The 2015-2016 epidemic of Zika virus (ZIKV) resulted in many ZIKV-infected mothers giving birth to infants with neurological defects, including microcephaly. While the causes of such defects remain unknown, one hypothesis links the birth defects with dysregulation of activity of RNA editing enzymes, ADARs, that in addition to their antiviral role also play a key role in neural transcriptome diversification. ADAR family consists of three genes, ADAR1, ADAR2, and ADAR3, with ADAR1 and ADAR2 catalyzing the hydrolytic deamination of adenosine (A) in pre-mRNA to inosine (I), which is then read as a guanine (G). ADAR editing activity is linked with the immune system via interferon-stimulated response element (ISRE) in the promoter of ADAR1 gene, which in response to viral infection - such as ZIKV - activates expression of ADARp150 isoform. While mice are used as model organisms to study many biological phenomena, ZIKV infections in mouse require knocking out the interferon pathway, which in turn disables the ISRE-ADAR link. To find a better-suited animal model we performed an evolutionary analysis of ADARp150 core promoter region to identify sequence similarities. Results show that genomic sequences from larger mammals such as sheep and pig are more similar to that of human than those from smaller animals like mice traditionally used in a lab setting. We also examined sequence conservation patterns of ADAR2 genes and explored the links between ADAR1 and ADAR2 variants and human diseases.
Dysregulation of RNA editing, via transcriptome regulatory gene ADAR, is hypothesized to play a role in microcephaly cases during the 2015-2016 Zika epidemic, because of ADAR’s role in editing viral and neural genes. ADAR is a family of three genes and deaminates adenosine (A) to inosine (I) in pre-mRNA, which is then read as a guanine (G). Important isoform, ADARp150, has an interferon-stimulated response element (ISRE) in its promoter region, providing a link with the host innate immune system. Current mice models appear not well suited for studying this. To find a better animal model, an evolutionary analysis of ADARp150 and ADAR2 genes was performed. Results show sequences from larger mammals, like sheep, are more similar to humans than mice offering a better model.