Researchers are keen to identify environmental causes of autism, using epigenetics. Twin studies in particular offer unique opportunities for clever researchers. The eye opening results of the California Autism Twins Study (CATS) study, were that autism had a ~60% genetics basis and a ~40% environmental basis. This news has facilitated the idea that there is an epigenetic molecular trail to follow, to identify environmental causes of autism. One of those environmental factors correlating to autism risk is low birth weight. Yes, yes, well that seems to makes sense when you think of it in the context of premature births. But here again, twin studies show us further complexity. (As a side bar check out this blog post from Genomes Unzipped, Identical twins usually do not die from the same thing.) First of all, an identical twin can have autism, while their twin does not. They are clones and they shared a womb. What environmental factors could be differing in their development?
It turns out that simple birth weight data is traceable through epigenetics applications. A recent study has shown that although low birth weight has a modest association with autism spectrum disorders (ASD) in the general population, amongst discordant twins – twins with 20%+ difference in birth weight – the smaller twin has 3X the risk of having ASD. With this idea in mind, check out this new paper, Gao, Yu et al. Increased Expression and Altered Methylation of HERVWE1 in the Human Placentas of Smaller Fetuses from Monozygotic, Dichorionic, Discordant Twins. (2012) PloS Vol. 7, Issue 3, e33503. It does not address autism directly. However, the work demonstrates that in identical twins pairs where each fetus develops in their own separate amniotic sacs (dischorionic), and are born with an average ~30% difference in weight (discordant), the human endogenous retroviral family W, Env(C7),member 1 gene (or HERVWE1) has higher expression in the smaller twin. HERVWE1 is a an acquired retroviral, functional placental morphogenesis gene conserved in hominids.
The group used placenta tissue to study intrauterine epigenetic modifications affecting fetal growth within normal birth weight range. The tissue samples came from 21 twin monozygotic, discordant, dischorionic pairs, 24 twin monozygotic, concordant, dischorionic pairs and 10 singleton controls born at same gestational age as all the twins.
RT PCR showed increases of mRNA HERVWE1 transcriptional expression in smaller twins. Immunohistochemistry of HERVWE1 protein mirrored the mRNA levels. IHC of overall 5mC showed no significant difference among groups. Pyrosequencing of all discordant twins and singleton controls to showed the methylation status of the HERVWE1 promoter was inverse to its gene expression. The group explored DNMTs profiles, with real time PCR. Only in discordant twin pairs, the smaller twin expressed less of DNMT3b3 isoform and more DNMT3b7. The DNMT3b3 transcription positively correlated with methylation of HERVWE1 promoter.
Further research in the epigenetics of in utero neurological development is necessary to link molecular mechanisms to proposed environmental causes of ASD. The translational research potential for autism is awesome. This is demonstrated by “bloomers”, people born with ASD, who received sufficient behavioral targeted therapy while their young minds still had high plasticity and were able to lose symptoms. Sadly, therapy treatment alone can’t help low functioning ASD people to be able to live an independent life. If autism can be teased apart into subtypes based on biological causes, perhaps we become that much closer to developing drugs for ASD treatment, providing the best shot possible.
Gao Y, He Z, Wang Z, Luo Y, Sun H, Zhou Y, Huang L, Li M, Fang Q, & Jiang S (2012). Increased Expression and Altered Methylation of HERVWE1 in the Human Placentas of Smaller Fetuses from Monozygotic, Dichorionic, Discordant Twins. PloS one, 7 (3) PMID: 22457770