By Rideeta Raquib ’19

The brain is a complex organ that is constantly being impacted by genetic and epigenetic factors. Mental illness patients are usually heterozygous in terms of inheriting one mutant allele. The random inactivation of the X-chromosome and genomic imprinting influences brain architecture and risk of disease. Studies on neuropsychiatric disorders uncovered a spectrum of data regarding the epigenetic dynamics of such dysfunction. Dr. Wei-Chao Huang and his team of researchers studied the epigenetic factors that influence the wild type allele and compared its influence to mutant alleles.

Allele-Specific expression (ASE) was analyzed in vivo and it was assumed that majority of genes express maternal and paternal alleles equally. The co-expression was tested by examining the maternal versus paternal expression in RNA sequence of biologically replicated F1 mice. Differential allele expression (DAEE), expression in which there there is a weak correlation between maternal and paternal alleles, was more prominent in the neonatal brain of the mice, while allele co-expression (CoEEs) was prevalent in later developmental stages. A major part of the experiment included analyzing how DAEE affected the expression of heterozygous mutations on a cellular level. Mutations that caused mental illness were heterozygous, meaning that one allele was mutant. When the heterozygous mutation occurred, some brain cells expressed the healthy and mutant copies of the gene, which were referred to as biallelic cells. When DAEE was present, some brain cells expressed the mutated copy, while others did not. These non-expressed cells were referred to as monoallelic cells. Based on this information, the researchers hypothesized that the monoallelic brain cells that expressed the mutated allele contributed to the development of mental illness. They furthered the screening process to analyze whether these DAEE effects are exhibited in primate brains, such as monkeys and humans, and whether they impacted genes linked to mental illness. They discovered that these DAEE effects play a role in various mental health-related conditions, such as Huntington’s disease and schizophrenia.

Overall, this study opens doors to further investigations regarding developmental changes in the X-linked allele co-expression. It also provides more insight on gene expression on X chromosomes, as well as how these gene expressions are related to behavior and risk of disease. Future research in the field will help uncover the mechanisms that contribute to mental illness and generate novel treatment options to combat these illnesses.

References:

1. WC. Huang, et al., Diverse non-genetic, allele-specific expression effects shape genetic architecture at the cellular level in the mammalian brain. Cell Press (2017). doi: 10.1016/j.neuron.2017.01.033
2. Image retrieved from: http://s1.thingpic.com/images/nu/oFb2xuT9ArbVSjtmrNqBcbcf.jpeg