Autism-Risk, Schizophrenia-Risk, and Central Nervous System-Related Genes Display Genomic Features Common to Genes of Developmental Regulation

Background:   A large subset of genes in the human genome are involved in regulation of developmental processes. These include functional subsets like chromatin remodelers, transcription factors, translational regulators, and intracellular signaling transducers. They typically contain large introns, produce longer more complex proteins, and preference retention of transposable element (TE) insertion into intronic sequences over time for reasons not entirely understood. Each of these features is related to general functions of these developmental genes. A previous study of ours reported higher absolute TE content in autism-risk genes (Williams et al., 2013). In addition, King et al. (2013) reported preliminary findings of longer gene size in risk genes. Therefore, in this study we investigate whether autism (ASD)-risk, schizophrenia (SZ)-risk, and central nervous system (CNS)-related genes share features with genes of developmental regulation, so that we may better understand the functions and mutational trends of our genes of interest.

Objectives:   Using whole genome control (WGC) for comparison, we determine whether ASD-risk, SZ-risk, and CNS-related genes are enriched in TEs, are longer, and code for larger proteins. Housekeeping (HK) genes are used as a comparison group due to their compactness.

Methods:   All known protein-coding genes were acquired from RefSeq to compile the WGC. Autism genes with 10+ rating were downloaded from AutismKB database (N = 451). Core SZ-risk genes were acquired from SzGene database (N = 38). CNS genes were taken from the human Neurogenesis and Neural Stem Cell (PAMM-404) PCR array from Qiagen to be used as a representative sample (N = 85). Human HK genes were taken from Eisenberg and Levanon (2003) (N = 565). TE content was acquired on human genome 18 from the TranspoGene database and data on gene and protein lengths from NCBI RefSeq. TE analysis was performed using a negative binomial regression, meanwhile a gamma regression was used for assessing gene and protein lengths.

Results:   All groups significantly varied from WGC in terms of intronic TE content; meanwhile, there were no significant differences in non-intronic (promoter, exonic, exonized) content in experimental groups versus control, with the exception of the HK genes, which displayed significantly greater numbers of exonized TEs and fewer exonic elements (p-values < 0.001). Gene length varied significantly across all groups: ASD, SZ, and CNS gene groups were significantly longer in length than WGC, while HK genes exhibited the opposite trend (p-values < 0.001). Protein lengths followed similar trends as gene length across groups, with the exception of the SZ gene group, whose protein lengths did not vary compared to WGC in spite of having the largest gene length average.

Conclusions:  

ASD-risk, SZ-risk, and CNS-related genes house considerable TE content, are larger, and produce larger protein products as compared to WGC. Meanwhile, HK genes, known for their overall compactness and small intronic sizes, exhibit opposite trends as seen in the other experimental gene groups. These results suggest that ASD-risk, SZ-risk, and CNS-related genes may be classed with developmental regulatory genes and, as such, likely follow functional and mutational trends in this large subset of mammalian genes.