It is very much conceptually linked to the DDD project, although organisationally separate. This is an international effort that comes from the challenge of interpreting variants - how do we interpret a variant that we've never seen before? We know damaging genetic variation can cause a disorder, but we also know that most genetic variation in a gene doesn’t actually damage the gene. Genes are impressively robust to genetic change. Hence, when we identify a new variant that we’ve never seen before, how do we interpret it? How do you gather enough evidence to determine if it is causing disease or not? Interpretation is a challenge we faced in the DDD project. We hope that the Atlas of Variant Effects will help with this.
We are currently performing experiments in which we create a pool of human cells, each with a different mutation in the same gene, and identify the subset of cells in which the mutation is damaging the gene. Because we can do these experiments in a highly parallel fashion, we can quickly assess the functional impact of every possible genetic variant in a disease-associated gene, including variants that have not yet been observed in a patient. This is in contrast to the current way of working, in which variants that have already been observed in patients are assessed one-by-one for their functional impact retrospectively.
Currently, this technology can only be applied to a subset of genes. What we now envisage, and propelled by new technology, is to prospectively determine the functional impact of every single possible change in a gene. Our aim is to create what could be called a variant effect map, where you literally just go through mutating every single possible base, and then you have a functional assay that allows you, in parallel, to read out which variants are damaging and which aren't. Essentially, an atlas comprising maps of every single disease-causing gene, with each map containing the effect of every single possible change in that gene.