The transcriptional legacy of developmental stochasticity
Preprint posted on December 12, 2019 https://www.biorxiv.org/content/10.1101/2019.12.11.873265v1
The phenotype of an individual is largely determined by genetic contribution and the influence of the environment. Stochastic variability of transcription, particularly during embryonic development, is also thought to affect phenotypic variation but it has always been a difficult component to isolate and study. In this work, the authors use an exceptional feature of the nine-banded armadillo (Dasypus novemcinctus) to study this developmental stochasticity. Armadillos have developed a unique reproductive strategy to produce litters of identical quadruplets. This system allows the control of genetic and environmental contributions to focus on the role of transcriptional stochasticity. Collecting blood samples and measuring gene expression at three different time points per armadillo quadruplet, the authors investigate the influence of transcriptional changes, and whether they may account for identity signatures among siblings.
The authors aimed to identify transcriptional differences in armadillo quadruplets – maintained throughout the three time points – that were sufficient to distinguish individuals among siblings. For that, the authors developed a machine-learning method that helped them identify differential transcripts consistently over time as indicators of identity.
Random X-chromosome inactivation signature. Like all mammals, female armadillos undergo X-chromosome inactivation to silence one of their X-chromosomes and balance the gene dosage content with males. This process is random when it first happens and, in armadillos, it actually takes place after the embryos have split. Therefore, each sibling will have a unique signature. Using their machine-learning method, the authors verified that imbalance of allelic ratios of X-linked genes are predictive of an individual within a quadruplet. Interestingly, this is not something exclusive of the X chromosome because they also observed allelic imbalances in autosomes which were predictive of individuality.
Gene expression differences as mark of identity. As opposed to allelic ratios, the authors then investigated the impact of gene expression. They took X-linked genes and autosome-linked genes separately to avoid biases in the analysis. Interestingly, the genes that acted as predictors of individuality were not differentially expressed in all the armadillo cohorts analysed. Those genes were always expressed in all quadruplets, indicating that identity signatures were not due to genes that are uniquely expressed in specific individuals. The functions of predictor genes were enriched in lifestyle stimuli such as cardiac muscle growth.
Individual signatures in human twins. In order to see if similar functional perturbations driving identity in armadillos could be observed in humans, the authors analysed data from human identical twins. Because the post-natal environment was not controlled as in armadillos, differences in gene expression could not be completely linked to transcriptional stochasticity. In fact, differences in gene expression in humans were higher than in armadillos. Differentially expressed genes were not associated with known eQTLs (genomic loci that affect expression levels), suggesting that those differences were not due to genetic variations. An interesting aspect is that genes that showed variation in gene expression in armadillos and humans are frequently perturbed in differential expression studies and could be associated with stimulus-responsive regulation.
General comments and why I chose this preprint
A non-heritable variability that complements the effect of the genotype and the environment for every phenotype has been appreciated and discussed in multiple organisms and contexts . I really liked the authors’ strategy of using armadillo quadruplets to study the effect of this component that has always been difficult to isolate from the effect of the environment. This is a beautiful example of how one of the most important things when addressing a question is to choose the model system to work with and why, although challenging, using a non-classical model organism can be the key.
The authors have done a very important effort in this work that opens many questions and predicts interesting directions in future individual stochasticity studies.
 Honegger and de Bivort (2018). Stochasticity, Individuality and Behavior. Curr Biol, 28 (1): R8-R12.
Questions to the authors
The authors see that genes that were differentially expressed and gave an identity among siblings were not always the same between armadillo quadruplets. Do the authors think the genes that provide individuality are completely random? Or do they think there may be some genes that are more prone to have differences in expression levels due to a less strict regulation?
Although the authors talk about “developmental stochasticity”, the analyses are performed on blood sample data and thus, some genes they can detect may be different from genes expressed during embryo development. Do the authors expect a different or broader set of genes to account for individual signature during embryo development?
Do the authors expect different functions for those genes which provide individuality during a specific period of time versus those genes whose differential gene expression are maintained during a longer time window?
Posted on: 23rd January 2020 , updated on: 24th January 2020Read preprint
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