© Uta Mackensen
Multiplexed Assays of Variant Effect (MAVEs) can measure the functional consequences of genetic variants at a scale, allowing the construction of comprehensive variant effect maps for genes and their regulatory elements. These maps are furthering fundamental understanding of how genes and proteins function, as well as enabling precision medicine by revealing the functional impact of variants found in human genomes. This article collection of Genome Biology showcases the power and potential of MAVEs and MAVE data.
The stage for this collection of articles is set by a short correspondence piece from the Atlas of Variant Effects (AVE) Alliance. In the perspective, the Alliance outlines 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.
Articles published in this collection have undergone the journal’s standard peer-review process and were subject to all of the journal’s standard policies.
Computational methods for assessing the likely impacts of mutations, known as variant effect predictors (VEPs), are widely used in the assessment and interpretation of human genetic variation, as well as in ot...
Computational variant effect predictors offer a scalable and increasingly reliable means of interpreting human genetic variation, but concerns of circularity and bias have limited previous methods for evaluati...
Multiplexed assays of variant effect (MAVEs) have emerged as a powerful approach for interrogating thousands of genetic variants in a single experiment. The flexibility and widespread adoption of these techniq...
Amino acid substitutions can perturb protein activity in multiple ways. Understanding their mechanistic basis may pinpoint how residues contribute to protein function. Here, we characterize the mechanisms unde...
Variants that disrupt mRNA splicing account for a sizable fraction of the pathogenic burden in many genetic disorders, but identifying splice-disruptive variants (SDVs) beyond the essential splice site dinucle...
Genetic variation in the human genome is a major determinant of individual disease risk, but the vast majority of missense variants have unknown etiological effects. Here, we present a robust learning framewor...
Metachromatic leukodystrophy (MLD) is a lysosomal storage disorder caused by mutations in the arylsulfatase A gene (ARSA) and categorized into three subtypes according to age of onset. The functional effect of mo...
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,...
Multiplexed assays of variant effect (MAVE) experimentally measure the effect of large numbers of sequence variants by selective enrichment of sequences with desirable properties followed by quantification by ...
Understanding coding mutations is important for many applications in biology and medicine but the vast mutation space makes comprehensive experimental characterisation impossible. Current predictors are often ...
Glucokinase (GCK) regulates insulin secretion to maintain appropriate blood glucose levels. Sequence variants can alter GCK activity to cause hyperinsulinemic hypoglycemia or hyperglycemia associated with GCK-...
The impact of millions of individual genetic variants on molecular phenotypes in coding sequences remains unknown. Multiplexed assays of variant effect (MAVEs) are scalable methods to annotate relevant variant...
Insertions and deletions (indels) enable evolution and cause disease. Due to technical challenges, indels are left out of most mutational scans, limiting our understanding of them in disease, biology, and evol...
A long-standing goal of evolutionary biology is to decode how gene regulation contributes to organismal diversity. Doing so is challenging because it is hard to predict function from non-coding sequence and to...
Lynch syndrome (LS) is a cancer predisposition syndrome affecting more than 1 in every 300 individuals worldwide. Clinical genetic testing for LS can be life-saving but is complicated by the heavy burden of va...
Multiplex assays of variant effect (MAVEs) are a family of methods that includes deep mutational scanning experiments on proteins and massively parallel reporter assays on gene regulatory sequences. Despite th...