Genes that “jump” can rewire neuronal function in the brain

Genes that “jump” can rewire neuronal function in the brain
Genes that “jump” can rewire neuronal function in the brain

Through, the misunderstanding


With the completion of the Human Genome Project in 2003 and technological advances in our ability to sequence DNA, great advances have been made in our understanding of genomics over the past few decades. For many years, however, a large portion of the genome (~ 97%) was dismissed and mistakenly labeled “junk” because it did not encode proteins. While some research groups pondered the role of this mysterious part of the genome, most genomic research in the 1990s focused on exons, sequences of DNA that code for proteins.

However, research studies by consortia like ENCODE showed that this “junk” landscape was simply misunderstood. “Junk DNA consists largely of repetitive sections of DNA, and it is therefore difficult to“ read ”these sections of our genome. However, recent advances in technology have revolutionized genomics. We are now able to analyze the genome of 10,000 individual cells in a short time, “said Dr. Christoph Driver, postdoctoral fellow at the Center for Neural Circuits and Behavior at Oxford University.

We now know that the non-coding part of the genome has various genetic elements with functional properties necessary for cell biology, for example transponierbare Elements, or Transposons.1

What are transposons?

Transposons are fractions of the genome that are often referred to as “jumping” genes because of their ability to move from one location in the genome to another. They were discovered by the late cytogeneticist Barbara McCicktock; Research that earned her the 1983 Nobel Prize in Physiology. Transposons make up ~ 44% of the human genome, ~ 37% of the mouse genome, and over 80% of the genome of certain plant species such as corn.2,3

There are many different types of transposons, and they have been given some pretty interesting names over the years, including Escaped and Hobo. By and large, transposons are divided into two categories:

Retrotransposons


Also known as class I transposons, they first require the transcription of DNA into RNA before the enzyme reverse transcriptase makes a DNA copy of the RNA that can be inserted in a new location in the genome. Comparable to the copy and paste mechanism in a Word document.

DNA-Transposons


Also known as Class II transposons, they often move through a “cut and paste” mechanism that effectively “cuts” the transposon from its position in the genome and pastes it directly in a new location.
4

The effect of transposons, or “jumping” genes, depends largely on where they land. They can be an important source of genetic mutations, the possible adverse effects of which have led to them being often referred to as “DNA parasites”. However, they are also considered major drivers of evolution as they contribute to the heritable genetic variation that diversifies species.

New research has also suggested that transposons are able to introduce non-heritable genetic changes in somatic Cells, especially neurons.5 In the brain, transposon insertions could affect the physiology of a particular group of neurons and contribute to certain brain functions such as behavior or cognition – effectively “rewiring” the brain. It also opens up the possibility that transposons could be involved in pathologies such as neurodegeneration or age-related cognitive decline.

This is driver’s research focus at Oxford University and the subject of his most recent publication in Through research in collaboration with Professor Scott Waddell.7 The research team used novel single cell sequencing methods to analyze the expression of transposons in the brain of Drosophila melanogaster Fruit flies. The Drosophila Fly is a widely used model that has been used in genetics and neuroscience for a century.6

Advances in single cell sequencing

In the past, it was extremely difficult to analyze somatic transposons because they occur in individual DNA molecules. However, according to driver, single cell sequencing has proven to be a real game changer.

“By accessing the transcriptome of 10,000 cells from the brain in a single experiment, we can analyze many cell types in parallel. We can also shed light on the complex expression patterns of transposons, ”he said Technology networks, and added, “In our research group, we pioneered the use of these new tools in the fly’s brain.”

An important role for transposons in the brain?

Analysis there Drosophila The brain at the single cell level showed that transposon expression was not random – it occurred in a pattern. “Amazingly, when looking at the“ junk ”sections of the genomes in the brain, a clear pattern emerged,” commented driver. “Our most important finding is that transposons are not randomly expressed in the brain. Instead, we found that their expression is determined by the genes surrounding them. ”

In addition, the scientists found a number of neuronal genes for which a significant portion of their mature mRNA transcript pool contained transposon sequences. They sometimes occurred in the open reading frame, in addition to a location where they could affect the translocation of the gene known as the untranslated region or UTR. “We show that many transposons are spliced ​​into cellular genes and thus possibly change the structure and function of proteins in the brain,” said Trebier.

Of course, changing the structure and function of a protein can ultimately lead to disease, depending on the role of the protein. Driver and Waddell identified 264 transposon genes in the Drosophila Brain. Of these 264 genes, there are several examples in which a disorder – or change – could potentially adversely affect neuronal function. “Housing flies Hobo im Sch and Escaped im cac may have changed voltage-controlled currents, while those with roo im The R1 will react differently to the modulatory allatostatin A neuropeptide “, write the authors in the work.

When asked why driver and Waddell jointly concluded that the transposons could alter neural function, he said, “The fruit fly brain is an established model that helps us shed light on basic principles about how our brains work Many of the genes modified by transposons have been shown to play key roles in a wide range of behaviors. Artificially induced changes in these genes, often induced by transposable elements, can lead to dramatic changes in behavior. ”

Development of software for other research areas


In the paper, the authors also state that they are the first (to the best of their knowledge) to investigate the proportion of transposon expression in somatic cells that consists of exonated transposon fragments.

What is exonization?

The number of exons in an organism’s genome is not fixed. It is constantly changing through the process of creating novel exons and losing existing exons. Exonization is the process by which genes extract new exons from DNA in non-protein coding regions.8

The ability to achieve such in-depth analysis in research is attributed to new software tools created by drivers. When asked to discuss the tools, he said, “Whole genome sequencing experiments on most higher organisms produce data on ‘junk’ DNA, but that information is usually discarded. Our new software tools enable us to “upcyclize” this “junk” and extract new, valuable data. We have optimized our tools for the fruit fly genome, but we can easily apply them to data from other organisms, including humans. Hopefully these tools will inspire many new research projects examining the interactions between transposons and genes. “

Functional consequences of transposon insertion


The findings that this work provides at the single cell level are certainly interesting for the field of neurobiology, but questions still remain. Treiger identified a possible limitation of the research: “So far we have shown that transposons change gene transcripts in the brain. We quantified the ratio of these altered versions to unchanged versions and found that they make up a significant portion of the transcripts. At this point it is not certain whether this frequency is also reflected in a cell’s protein pool. ”

The functional consequences of the transposon-altered genes will be the next focus for the scientists at Oxford University on both the cellular and behavioral level. “This is a particularly exciting path because we know that transposon insertions are very different within a population. Hence, the close relationship between transposons and genes that we describe in our study could lead to an exciting prospect: “Junk” DNA could play a key role in making individuals behave idiosyncratically, “concluded Driver.

Christoph Driver spoke to Molly Campbell, Science Writer, Technology Networks.

References::

1. Jo BS, Choi SS. Introns: The functional advantages of introns in genomes. Genomics Inform. 2015; 13 (4): 112-118. doi: 10.5808 / GI.2015.13.4.112.

2. Mouse Genome Sequencing Consortium, Waterston RH, Lindblad-Toh K. et al. First sequencing and comparative analysis of the mouse genome. Nature. 2002; 420 (6915): 520-5. 562. doi: 10.1038 / nature01262.

3. San Miguel P, Tikhonov A, Jin YK, et al. Nested retrotransposons in the intergenic regions of the maize genome. Science. 1996; 274 (5288): 765. doi: 10.1126 / science.274.5288.765

4. Bourque G., Burns KH, Gehring M. et al. Ten things you should know about transposable elements. Genomic biology. 2018; 19 (1): 199. doi: 10.1186 / s13059-018-1577-z.

5. Muotri AR, Chu VT, Marchetto MCN, Deng W., Moran JV, Gage FH. Somatic mosaicism in neuronal progenitor cells mediated by L1 retrotransposition. Nature. 2005; 435 (7044): 903- 910. doi: 10.1038 / nature03663.

6. Bellen HJ, Tong C, Tsuda H. 100 Years of Drosophila Research and Its Impact on Vertebrate Neuroscience: A History Lesson for the Future. Nat Rev Neurosci. 2010; 11 (7): 514- 522. doi: 10.1038 / nrn2839.

7. Driver CD, Waddell S. Transposon expression in the Drosophila brain is controlled by neighboring genes and diversifies the neural transcriptome. Genome research. doi: 10.1101 / gr.259200.119.

8. Sorek R. The Birth of New Exons: Mechanisms and Evolutionary Consequences. RNA. 2007; 13 (10): 1603- 1608. doi: 10.1261 / rna.682507.

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