Loss of critical developmental and human disease-causing genes in 58 mammals

Abstract

Gene losses provide an insightful route for studying the morphological and physiological adaptations of species, but their discovery is challenging. Existing genome annotation tools and protein databases focus on annotating intact genes and do not attempt to distinguish nonfunctional genes from genes missing annotation due to sequencing and assembly artifacts. Previous attempts to annotate gene losses have required significant manual curation, which hampers their scalability for the ever-increasing deluge of newly sequenced genomes. Using extreme sequence erosion (deletion and non-synonymous substitution) as an unambiguous signature of loss, we developed an automated approach for detecting high-confidence protein-coding gene loss events across a species tree. Our approach relies solely on gene annotation in a single reference genome, raw assemblies for the remaining species to analyze, and the associated phylogenetic tree for all organisms involved. Using the hg38 human assembly as a reference, we discovered over 500 unique human genes affected by such high-confidence erosion events in different clades across 58 mammals. While most of these events likely have benign consequences, we also found dozens of clade-specific gene losses that result in early lethality in outgroup mammals or are associated with severe congenital diseases in humans. Our discoveries yield intriguing potential for translational medical genetics and for evolutionary biology, and our approach is readily applicable to large-scale genome sequencing efforts across the tree of life.