The role of AUTS2 in neurodevelopment and human evolution

Abstract

The autism susceptibility candidate 2 (AUTS2) gene is associated with multiple neurological diseases, including autism, and has been implicated as an important gene in human-specific evolution. Recent functional analysis of this gene has revealed a potential role in neuronal development. Here, we review the literature regarding AUTS2, including its discovery, expression, association with autism and other neurological and non-neurological traits, implication in human evolution, function, regulation, and genetic pathways. Through progress in clinical genomic analysis, the medical importance of this gene is becoming more apparent, as highlighted in this review, but more work needs to be done to discover the precise function and the genetic pathways associated with AUTS2.

Keywords: AUTS2; autism; human evolution; neurodevelopment.

Figure 1

Schematic of the AUTS2 protein. AUTS2 (1259 amino acids) is shown as a gray bar (individual amino acids in single-letter code). The locations of predicted domains, motifs, regions of homology, and other characterized sequences are shown below and within the protein. Numbers in parenthesis represent the amino acid location. The figure is based on predicted features in [6,12].

Figure 2

Schematic of the AUTS2 genomic region. Numbers to the left of the lines correspond to reference numbers. Human accelerated sequences are shown as blue lines above the gene [–68]. Structural variants [,,–,–30,48,49] are represented as colored lines (red, deletion; orange, inversion; green, duplication; purple, translocation). Single-nucleotide polymorphisms (SNPs) are shown as magenta stars. rs6943555 is associated with alcohol consumption [42]. SNPs in [46,47] are associated with bipolar disorder. SNPs in [46] are reported to be in strong linkage disequilibrium with each other. Arrows in bars signify that the structural variant extends past the gene in that direction. Exons are depicted as light-blue rectangles, as defined by the RefSeq genes track in the University of California, Santa Cruz (UCSC) Genome Browser. DD, developmental delay; DF, dysmorphic features; HACNS, human accelerated conserved non-coding sequence; HAR, human accelerated region; ID, intellectual disability; LD, language disability; MCA, multiple congenital anomalies; SD, seizure disorder. Figure adapted from [17].

Figure 3

auts2 zebrafish knockdown phenotype. (A) At 48 hours post-fertilization (hpf), fish injected with a 5 bp mismatch auts2 morpholino (MO) control have a similar morphology to wild type fish, whereas fish injected with a corresponding translational MO display a stunted developmental phenotype that includes a smaller head, eyes, body, and fins. (B) At 48 hpf, HuC–GFP fish injected with a 5 bp mismatch auts2 control MO display normal levels of developing neurons in the brain, whereas translational MO injected fish display less developing neurons in the cerebellum (ce), optic tectum (ot), and retina (ret). (C) At 120 hpf, fish injected with an auts2 splicing MO and stained with Alcian blue show a significant reduction in the distance between the Meckel (Mk) and ceratohyal cartilages (ch) (shown as a red line) compared to controls, indicating a reduced lower-jaw size. Panels (A, B) adapted from [17], (C) adapted from [26].