First verification of genetic variation mechanism in humans

27 Feb 2014

Epistasis, the interactive effect of two or more genetic mutations in the genome, influences the expression of genes in human populations in a world first study published in Nature by researchers at QBI.

Scientists at the QBI and the UQ Diamantina Institute have found that epistasis – the long debated effect of whether mutations interact with each other – exists throughout human populations.

This could be applied when treating diseases including Alzheimer’s, after 16 independent pairs of polymorphisms were shown to have an epistatic affect the expression levels of TRAPPC5, a gene known to be involved in the disease.

This new information can be used by other researchers to investigate the functional role that these interacting acting mutations have on susceptibility to developing Alzheimer’s.

Dr Joseph Powell of the QBI said that the study detected hundreds of pairs of common, natural polymorphisms in humans that exhibit epistasis.

“These polymorphisms were shown to have an effect on the levels of amount of gene expression, the mechanism by which genes produce proteins,” Dr Powell said.

“No one really knew how prevalent it was. There has been a huge discussion in the community about how common these types of genetic effects are and how much of the genetic variation was caused by them,” he said.

“Epistasis has been shown in model organisms, but the genetic variations have been artificially created.

“We honestly didn't know what to expect, partly because we needed to apply very stringent statistics to be certain anything we found was ‘real’, and because of the wide ranging debate within the community.”

The findings open up further research into understanding how mutations are carried within the population, which can impact disease susceptibility knowledge.

“Discovering that two mutations effect the expression of a particular gene may lead to treatment or prevention by understanding those gene interactions.”

The study was conducted by creating a sophisticated statistical test for discovering the association between the combination of alleles carried at a pair of mutations and the gene expression levels of a gene.

Using a genetic data from 846 people over 1 quadrillion statistical tests were conducted testing for epistatic effects across the whole genome. In order to test these relationships the researchers accessed the National Computing Infrastructure Fornax supercomputer cluster.

“This study is perhaps the largest statistical analysis ever performed in the field of genetics,” Dr Powell said.

“Total analysis took about five months nonstop day and night and represents roughly 25 million CPU hours, which would take a standard desktop computer 750 years to run.”

The results of matching gene pairs were then verified against data from populations in the Netherlands and Estonia, proving the existence of natural genetic variability across populations. The researchers then investigated possible functional molecular effects for the epistatic loci.

An international team of scientists led by QBI also included the QIMR Berghofer Medical Research Institute; University of Groningen, The Netherlands; University of Tartu, Estonia; Cambridge Broad Institute, Boston Children’s Hospital and Georgia Institute of Technology, USA.

The study is published in Nature on 27 February 2014, and was funded by the National Health and Medical Research Council (NHMRC), Australian Research Council (ARC) and National Institutes of Health (NIH).

View an interactive version of the identified epistatic interactions online at

Media: Mikaeli Costello, Director Advancement and Communications, Queensland Brain Institute, +61 401 580 685 or; Dr Joseph Powell, Queensland Brain Institute, +61 7 3346 6393, or