Signposts for genetically unexplained brain disorders

Genetics is more than just genes; this has been known for some time. But how do you find your way around the millions of pieces of DNA whose function is not yet known? Researchers at Erasmus MC took a big step in separating the wheat from the chaff during brain development.

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DNA genes

It was called junk DNA: the more than 98 percent of human genetic material that does not code for a gene directly. In recent years, that name proved to be unjustified because these pieces of DNA do have a function. For example, they contain bits of code that can increase the transcription of genes. Geneticists call these enhancers.

On switches

The function of all non-coding ‘junk’ DNA is not yet known, but thanks to researchers at Erasmus MC, another piece of the puzzle has been solved. In the scientific journal Genome Medicine, they reveal the location and function of various enhancers, or ‘on switches’, of genes involved in brain development.

This is important because it gives them a search direction for patients with genetically unexplained brain disorders. ‘Even with extensive DNA tests looking at all genes, in the best case we find an explanatory mutation in 30 to 50 percent of cases. If that fails, the disease-causing mutation may be located in non-coding DNA. But until recently, finding it was like looking for a needle in a haystack. The genome is huge, there are millions of genetic variants, and we don’t know whether they influence function or not. With our new findings, we’ve made the haystack a lot smaller,’ explains physician and researcher Stefan Barakat of the department of Clinical Genetics.

1.6 million enhancers

For the study, which required an enormous amount of complex data analysis and interpretation, the collaborative work of geneticists and bioinformaticians was critical. The starting point was a collection of 1.6 million previously reported possible enhancers of brain genes. ‘By cleverly integrating these data, we were able to reduce this number to 200,000 suspected enhancers. Of these, 40,000 are of extra interest because they change activity over time. This suggests that they have a role in embryonic brain development,’ explains Eskeatnaf Mulugeta of the department of Cell Biology. Moreover, the researchers proved that many of these 40,000 enhancers are linked to known brain disease genes.

‘We are now beginning to understand where we need to look beyond the genes’

The researchers argue that it is probably one of the most extensive bioinformatics studies on enhancers of brain development genes. Barakat: ‘It was not only a lot of work, but especially also for Ph.D. student Soheil Yousefi – about three to four years – but also very complex work. We have combined all the knowledge that was spread across various sources into a workable overview.’

Soheil Yousefi, Stefan Barakat, and Eskeatnaf Mulugeta worked on one of the most extensive bioinformatics studies on enhancers of brain development genes.

Consultation room

With this overview, Barakat, Mulugeta, and their colleagues worldwide can move forward. Both in fundamental research into the genetics behind brain development and the consultation room. Barakat: “At Erasmus MC, we are in the process of implementing whole-genome sequencing for routine care at the Clinical Genetics department. This involves mapping out the entire genome, both the genes and the non-coding parts. We are starting with small groups of dedicated patients, but over time the intention is that this will replace the current DNA diagnostics where we only look at genes. Our findings will play an important role in that process because we are now beginning to understand where we need to look beyond the genes.’

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