AUTS2: an in silico study

Abstract

Autism Susceptibility Candidate Gene 2 (AUTS2) is a gene associated with a syndromic condition known as ‘AUTS2 syndrome’. The phenotypic profile of AUTS2 syndrome consists of intellectual disability, developmental delay and microcephaly, with the frequent presentation of autistic-like behavioural traits. AUTS2 plays an important role in neurodevelopment through its effect on neuronal migration. The C-terminal of AUTS2 is thought to be integral to its biological function as a potential transcription factor, due to observations linking more severe disease phenotypes to patients with mutations involving this region. The aim of this research was to investigate the biological role of AUTS2 in both normal development and disease through the use of phylogenetic and systems biology approaches. Phylogenetic analyses were applied to assess the relationship of AUTS2 with potential family members (FBRLS1 and FBRS) and a potential ancestral gene found in Drosophila (Tay bridge). Investigations were also carried out to identify regions displaying high sequence similarity between the AUTS2 family proteins as these may have functional properties. Network biology techniques were employed to probe the biological function of AUTS2 through its capacity as a transcriptional regulator. These studies identified AUTS2, FBRSL1 and FBRS as an interrelated protein family which share an ancestral heritage with the Drosophila protein, Tay bridge. The inclusion of AUTS2 homologues within the genome of invertebrates would suggest that homologues of AUTS2 have been present within the genomes of the early ancestors of the Bilateria clade, which could allude to the involvement of Auts2 and its progenitors in the basic formation of the nervous system. In-depth conservational analysis of the AUTS2 protein sequence identified novel regions of high-identity homologous sequence, which may have functional and/or structural importance. These include previously unknown, highly conserved elements within the N-terminal sequence, a region with structural and nucleotide variation associated with AUTS2 syndrome. Network analysis of the downstream pathways modulated by AUTS2, through its function as a transcription factor, indicates that AUTS2 plays a role in neuronal cell-cycle suppression, differentiation, migration and intracellular signalling. This is in line with previous evidence regarding the nuclear function of AUTS2, but also opens up avenues of research into the function of AUTS2 outside of a neurodevelopmental paradigm.

Date of Award	1 Aug 2017
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Mayada Tassabehji (Supervisor) & Adam Stevens (Supervisor)