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)
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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
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3
Q

Obligate carriers:

A
  • Denoted by a dot
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4
Q

Manifesting carriers:

A
  • X-inactivation - different X chromosomes activated in different cells so females may be strongly or slightly affected
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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
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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
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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
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8
Q

Define expressivity:

A
  • Degree to which an individual with the relevant genotype displays the characteristics of a condition
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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
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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
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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
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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
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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
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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
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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)
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16
Q

+ How is CF screened for?

A
  • Heel prick blood sample is assessed for trypsin levels
  • Elevated trypsin -> triggers investigation into potential mutations