Genetic Interaction Models

Variable expressivity and epistasis go hand in hand when talking about genetic disorders. Knowing what they mean will help you really understand the kind of complications researchers are up against. In this article I’ll illustrate these concepts using a recently published paper on the causes of autism as an example.

One of the genetic risk factors for autism is a small deletion in a region of the genome called 16p12.1 (That’s just an address telling researchers where to look in the genome). This deletion is enriched in individuals with mental retardation, schizophrenia and autism. The thing is, the deletion is considered a risk factor only, because seemingly healthy individuals also have the deletion. More autistic individuals have the deletion than unaffected individuals, but because it is found in unaffected individuals*, it’s clearly not the sole cause of autism. So if this little deletion is not causing autism, than what is?

Remember that every gene interacts with lots of other genes, at the DNA, mRNA and protein level. When we think about genes it’s more like a complex network than one role of single genes. Sometimes, it’s the combination of specific mutations (or alleles) that cause disease.

Take a look at the diagram on the left. What we consider are two pathways, which means groups of interacting genes. The dots represent a gene and connecting lines mean that somehow those genes influence each other’s activity. The single mutation in scenario A is like the deletion at 16p12.1, it results in a mild to negligible effect. The next two scenarios are particularly interesting.

In part B a second mutation occurs affecting a gene in another pathway. The evidence for this model is that secondary mutations in individuals with the 16p12.1 deletion are varied, they’re all over the genome. This additive effect could result in variable expressivity, i.e. the wide variety of characteristics that we call autism or schizophrenia. It’s because different secondary mutations disrupt different secondary pathways, resulting in autism, plus a variety of other characteristics.

Scenario C highlights epistasis: mutations in genes that belong to the same pathway (i.e. network). The combined affect of these mutations, which may be mild or even benign on their own, lead to more severe conditions.

All this points to the difficulty of uncovering the genetic basis of complex diseases. Many different mutation combinations can lead to variable expressivity and epistatic interactions of normally mild mutations can interact in powerful ways. Uncovering how different mutations interact to cause diseases will be a major undertaking of genetics in the years to come.

*One closer inspection it turned out that supposedly unaffected individuals did report higher incidence of learning disabilities, seizures and other symptoms, but much milder than autism, mental retardation or schizophrenia.

Citations and Image:

Veltman, J., & Brunner, H. (2010). Understanding variable expressivity in microdeletion syndromes Nature Genetics, 42 (3), 192-193 DOI: 10.1038/ng0310-192

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