Better maths with genes

Medical specialists publish results of RNA study in Nature

Door Bart Braun

All sorts of characteristics are determined by our genes, but which genes are “turned on” and how? Researchers at Leiden took part in the largest transcriptomics study ever conducted.

Let’s start at the beginning: genomics. Almost every cell in our body contains DNA, genetic material stored in relatively large molecules we call chromosomes. We inherit half of these chromosomes from our fathers and half from our mothers.
DNA is a long chain of smaller molecules, like beads, and there are only four sorts of them. If scientists do their best, they can determine the complete order of all those “beads”, a process called sequencing. The result is called a genome and the science that studies genomes is called genomics.
The first genome to be elucidated, which happened in the seventies, was that of a virus. The first living creature – a bacterium – followed in 1995 and then things started to take off. Techniques improved more and more rapidly, scientists grew more adept at sequencing and the demand increased, inspiring more technological improvements, and so on and so forth. In 2000, Bill Clinton and Tony Blair announced the end of the Human Genome Project and although the definition of “end” is debatable, we now had a “blueprint of life” as it was known back in the day.
Just as the blueprint of a house does not mean much to a novice, scientists were stuck with the genome: what did it mean? Identical twins have the same genetic makeup, but it is usually quite easy to distinguish between the two. Our brain cells and our intestinal cells differ immensely although both sorts contain the same DNA.
There is more to it than just the DNA sequence: it matters which genes are “turned on” and what turned them on. If a cell wants to do something with a gene, it “copies” the DNA: the DNA is used as a template to make another molecule: RNA. In scientific terms, a “copy”, is called a “transcription” and so research into all the RNA in a cell is known as “transcriptomics”.
Last month’s issue of Nature, the leading science journal, featured a paper by the Geuvadis Consortium, a European partnership project in which geneticists from Leiden are participating. The team of scientists have determined the transcriptomes in a certain kind of white corpuscle from 462 individuals. Because the regular human genome had already been determined thanks to the “1000 genomes” project, the scientists make a large-scale comparison between the two “omics” for the first time. We already knew that humans, in genetic terms, are very similar. If you were to catch two monkeys from the same tree, they would probably differ more than any two people anywhere in the world. The scientists have concluded that there is much more variety in the way our genes are regulated and deleted. This information is useful for people who want to know how a cell works or how humans work but more particularly for people who want to help when these things break down: doctors.
Many disorders are connected to DNA, but the link is quite weak. A certain variation of a gene may mean a greater risk of something like multiple sclerosis or diabetes, but luckily not everyone with that variation actually becomes ill. “The associations with RNA are often far more direct”, explains bioinformatician Peter-Bram ’t Hoen from the LUMC department of Human Genetics. “Transcriptomics are a vital intermediary step and we need it to study the connection between genes and disorders.”
“There has always been some debate about what exactly is determined by genes, and how much is affected by our environment”, continues ’t Hoen, one of the co-authors of the Nature article. “The impact of the environment in this study is relatively small, because we examined cells that had been cultivated in a standardised environment. In the future, we will be able to use techniques like this to determine the interactions between genes and the outside world. If we had used brain cells used instead of these corpuscles, the transcriptomes would be different, of course. Obviously, it would be useful to add other kinds of cells to this study. Certain genes that are very specific for a certain type of cell – brain cell genes, for example – are not active here, but much of this information can be used to extrapolate information about other cell types.”
Part of Leiden’s contribution to the project consisted of ironing out wrinkles in the research method. ’t Hoen is the first author of a separate article in Nature Biotechnology in which the consortium explains how they needed to make the method as uniform as possible and examines how well they succeeded in doing that. It sounds easier than it was, because RNA is famously difficult to work with. “There are techniques that we know will still produce different results even if two analysts follow the same protocol. The method we chose was not too bad, thankfully, but even so, we still discovered deviances now and then, because one group had not used exactly the same device for the preliminary processing, for instance.”
The Leiden researchers are teaming up with research groups in Groningen, Rotterdam and Amsterdam for the next step: to determine the transcriptomes of four thousand Dutch people – and not just one type of blood cell, but the complete cocktail of the different cell types you find in a blood sample. “It’s far more complex, but the information will be much richer.”
How far can you go with this information? “It really is a fallacy to suppose that once we have all the transcriptomes, we will know the secret of life”, the researcher says emphatically. “That secret is far more complicated than we could ever imagine.”

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