Abstract
To better understand the health implications of personal genomes, we now face a largely unmet challenge to identify functional variants within disease-associated genes. Functional variants can be identified by trans-species complementation, e.g., by failure to rescue a yeast strain bearing a mutation in an orthologous human gene. Although orthologous complementation assays are powerful predictors of pathogenic variation, they are available for only a few percent of human disease genes. Here we systematically examine the question of whether complementation assays based on paralogy relationships can expand the number of human disease genes with functional variant detection assays. We tested over 1,000 paralogous human-yeast gene pairs for complementation, yielding 34 complementation relationships, of which 33 (97%) were novel. We found that paralog-based assays identified disease variants with success on par with that of orthology-based assays. Combining all homology-based assay results, we found that complementation can often identify pathogenic variants outside the homologous sequence region, presumably because of global effects on protein folding or stability. Within our search space, paralogy-based complementation more than doubled the number of human disease genes with a yeast-based complementation assay for disease variation.
Highlights
As a result of rapid developments in sequencing technology, we are identifying many rare variants in individual human genomes [1]
Functional complementation assays of human disease-associated gene variants can reveal many more human disease variants at high confidence than current computational approaches, even using highly-diverged model organisms. This has generally only been possible for a minority of human disease genes for which orthologous complementation is known in the relevant model organism, so that alternative assays are urgently needed
Core cellular biology is well conserved between yeast and humans, with ~60% of yeast genes having human homologs and 87% of yeast protein domains being present in a human protein [13]
Summary
As a result of rapid developments in sequencing technology, we are identifying many rare variants in individual human genomes [1]. To fully exploit this resource, we must be able to rapidly identify which of the many variants in each individual are most likely to be functional and disease-causing. The scale of experiments in yeast ranges from individual assays to high-throughput genome-wide experiments [10,11,12]. Functional complementation assays using model organisms can allow us to, for example, assess the functions of all possible missense variants of a gene in advance of their first appearance in the human population [14,15,16]
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