Nine billion and counting – Mapping the human variants and their effects on health and disease

The Atlas of Variants Effects Alliance (AVE) is an international collaborative project with the aim of creating an atlas and assessing the effects of all the possible variants of human genes in the genome. The Alliance is spearheading efforts to advance the use of mutational scanning technologies. It is a collaboration of multiple institutes including the University of Washington, the Wellcome Sanger Institute, the Brotman Baty Institute, Stanford University and the Broad Institute among others, with 500 members from 105 institutes and 30 countries.

“Over the last few decades, we've sequenced hundreds of thousands, if not millions, of human genomes, and we've got a much better picture of what the problem is. We all carry a large number of DNA variants, but we don't know what that variation does.”

Dr Dave Adams
Group Leader in the Cancer, Ageing and Somatic Mutations programme at the Sanger Institute and member of the Executive Committee at AVE

“There is a quotation from Eric Lander, founding member of the Broad Institute, from when the genome became available - ‘bought the book, hard to read.’ That's where we are, we have the genome but interpreting it is a whole different game.”

Professor Frederick ‘Fritz’ Roth
University of Toronto, and a member of the Executive Committee at AVE

Even though all humans share over 99.9 per cent of the same genome sequence, an individual’s genome can vary slightly due to inherited or acquired changes in the DNA sequence. These small changes are called variants and they are what make each of us unique. Understanding the impact of variant effects on health and disease is the primary goal of the Atlas of Variant Effects Alliance, and is being conducted using a combination of experimental and computational methods known as mutational scanning. These methods look closely at variants in our DNA with the aim of understanding how each variant impacts factors such as our physical traits, health, and disease risk at a much larger scale than previously used analysis techniques.

These new methodologies, also referred to as Multiplex Assays of Variant Effect (MAVE), are key to variant interpretation and are transforming our understanding of the human genome. The Alliance also serves as a platform to discuss how to apply data gathered in these experiments in a clinical setting - from diagnosing rare developmental diseases to understanding the basic mechanisms of disease gene function. It also develops standards and best practices, sharing data broadly and coordinating the further development of MAVE technologies.

Genetic testing can reveal whether or not a person carries a variant that puts them at a vastly increased risk for pathologies such as cancer and cardiovascular disease. For example, individuals with variants that are known to be pathogenic in genes like BRCA1 and BRCA2 cause an increased risk of breast and ovarian cancer. Medical intervention, such as risk-reducing surgery, can keep these individuals from developing cancer.

However, on many occasions, new or very rare variants are identified by genetic testing and there is not enough information to know if the variant can cause disease. These variants, called variants of uncertain significance, are a medical dead end. They cannot be used to guide treatment decisions, can cause confusion for physicians and often cause anxiety for patients.

By measuring the functional effects of all possible variants in a gene, data generated by Alliance members can help clinicians understand whether any variant identified by genetics is pathogenic. At the Sanger Institute, Dr Dave Adams, Professor Matt Hurles and their teams are using saturation genome editing, a method in which all the possible variants within a gene are measured for effects on function. This allows scientists to ask the question about every single possible alteration that someone might inherit and ask - what does that do in terms of the function of that gene? By inference, what does that do in terms of influencing their risk of the development of disease?

“MAVE technologies allow us to explore variation at a scale and with the accuracy that we would want and that we've dreamed of for a long time. We are trying to extend that paradigm across all disease-associated genes and then, ultimately, to all genes in the genome, so that we can interpret what variation means in terms of disease risk.”

Dr Dave Adams
Sanger Institute

Researchers hope that these efforts will allow clinicians to intervene earlier, and be able to screen patients if they're at increased risk. It will enable health professionals to counsel patients and their families about, for example, behaviours that they may or may not consider to reduce their risk. Dave Adams believes it can also potentially help in drug development efforts as well. A better understanding of patients who go into clinical trials can help, in turn, to gather information about crucial aspects, such as drug response.

For Professor Doug Fowler, executive member committee and Professor at the Department of Genome Sciences at the University of Washington, the Atlas of Variant Effects is the continuation of the legacy of the Human Genome Project.

“I was a college student as I saw what was happening with phase one of the Human Genome Project, and I just saw it all unfold, thinking, what is next? Well, we’re now in the second phase of the Human Genome Project. Technology is allowing for cheaper sequencing, and we have clinical genetic tests, but then comes the blockroad - we often don’t understand the function of the variants we find. We are now in a moment in which we can tackle variant function and deliver on the promise of genome sequencing. But we need a community, we can’t do this alone.”

Professor Doug Fowler
Department of Genome Sciences at the University of Washington and member of the Executive Committee of AVE

Doug and colleagues wrote a landmark paper in 2017. In it, they argued that MAVEs could be used to measure the functional consequences of all possible variants in disease-relevant locations, which would be a game changer for interpreting genetic variation in clinically actionable genes. Following the publication, Doug Fowler, Fritz Roth, Lea Starita, Alan Rubin, Dave Adams, Matthew Hurles, and others met in Seattle on 14 January 2020 at the Brotman Baty Institute, to discuss what a collaboration moving forward would look like.  That was when the Alliance formally began.

For Dr Lea Starita, Associate Professor at the University of Washington, it’s harnessing the knowledge and work of incredibly talented people and creating a resource that is findable, accessible, interoperable and reusable.

“As with all emerging fields, there needs to be an organising force to add standards and make sure that the data being gathered adhere to a set of principles. This, in turn, will allow the data to be useful further down the line, for clinical use or to feed generative neural networks. That’s what the Atlas is set out to accomplish.”

Dr Lea Starita
Associate Professor at the University of Washington

Four years after its conception, AVE is now a recognised player in the genomics landscape. “I do believe that we have made a place for ourselves in the international genomics community,” adds Dr Lea Starita. “The Atlas of Variant Effects participated in this year’s National Human Genome Research Institute’s cross consortia day, giving visibility to the project. This puts AVE at the same level as other ambitious projects in the United States, such as the Human Pangenome Research Consortium.”

At the heart of the Alliance is the executive committee, co-chaired by Doug Fowler and Matthew Hurles. Lara Muffley from the University of Washington is one of the central organising forces within the Alliance. Lara coordinates Alliance efforts, keeps workstreams and committees focused on their goals and facilitates ongoing work to ensure project success. “As program manager for the Alliance, I help build and support our global MAVE community. It is honestly a real joy to get to work with everyone dedicating their time to support this collective grand endeavour.”

The Alliance is only four years of age and is gaining momentum. Their latest symposium at the Wellcome Genome Campus in July is thought to be one of the most diverse events on site, with over 400 researchers from 50 countries. Motivations to join the Alliance are varied: from a more translational approach such as precision medicine - understanding how variation affects disease and improving the diagnosis of patients with a genetic disease - to fundamental biological questions about the function of genes, proteins or genetic pathways.

All executive members agree that anyone should be able to participate. With this in mind, removing any technical barriers has been a must from the get go.

“We don't want people within the community discarding datasets just because they're in the wrong system, or because they don't use the right technology. We have very general standards. Guidelines that everybody should be able to follow now and that will support emerging methods.”

Dr Alan Rubin
Computational biologist at the Walter and Eliza Hall Institute of Medical Research in Melbourne and chair of the data curation and dissemination work stream

Looking into the future, David Adams believes that as more data is generated, machine learning based approaches will blossom. Data from AVE is already being placed into AI systems, trying to predict the function of a variant and new biological effects. These are called Variant Effect Predictors, and can infer the fitness effects of human (and non-human) variants. Even though these are still considered a supporting source of clinical evidence, advances in the field of AI may help move this forward in the short term.

The next AVE symposium will take place at the Broad Institute, in Boston, USA, from the 22 to 24 of May 2024. For more information on the Alliance, you can visit their website, or become a member to join their mailing list and slack channel.