Allelic penetrance approach as a tool to model two-locus interaction in complex binary traits

Abstract

Many binary phenotypes do not follow a classical Mendelian inheritance pattern. Interaction between genetic and environmental factors is thought to contribute to the incomplete penetrance phenomena often observed in these complex binary traits. Several two-locus models for penetrance have been proposed to aid the genetic dissection of binary traits. Such models assume linear genetic effects of both loci in different mathematical scales of penetrance, resembling the analytical framework of quantitative traits. However, changes in phenotypic scale are difficult to envisage in binary traits and limited genetic interpretation is extractable from current modeling of penetrance. To overcome this limitation, we derived an allelic penetrance approach that attributes incomplete penetrance to the stochastic expression of the alleles controlling the phenotype, the genetic background and environmental factors. We applied this approach to formulate dominance and recessiveness in a single diallelic locus and to model different genetic mechanisms for the joint action of two diallelic loci. We fit the models to data on the genetic susceptibility of mice following infections with Listeria monocytogenes and Plasmodium berghei. These models gain in genetic interpretation, because they specify the alleles that are responsible for the genetic (inter)action and their genetic nature (dominant or recessive), and predict genotypic combinations determining the phenotype. Further, we show via computer simulations that the proposed models produce penetrance patterns not captured by traditional two-locus models. This approach provides a new analysis framework for dissecting mechanisms of interlocus joint action in binary traits using genetic crosses.

Bayesian analysis of allelic penetrance models for complex binary traits

“…Since the same model is also the best according to PMP and DIC, we can state that infection susceptibility seems under control of an independent action between a dominant allele of the resistant strain at locus A and a type I recessive allele of the susceptible strain at locus B. Previously, IAM(A 2 /b 1 ) with b 1 as a type II recessive allele was considered to be the best model for the data (Sepúlveda et al, 2007). Therefore, this analysis improves on previous results by considering a type I recessive allele at locus B.…”

“…Moreover, the phenotypic expression of the alleles seems to be a stochastic event, which can be explained by the epigenetic state of the alleles (Rakyan et al, 2002) or to be an intrinsic property of loss-of-function alleles (Lalucque and Silar, 2004). Therefore, it is reasonable to put forward the notion of allelic penetrance, which embodies the probability of an allele being expressed at the level of the phenotype (Sepúlveda et al, 2007). By doing this, internal penetrance can be modeled as a function of allelic penetrances, describing different genetic mechanisms, as we will see below.…”

“…In previous work, we adopted an alternative definition for the action of a recessive allele (Sepúlveda et al, 2007). There, the heterozygotes might manifest the phenotype by the expression of recessive allele a when the dominant allele b is not active.…”

“…The goal of the analysis is to infer the joint action of both loci with respect to susceptibility. Previously, we fitted the allelic penetrance models considering type II recessive alleles (Sepúlveda et al, 2007). We found an independent action between a dominant allele inherited from the resistant strain at locus A and a type II recessive allele derived from the susceptible strain at locus B.…”

“…Recently, we proposed an allelic penetrance approach to model penetrance in experimental populations (Sepúlveda et al, 2007). Under this new framework, the alleles themselves are assumed to have a probability of being expressed at the level of the phenotype.…”