L2, Genetic analysis in humans' Flashcards
1
Q
Outline key problems for genetic analysis in humans:
A
- Can’t do controlled matings
- Few progeny
- Long generation time
- Few useful single gene variants
- -> Analysis based on pedigrees
- -> Use of model organisms instead (e.g. flies which have very few chromosomes; identifying locus of markers)
2
Q
Human error in genetic pedigrees:
A
- Cheating: In discussions of pedigrees it is relevant to note that not all explanations for an unexpected phenotype are genetic in origin or a de nuovo mutation; could be result of extramarital sex
- Adoption: Adopted individuals can be included in pedigrees but with a box around
3
Q
Obligate carriers:
A
- Denoted by a dot
4
Q
Manifesting carriers:
A
- X-inactivation - different X chromosomes activated in different cells so females may be strongly or slightly affected
5
Q
Alternatives to single gene disorders:
A
- Chromosomal defect -> usually quite characteristic
- Not inherited (not all congenital disorders are genetic disorders)
- Multifactorial (several genes involved)
- Mitochondrial
6
Q
Mitochondrial inheritance: Pedigree characteristics, example
A
- Maternal inheritance; all children of affected mothers are affected
- ‘Mother’s curse’ - as per evolutionary theory, the maternal inheritance can result in a disorder which is harmful in males but evolutionarily neutral in women -> remains prevalent
- e.g. Some form of Leigh’s disease (movement disorder
7
Q
Define penetrance: What might cause lower penetrance in a disorder?
A
- Proportion of people with relevant genotype who show the character
- Lowered penetrance likely as a result of modifier alleles
- e.g. Neurofibromatosis ranges from mild cafe au lait patches to small to very large neurofibromas
- Penetrance measuring can be impeded by age in the case of late-onset disorders like Huntington’s
8
Q
Define expressivity:
A
- Degree to which an individual with the relevant genotype displays the characteristics of a condition
9
Q
How are disease genes identified in mapping?
A
- Pedigree analysis to identify mode of inheritance
- Recombination mapping using molecular markers (VNTRs/STRs)
- Haplotype analysis -> narrow region down
- Identify small set of candidate genes
- Identify mutations by sequencing of exons
10
Q
LOD score:
A
- Z = measure of probability of linkage between a disease gene and marker in a given pedigree.
- Affected by allele frequency
- ‘Logarithm of odds’
- z>3 likely to be linked
- z<-2 unlikely to be linked
- Used in GWAS
11
Q
ADAR mutation: Identification and background
A
- Found in mapping of DSH patients (Dyschromatosis Symmetrica Hereditaria)
- LOD scores were used to localised gene of interest to a 4cM region (~4 million bp)
- Haplotype analysis used; recombinant individuals indicated a smaller region for DSH gene
- Seven candidate genes identified -> Sanger sequencing of all exons from genes identified ADAR mutation (none of the variants of which appeared in normal Japanese population
- ADAR produced RNA-specific adenosine deaminase 1 -> used for editing bases (adenosine to inosine)
- Editing helps to stop immune targeting of body’s own tissue
- Also thought to prevent replication of certain viruses
12
Q
Which mutations are likely to have a strong effect on the protein?
A
- Nonsense
- Frameshift -> extensive missense
- Strong missense
- Splice site mutation
- Deletions which remove all or part of the coding sequence
13
Q
What are two characteristics of a gene responsible for a disease?
A
- Unrelated individuals with the same condition have mutations in the same gene
- Mutation not found in unaffected or non-carrier individuals
14
Q
+ Example of X-linked dominant condition
A
- Rett syndrome
- Usually arises as a new mutation with no family history but can be mild in some women and so can be passed on to a daughter
- Affects brain development, resulting in severe mental and physical disability
15
Q
+ In the UK, what screening is carried out on newborns by the NHS?
A
- Physical examination
- Hearing screening
- Blood spot screening (heel prick) -> phenylketonuria, congenital hyperthyroidism, sickle cell disease, cystic fibrosis, medium-chain acyl-CoA dehydrogenase deficiency (MCADD)
