Dissection of Biallelic Effects from other Determinants of Phenotype
Although phenotypic consequences, referred to here as biallelic effects, resulting from two different mutant alleles in compound heterozygote patients have been postulated, such effects have historically been difficult to distinguish from the influence of environment and genetic background. We used a genetically defined mammalian model system under controlled environmental conditions to reveal phenotypic effects attributable specifically to combinations of differentially mutated Xpd alleles.
The observed biallelic effects were of three general types. In the first, the allele associated in a homozygous state with a phenotype closer to wt singularly determined the phenotypic outcome, a phenomenon widely known in human recessive disease. Because these Xpd alleles functioned at or near wt levels with respect to a particular function, we call these effects “dominant”. Such alleles can also be referred to as “separation of function” alleles, because they allow dissection of the roles of multifunctional proteins in specific phenotypes.
Secondly, highlighting the potential relevance of current findings to all diploid organisms including humans was the observation that in one compound heterozygous animal, the Xpd allelic relationship could shift from A dominant |a recessive to A recessive |a dominant with respect to different phenotypes in a time-dependent and tissue-specific manner (see below and Table 2).
In the third type of biallelic effect, known as interallelic complementation, two mutant alleles produced a phenotype closer to wt than either could alone in a homo- or hemizygous state. As summarised in Table 2, examples of all types of biallelic effects were observed in a variety of Xpd-associated phenotypes, ranging from brittle hair to segmental progeria.