Lecture 22 - Inherited disorders 2 Flashcards
What were the main limitation of Mendel’s studies
that he always looked at dichotomous/binary traits in more simple organisms such as plants
What is the polygenic/infinitesimal model
In 1918 RA Fisher, the founder of ‘quantitative genetics’, provided a solution
He suggested that several Mendelian units, or genetic variants, contribute additively to the end phenotypic outcome of a particular trait
for polygenic disease the proportion of siblings affected within families would generally be much lower than that observed for Mendelian disease
What is the observed recurrence risk amongst siblings for complex genetic diseases
~5-10%
What is the Fishers model
Slide 8
Comparatively smaller recurrence risk amongst offspring expected due to larger number of risk alleles (each of smaller effect) needing to be inherited for disease manifestation
What is the polygenic threshold model
However, many polygenic diseases, whilst displaying these reduced recurrence risks, do in fact display a binary character rather than a continuous variation of the phenotype
To account for this, the idea of ‘disease threshold’ was introduced
What is the Carter effect
Some complex genetic diseases also display sex dimorphism: an explanation for these might be provided by polygenic threshold model
What is heritability and its estimation
The phenotypic variation in a given population that is due to variation in genetic factors within the population is referred to ‘heritability’
It is a population-specific parameter that relates to variance first described by Fisher
It has classically been estimated via ‘twin studies’ which aim to estimate the extent to which a particular trait is determined by genetics vs environment
What is the maths behind the liability threshold model
Phenotypic variance (VP) = Heritable genetic variance (VG)
+ Environmental variance (VE)
Total (or ‘broad sense’) heritability = VG/VP
What is Falconers formula
Heritability (broad sense) = 2 ( CRMZ – CRDZ )
(sl;ide 17)
Views
In the classical view of the polygenic/infinitesimal model, genetic variants each contribute additively to heritability (referred to as narrow-sense heritability)
However, broad sense/total heritability estimates (such as those from twin studies) include the potential for non-additive genetic contributions too
Such non-additive contributions can result from interaction between genetic variants, and two types can be defined
What are somatic mutations in non-cancerous disease
Mutations/genetic variations occur continually throughout normal growth
These are very difficult to detect, and in any case, they are currently generally thought not to play any significant role in disease
However, modern sequencing approaches have recently revealed that somatic mutations may indeed also cause non-cancerous diseases
So far the number of actual reports of these have been very limited and it is unclear whether such events might be common in reality
But in such situations, what might we expect/could we predict??…….
dominant vs epistatic interaction
slide 19
What is the trend of risk of disease and timing
The later on in life the mutation occurs, the lower the risk of adverse affect
Mutation position slide 24
Brain needs fewer mutations to lead to adverse affects
