Students in grade school these days learn that DNA (containing genes) is transcribed into full-transcript RNA, which is then spliced into messenger RNA (mRNA), which gets translated into protein. By knowing the DNA sequence of any individual’s gene therefore leads to our knowing the sequence of the RNA transcript and subsequently, inference of the translated protein. Not only has whole-genome sequencing (WGS) become very popular –– but “RNA-seq”, which measures the DNA-specific transcribed RNA, is now also widely performed; this study is termed “transcriptomics.” In recent years, WGS and RNA-seq were carried out on tissues or total organs. Recently, these techniues have been scaled down so that individual cells can be identified, isolated, and then these methods performed on individual cells. This is the topic of the attached article.
Parkinson Disease (PD) is the most common progressive neurodegenerative movement disorder. Incidence of PD increases with age, affecting world-wide an estimated 1% of the population over 70 years of age. PD is a multifactorial trait (phenotype), i.e. representing the contribution of hundreds if not thousands of genes, plus epigenetic factors, plus environmental effects. Several large-cohort genome-wide association studies (GWAS) have identified ~49 genetic loci statistically significantly associated with (non-familial or) sporadic PD. Although PD ultimately affects multiple neuronal centers, preferential degeneration of dopamine neurons in the substantia nigra (a specific location in the base of the brain), leading to loss of fine-motor control. One can reasonably assert that a significant fraction of PD-associated variation likely mediates its influence specifically within the substantia nigra. There is a mouse model for PD in which the Cplx1 gene is deleted. Authors [attached article] thus carried out single-cell RNA-seq analyses of multiple dopamine nerve-cell populations in the PD-mouse brain, including those in the substantia nigra.
Characterizing dopamine-containing neuron populations in the mouse brain at embryonic vs early postnatal time-points, authors determined unique transcriptional profiles –– including a postnatal neuroblast population (immature cells similar to stem cells) and substantia-nigra dopamine-containing neurons. They used these population- specific findings to develop a scoring system to prioritize candidate genes in all 49 DNA segments that had been implicated in PD risk (by GWAS), including genes with known PD associations and many with extensive supporting literature. As proof of principle, authors confirmed that the substantia nigra-striatal pathway is compromised in the Cplx1-null mouse model. Authors believe that this systematic approach “establishes biologically-pertinent candidates and testable hypotheses for sporadic PD, opening up a new avenue in PD genetics research.”
Am J Hum Genet 1 Mar 2o18; 102: 427–446