Wednesday, September 23, 2009

Where's the missing heritability?

Epigenetic inheritance and the missing heritability
Slatkin, M. Genetics 182, 845–850 (2009)

Summary of my reading of the paper:

The author derives the standard population genetic model for locus contribution to average risk and recurrence risk......

Derives the same sets of equations for epigenetic marks with the difference being that there are loss and gain rates of epigenetic marks to be taken into account

For traditional genetic loci: Describe the relation between two variables 1. allele frequency and 2. locus contribution to risk leading to two outcomes 3. recurrence risk and 4. average risk

Do the same for ‘epigenetic loci’ with the difference that for epigenetic loci in their model:
The equilibrium frequency of a two-state Markov process incorporating the transition probabilities α and β, the rates of loss and gain of epigenetic marks per meiosis, acts as a proxy for population frequency of epigenetic marks and has great bearing on average risk

α + β, the turnover rate of the marks, affects recurrence risk in sibs
i. Analogous to the genetic situation, alpha has to be low and epialleles have to be relatively stable for recurrence risk to be elevated
ii. Stables epialleles are likely to act like mutations and be detected in linkage studies
iii. High frequency epialleles with low effects (and even if they change with every generation, i.e, are not stable) may affect average risk substantially
5. Stated Conclusion: Epialleles, in this model, may account for missing causality but unlikely to account for missing heritability because the higher rate of loss of epigenetic modifications means that identity by descent does not imply identity in state; consequently, it will be difficult for epigenetic changes to account for the missing heritability of complex diseases unless they are more common than mutations or have more pronounced effects on disease risk.

is transgenerational
does not allow for epistatic interactions between loci