Abstract
Autism susceptibility candidate 2 (AUTS2) is a neurodevelopmental regulator associated with an autosomal dominant intellectual disability syndrome, AUTS2 syndrome, and is implicated as an important gene in human-specific evolution. AUTS2 exists as part of a tripartite gene family, the AUTS2 family, which includes two relatively undefined proteins, Fibrosin (FBRS) and Fibrosin-like protein 1 (FBRSL1). Evolutionary ancestors of AUTS2 have not been formally identified outside of the Animalia clade. A Drosophila melanogaster protein, Tay bridge, with a role in neurodevelopment, has been shown to display limited similarity to the C-terminal of AUTS2, suggesting that evolutionary ancestors of the AUTS2 family may exist within other Protostome lineages. Here we present an evolutionary analysis of the AUTS2 family, which highlights ancestral homologs of AUTS2 in multiple Protostome species, implicates AUTS2 as the closest human relative to the progenitor of the AUTS2 family, and demonstrates that Tay bridge is a divergent ortholog of the ancestral AUTS2 progenitor gene. We also define regions of high relative sequence identity, with potential functional significance, shared by the extended AUTS2 protein family. Using structural predictions coupled with sequence conservation and human variant data from 15,708 individuals, a putative domain structure for AUTS2 was produced that can be used to aid interpretation of the consequences of nucleotide variation on protein structure and function in human disease. To assess the role of AUTS2 in human-specific evolution, we recalculated allele frequencies at previously identified human derived sites using large population genome data, and show a high prevalence of ancestral alleles, suggesting that AUTS2 may not be a rapidly evolving gene, as previously thought.
Highlights
Autism susceptibility gene 2 (AUTS2) is a neurodevelopmental regulator associated with an autosomal dominant neurological syndrome with ASD-like (Autism Spectrum Disorder-like) features
The results show that the AUTS2 family consists of three members, AUTS2, Fibrosin-like protein 1 (FBRSL1) and FBRS, within the majority of Gnathostome species (Fig 1)
The phylogenetic analysis produced here suggests that AUTS2 is evolutionary closer to FBRSL1 than to FBRS, i.e. sharing a most recent common ancestor (Fig 1), which is supported by average pairwise identity (Table 1; S2–S6 Tables)
Summary
Autism susceptibility gene 2 (AUTS2) is a neurodevelopmental regulator associated with an autosomal dominant neurological syndrome with ASD-like (Autism Spectrum Disorder-like) features. Ancestry of the AUTS2 gene family disability (ID), microcephaly, feeding difficulties and mild dysmorphic facial features including highly-arched eyebrows, short philtrum, ptosis and micro/retrognathia along with mild abnormalities of the hands and feet [1]. Hemizygous deletion of AUTS2, alongside deleterious truncating point mutations, have highlighted the C-terminus as being associated with more severe clinical manifestations of the syndrome [2]. Homozygous deletion of Auts in mice is prenatally lethal, and heterozygosity results in a similar phenotype to that of patients, including: short stature, reduction in body mass, impaired recognition of learned objects and attenuation of associative memory with no notable social deficit [3,4,5]. Increased levels of Auts expression have been identified as a protective factor against behavioural sensitization to heroin addiction in a mouse model [7]
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