Atlas of Variant Effects Timeline

Predicting the impact of amino acid substitutions on protein function and fitness has always been a key goal of molecular evolution research. An early approach compared proteins among related species to determine which amino acids were most substitutable over evolutionary time. Highly similar proteins were gathered, and the frequency of different amino acid substitutions in these sequences were used to determine a substitution matrix, called BLOSUM.

Sorting intolerant from tolerant (SIFT) and polymorphism phenotyping (PolyPhen) are bioinformatics tools that predict whether nonsynonymous changes are likely to have a deleterious effect on protein function. Both programs use sequence homology of related proteins to predict whether an amino acid substitution (AAS) is likely to be deleterious to protein function based on the degree of conservation of the affected base throughout evolution.

On April 14, 2003, the International Human Genome Sequencing Consortium announced the successful completion of the Human Genome Project. Sequencing the human genome (~3 billion bp) took 13 years and thousands of researchers.

Invention of highly parallel in situ oligonucleotide synthesis enables the multiplex construction of genetic variant libraries.

Next-generation sequencing (NGS), also referred to as high-throughput sequencing (HTS) or 2nd generation sequencing, started with the development of pyrosequencing and was first commercially available in 2005 as the 454/Roche platform. NGS utilizes a massive parallel sequencing approach, with the ability to process large DNA samples at a significantly reduced cost and time.

Starting in October 2002, the International HapMap project aimed to develop a haplotype map (HapMap) of the human genome to describe the common patterns of human genetic variation. HapMap is used to find genetic variants affecting health, disease and responses to drugs and environmental factors. The information produced by the project is made freely available for research. It comprises two phases; the complete data obtained in Phase I were published on 27 October 2005.

UK Biobank is a large long-term biobank study in the United Kingdom (UK) which is investigating the respective contributions of genetic predisposition and environmental exposure (including nutrition, lifestyle, medications etc.) to the development of disease. The study is following about 500,000 volunteers in the UK, enrolled at ages from 40 to 69, and is still ongoing.

Innovations in library scale DNA synthesis and high throughput sequencing have enabled ‘multiplexed assays for variant effects’, or MAVEs, to functionally characterize hundreds to thousands of sequence variants in a single, highly multiplexed experiment. MAVE experiments have mapped sequence–function relationships with base-pair resolution for both proteins and regulatory elements in the form of deep mutational scans (DMS) and massively parallel reporter assays (MPRA), respectively. The first MAVE was developed by Jay Shendure to interrogate promoter activity (published in 2009)

Deep mutational scanning (DMS), also known as massively parallel mutagenesis, involves making a comprehensive protein mutant library followed by high-throughput phenotyping and deep-sequencing of the mutant libraries before and after selection. DMS was developed by Doug Fowler and Stanley Fields.

Enrich: software for analysis of protein function by enrichment and depletion of variants. It is a tool for analyzing such deep mutational scanning data.

Emmanuelle Charpentier in collaboration with Jennifer Doudna at the University of California, Berkeley developed CRISPR-Cas9, a genome editing technique that enables scientists to remove and add pieces of genetic material with exquisite precision. It can be used to disable genes, correct genetic disorders or to insert genes to create animal models of human disease.

Starting January 2008, the 1000 Genomes Project (1KGP) was an international research effort to establish the most detailed catalog of human genetic variation at the time. Scientists planned to sequence the genomes of at least one thousand anonymous healthy participants from a number of different ethnic groups within the following three years, using advancements in newly developed technologies. In 2015, two papers in Nature reported results and the completion of the project and opportunities for future research.

In 2017, Google released DeepVariant , an open-source variant caller tool which identifies genome variants in sequencing data using a convolutional neural network (CNN). DeepVariant significantly improves the accuracy in identifying variant locations and reduces the error rate by more than 50%.

To accommodate the growing number of MAVEs published, MaveDB was created. MaveDB is a central repository that allows researchers to store and publish processed MAVE datasets, associated metadata, and linked raw data using a machine-readable, standardized, and searchable format.

The Atlas of Variant Effects Alliance is an international collaborative group comprising hundreds of researchers, technologists and clinicians dedicated to realising an Atlas of Variant Effects to help deliver on the promise of genomics. The strategic plan is available here.

Alliance Workstreams are responsible for realizing the goals of the Alliance in key areas by setting standards, providing tools and disseminating information.

In this series, early-career scientists from around the globe share and discuss their research related to interpreting human genetic variation.

Developments in unsupervised generative modeling generates computational models for classifying human genetic variants. One notable example is EVE, a computational method developed in 2021 for the classification of human genetic variants trained solely on evolutionary sequences.

In this report , Atlas of Variant Effects (AVE) Alliance annual reports summarize, celebrate and showcase our work. The reports also provide an introduction to our organization and serve as a resource for new and existing community members.

Each year, the Atlas of Variant Effects Alliance hosts the Mutational Scanning Symposium where experts in the fields of functional genomics, protein science, precision medicine, variant interpretation, and computational genetics come from around the world to connect, present their work, discuss new methods and provide insights into the future of this science. Our 5th annual Mutational Scanning Symposium in 2022 marked the first time the event was held outside of the United States.

The Global Alliance for Genomics and Health (GA4GH) is an international consortium that is developing standards for responsibly collecting, storing, analyzing, and sharing genomic data in order to enable an "internet of genomics". AVE became an organizational member or GA4GH in 2023.

In this perspective, the Alliance outlined its vision and specific approach for creating a comprehensive Atlas, which would characterize the function of every possible single nucleotide change in most genes in the human genome..

The Symposium was held at the Wellcome Genome Campus in the UK (and online). There were a total of 407 attendees (217 in-person attendees plus another 190 participating virtually in real time) from 50 countries.

In 2000, Mexico’s health authority asked more than 40,000 rural and urban residents to donate blood as part of a massive, ongoing effort to create a nationally representative health database. Released in 2023, the repository represents the most diverse collection of genetic information in the Global South and provides new clues about the genetic composition of people from Mexico, such as the extent of Indigenous and European ancestries within each region of the population, and how this makeup might influence their health.

AVE is growing! Check out our LinkedIN page and our Zenodo page.