Dark DNA: The missing matter at the heart of nature

The discovery that some animals thrive despite having hugely mutated DNA hidden in their genome is forcing us to rethink some basics of evolution. A puzzle posed by segments of ‘dark matter’ in genomes — long, winding strands of DNA with no obvious functions — has teased scientists for more than a decade. Now, a team has finally solved the riddle.
The conundrum is centered on DNA sequences that do not encode proteins, and yet remain identical across a broad range of animals. By deleting some of these ‘ultra-conserved elements’, researchers have found that these sequences guide brain development by fine-tuning the expression of protein-coding genes.
The discovery of dark DNA is so recent that we are still trying to work out how widespread it is and whether it benefits those species that possess it. However, its very existence raises some fundamental questions about genetics and evolution. We may need to look again at how adaptation occurs at the molecular level. Controversially, dark DNA might even be a driving force of evolution.

When nothing happens

Bejerano and his colleagues originally noticed ultra-conserved elements, when they compared the human genome to those of mice, rats and chickens, and found 481 stretches of DNA that were incredibly similar across the species. That was surprising, because DNA mutates from generation to generation — and these animal lineages have been evolving independently for up to 200 million years.
Genes that encode proteins tend to have relatively few mutations because if those changes disrupt the corresponding protein and the animal dies before reproducing, the mutated gene isn’t passed down to offspring. On the basis of this logic, some geneticists suspected that natural selection had similarly weeded out mutations in ultra-conserved regions. Even though the sequences do not encode proteins, they thought, their functions must be so vital that they cannot tolerate imperfection. But this hypothesis hit a road block in 2007, when a team reported knocking out four ultra-conserved elements in mice — and found that the animals looked fine and reproduced normally. “That was shocking — those mice should have been dead,” says Diane Dickel, a geneticist at Lawrence Berkeley National Laboratory in California, and first author of the study in Cell1.

A closer look

Dickel and her colleagues revisited the problem using the gene-editing tool CRISPR–Cas9. In mice, they deleted four ultra-conserved elements — individually and in various combinations — that lie within regions of DNA that also contain genes important in brain development. Again, the mice looked okay. But when the investigators dissected the rodents’ brains, they discovered abnormalities.
She suggests that the resulting cognitive defects would endanger mice in the wild. Therefore, variations in these ultra-conserved regions would not spread through a population, because afflicted individuals would be less successful at reproducing than those who were unaffected.
Future studies might explore whether people with Alzheimer’s disease, dementia, epilepsy or other neurological disorders have mutations in these overlooked non-coding sequences. Although the functions of many other ultra-conserved sequences remain unknown, Bejerano feels confident that they, too, will prove essential. But he remains perplexed by the level of conservation — up to 100% — in some of the sequences because biology often tolerates minor variations. “Mysteries are still on the table,” Bejerano says.

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