Evolution and humans: how our small gene number works (Evolution)

by David Turell , Tuesday, March 19, 2024, 19:55 (247 days ago) @ David Turell

The latest ENCODE work:

https://medicalxpress.com/news/2024-03-wiring-human-genome.html#google_vignette

"Understanding the non-coding portion of our DNA is critical for understanding the genetic components of disease, says Steven Reilly, an assistant professor of genetics at Yale School of Medicine who co-led the study.

"'When we find mutations in DNA that are associated with some trait or disease, they're often in these non-coding regions," said Reilly. "Being able to understand which genes these mutations impact is really critical."

"For the study, Reilly and his colleagues set out to understand how non-coding regions of DNA known as "enhancers" and "promoters" are linked to genes. Promoters are bits of DNA just upstream of genes that control whether the genes are transcribed into mRNA, which will eventually be turned into protein. Molecules that activate genes bind to promoters to initiate the process.

"Enhancers are regions of DNA that act as additional control elements for promoters, instructing them where and when to turn on. However, they can be quite far away from the genes they control, making it hard to predict which genes a mutation in an enhancer might impact.

"Essentially, these genetic regulators help turn genes on and off.

"The research effort is part of a 20-year-long project known as the Encyclopedia of DNA Elements, or ENCODE, Consortium.

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"'The good news was that the only things that seemed to do anything were the things we'd already mapped out as enhancers or promoters," said Reilly. "So there weren't some secret light switches we hadn't known about. That confirms that when we're looking at a DNA variation that might impact disease, the enhancers and promoter maps we have are the places to look."

"In a more surprising finding, the researchers discovered that individual enhancers could affect multiple genes. It was as if one light switch turned on several lights.

"'We originally had tended to think that one enhancer was affecting one gene, but we found it was really common for one enhancer to impact many genes," said Reilly. "That says that if you have a mutation in an enhancer that's associated with a disease, you might need to be looking for several impacted genes, not just one."

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"'Depending on which strand you target, you will get different results of how big of an effect the CRISPR-mediated DNA repression has on genes," said Reilly. "Knowing these differences will allow researchers to design the right analysis methods."

This particular finding wouldn't have been possible without the large collaborative effort of this work, he added.

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"The ENCODE Consortium, which was launched in 2003, is coming to an end with many of its main goals achieved. Going forward, Reilly aims to use the best practices that have come out of this work to do these types of analyses in more complicated systems. One goal is to better understand how many genes are involved in the development of disease or in conferring observable traits like height.

"'We have a good sense of what DNA variants exist, but we don't have a good sense of how those variants affect genes," said Reilly. "This study gives us a roadmap to do those experiments better.'"

Comment: 21 years of work are coming to a very fruitful close. Our gene total may by relatively small but the 3-D relationships, the complexities of teamed genes, and the work of promoters and enhancers all create a very powerful control system.