Putative contributions of the sex chromosome proteins SOX3 and SRY to neurodevelopmental disorders

• Published in: American journal of medical genetics. Part B, Neuropsychiatric genetics Vol. 180; no. 6; pp. 390 - 414
• Main Authors: Tahira, Ana Carolina, Barbosa, André Rocha, Feltrin, Arthur Sant'Anna, Gastaldi, Vinicius Daguano, Toledo, Victor Hugo Calegari, Carvalho Pereira, José Geraldo, Lisboa, Bianca Cristina Garcia, Souza Reis, Viviane Neri, Santos, Ana Cecília Feio, Maschietto, Mariana, Brentani, Helena
• Format: Journal Article
• Language: English
• Published: Hoboken, USA John Wiley & Sons, Inc 01-09-2019; Wiley Subscription Services, Inc
• Subjects: Animals; Autism; Autism Spectrum Disorder - genetics; Databases, Genetic; DNA methylation; DNA-Binding Proteins - genetics; Female; Gene Expression Regulation - genetics; Gene regulation; Gene Regulatory Networks; Genes; Genetic Predisposition to Disease; Genetics; Genomes; Gestation; Humans; Male; Mice; Mice, Inbred C57BL; neurodevelopmental disorder; Neurodevelopmental disorders; Neurodevelopmental Disorders - genetics; Neurogenesis; Preservation; Risk Factors; sex; Sex Chromosomes - genetics; Sex Factors; Sex hormones; Sex-Determining Region Y Protein - genetics; Sex-Determining Region Y Protein - metabolism; Sexes; SOX3; SOXB1 Transcription Factors - genetics; SOXB1 Transcription Factors - metabolism; SRY; stress; Transcription Factors - genetics; SOX3; stress; SRY; neurodevelopmental disorder; sex
• ISSN: 1552-4841; 1552-485X
• DOI: 10.1002/ajmg.b.32704

The male‐biased prevalence of certain neurodevelopmental disorders and the sex‐biased outcomes associated with stress exposure during gestation have been previously described. Here, we hypothesized that genes distinctively targeted by only one or both homologous proteins highly conserved across therian mammals, SOX3 and SRY, could induce sexual adaptive changes that result in a differential risk for neurodevelopmental disorders. ChIP‐seq/chip data showed that SOX3/SRY gene targets were expressed in different brain cell types in mice. We used orthologous human genes in rodent genomes to extend the number of SOX3/SRY set (1,721). These genes were later found to be enriched in five modules of coexpressed genes during the early and mid‐gestation periods (FDR < 0.05), independent of sexual hormones. Genes with differential expression (24, p < 0.0001) and methylation (40, p < 0.047) between sexes were overrepresented in this set. Exclusive SOX3 or SRY target genes were more associated with the late gestational and postnatal periods. Using autism as a model sex‐biased disorder, the SOX3/SRY set was enriched in autism gene databases (FDR ≤ 0.05), and there were more de novo variations from the male autism spectrum disorder (ASD) samples under the SRY peaks compared to the random peaks (p < 0.024). The comparison of coexpressed networks of SOX3/SRY target genes between male autism and control samples revealed low preservation in gene modules related to stress response (99 genes) and neurogenesis (78 genes). This study provides evidence that while SOX3 is a regulatory mechanism for both sexes, the male‐exclusive SRY also plays a role in gene regulation, suggesting a potential mechanism for sex bias in ASD.