ADATscan – A flexible tool for scanning exomes for wobble inosine-dependent codons reveals a neurological bias for genes enriched in such codons in humans and mice

Abstract

The conversion of adenosine to inosine at the wobble position of select tRNAs is essential for decoding specific codons in bacteria and eukarya. In eukarya, wobble inosine modification is catalyzed by the heterodimeric ADAT complex containing ADAT2 and ADAT3. Human individuals homozygous for loss of function variants in ADAT3 exhibit intellectual disability disorders. We created a flexible computational tool to scan the human, mouse, nematode, fruit fly, and yeast exomes for genes either enriched or depleted in ADAT-dependent codons as compared to background models of codon bias derived from the exomes themselves. We find that many genes are enriched or depleted for ADAT-dependent codons as compared to the genomic background in all five species. Among those genes enriched for ADAT-dependent codons in humans, we find there is significant Gene Ontology (GO) enrichment for genes involved in diverse neurological processes. This pattern persists in the mouse exome but not the fruit fly or nematode exome. In the nematode exome, genes enriched in ADAT-dependent codons are GO enriched for translation associated genes, and in yeast there is GO enrichment for genes involved in metabolic functions. There is also GO-term overlap between yeast and fruit flies. Importantly, in its generalized form, ADATscan can also be used to scan any exome for genes enriched in any subset of codons specified by the user.