An Atlas of Variant Effects to understand the genome at nucleotide resolution

Abstract

Sequencing has revealed hundreds of millions of human genetic variants, and continued efforts will only add to this variant avalanche. Insufficient information exists to interpret the effects of most variants, limiting opportunities for precision medicine and comprehension of genome function. A solution lies in experimental assessment of the functional effect of variants, which can reveal their biological and clinical impact. However, variant effect assays have generally been undertaken reactively for individual variants only after and, in most cases long after, their first observation. Now, multiplexed assays of variant effect can characterise massive numbers of variants simultaneously, yielding variant effect maps that reveal the function of every possible single nucleotide change in a gene or regulatory element. Generating maps for every protein encoding gene and regulatory element in the human genome would create an 'Atlas' of variant effect maps and transform our understanding of genetics and usher in a new era of nucleotide-resolution functional knowledge of the genome. An Atlas would reveal the fundamental biology of the human genome, inform human evolution, empower the development and use of therapeutics and maximize the utility of genomics for diagnosing and treating disease. 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.

Keywords: Functional genomics; Genome interpretation; Global alliance; Multiplexed assay of variant effect; Saturation mutagenesis; Variant effect.

Fig. 1

Schematic representation of areas of high impact resulting from an Atlas of Variant Effects

Fig. 2

A (top panel) MAVEs can measure a wide variety of protein and regulatory DNA functions, and they produce comprehensive variant effect maps representing the effects of nearly all possible nucleotide or amino acid variants in the scanned functional element. A variant effect map is shown for a small region of a protein-coding gene; each column in the map is a position in a gene and each row is an amino acid substitution. Tiles are coloured based on the measured effect of the variant. B (bottom panel) MAVEs have been applied to hundreds of functional elements and, collectively, ~ 11 million variant effect measurements have been made with MAVEs. Data available at 10.5281/zenodo.7662580

Fig. 3

Stages of Atlas of Variant Effects completion