How the Placement of a Gene Makes It Fun

How the Placement of a Gene Makes It Fun ...

The quote, What I cannot create, I do not understand, is credited by Prof. Richard Feynman. It''s a good way of describing synthetic biologists'' motivations, coupled with their ability to develop and construct synthetic genomes. By developing and constructing synthetic genomes, they aim to better understand the code of life.

Synthetic biology has been established based on the notion of using DNA sequences as part of their reproducible functions. Now, through successful collaborations and the use of cutting-edge technologies, the EMBLs Steinmetz Group has gained an important insight into the variation of gene expression that has erupted from these DNA parts within the genome.

Amanda Hughesco-lead author and postdoc in theSteinmetz Groupsaid: In synthetic biology, you tend to break things down into modular, plug-and-play parts. These are promotor components, coding regions, and terminator components. We wanted to investigate whether these pieces actually are plug-and-play, functioning the same way in any context, or whether their structure may affect their functions. We wanted to understand how the linear organisation of genes influences their beliefs and identify general design principles that might be applied to building genome

A synthetic biology toolbox enables contextual insights.

The use of two key technologies in the genome sequencing was achieved: synthetic yeast strains from the Sc2.0 consortium and long-read direct RNA sequencing. This capability, according to a research conducted by EMBL, enabled the team to discern both the start and end of RNA molecules and their assignment to particular rearrangements.

The study, published inScience, showed that context and in particular transcriptional context altered the RNA output of a gene. Using long-read direct RNA sequencing, participants were able to observe changes in the start, end, and amount of whole-length RNA molecules expressed from random rearranged a gene; however, these changes were not always explained by the new adjacent DNA sequence. It seemed to be transcription occurring around it rather than the sequence itself, which altered a genes RNA output.

Using such a large, stochastic dataset was not a trivial task, as explained by the lead author. Nevertheless, we had to research genes in many other genetic contexts, which were present in the SCRaMbLE strains. Having the pieces back together, however, was a major task. We had to develop a vast sequencing dataset, which required us to develop new software tools. Similarly, when a gene was relocated next to a highly expressed neighbour, its expression tended to increase

Definition of design principles for genome building

The researchers also discussed the connection between RNA abundance and neighbouring gene expression. Specifically, they found that the length of an RNA was affected by the proximity and abundance of adjacent transcripts. Jef Boeke, the co-author and director of the Sc2.0 consortium, remarked on these insights: Deep transcriptional profiling combined with the genome variations created using the SCRaMbLE system have given us further insight into the flexibility of the yeast genome and said that the rules of where transcripts end can be surprisingly context dependent

By observing the length of RNA molecules, the researchers examined the transcription of a nearby gene. The researchers demonstrated that the lessons learned from the SCRaMbLEd genome sequencing can be used to reconstruct RNAs with desired functions. The researchers also proposed a new synthetic biology design technique that may be used to alter its stability, translation into protein, or even localisation. All of this could be accomplished by controlling the expression of a convergent, adjacent gene rather than the gene itself.

The unbiased and high-throughput nature of the gene reshuffling approach here allows us to discover functions of genomic sequences in different geographical situations, something that previously was not possible at scale. Ultimately, the work reveals that there is a fine-tuned interlinked relationship between various genetic components, spanning multiple genes, that can be interpreted as a blueprint for genome development; i.e. where genes are best located and how should they be positioned relative to each other. These insights further enrich the

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