g. linkage disequilibrium between candidate gene and true disease susceptibility gene located in the same chromosomal region gives significant allele frequencies

2) Animal models
Cross breeding of imbred strains of mice to produce F2 generation (detailed no required)

results found on alcoholism- relation:
A cluster of GABAa receptor subunit genes mapped to chromosome 11
Other chromosomes for alcohol withdrawal: 1, 2, 4 & 9
esp 9* which contains Drd2 (dopamine d2 receptors) and 5-ht1b (serotonin 1b receptors)

to find gene after qtl identified, make use of congenic strains to narrow down to causative?

3) Family twin/adoption studies
Compare risk of biological relatives with risk to adoptive relatives of alcoholics

*COGA, RFLPs, isolated population studies, genome-wide analysis all in the notes