The DNA ‘Dark Matter’ Influences – The Development of The Brain.

A puzzle posed by segments of “dark matter” in genomes, long and sinuous strands of DNA without obvious functions, has annoyed scientists for more than a decade. Now, a team has finally solved the riddle.

The enigma has focused on DNA sequences that do not encode proteins and yet remain identical in a wide range of animals. By eliminating some of these “ultraconserved elements,” researchers have found that these sequences guide brain development by fine-tuning the expression of protein-coding genes.

The results1, published on January 18 in Cell, could help researchers better understand neurological diseases such as Alzheimer’s. They also validate the hypotheses of scientists who have speculated that all ultraconserved elements are vital to life, despite the fact that researchers knew very little about their functions.

“People told us that we should have waited to publish until we knew what they did. Now I’m like, my friend, it took me 14 years to solve it, “says Gill Bejerano, a genomic scientist at Stanford University in California who described the ultra-conserved elements in 20042.

When Nothing Happens:

Bejerano and his colleagues originally noticed ultraconserved elements when they compared the human genome with those of mice, rats and chickens, and found 481 stretches of DNA that were incredibly similar throughout the species. That was surprising, because DNA mutates from generation to generation, and these animal lineages have evolved independently for up to 200 million years.

The genes that encode proteins tend to have relatively few mutations because if those changes interrupt the corresponding protein and the animal dies before reproducing, the mutated gene is not transmitted to the offspring. On the basis of this logic, some genomicists suspected that natural selection had eliminated similar mutations in ultra conserved regions. Although the sequences do not encode proteins, they thought, their functions must be so vital that they can not tolerate imperfection.

But this hypothesis reached an obstacle in 2007, when a team reported having eliminated four elements ultraconserved in mice, and found that the animals looked good and reproduced normally3. “That was shocking: those mice should have died,” says Diane Dickel, genomics at Lawrence Berkeley National Laboratory in California, and first author of the study on Cell1.

A Closer Look:

Dickel and his colleagues reviewed the problem using the CRISPR-Cas9 gene editing tool. In mice, they eliminated four ultraconserved elements, individually and in various combinations, that lie within regions of DNA that also contain important genes in brain development. Once again, the mice looked good. But when the researchers dissected the brains of the rodents, they discovered anomalies.

Mice lacking certain sequences had abnormally low numbers of brain cells that have been implicated in the progression of Alzheimer’s disease. And those with another ultraconserved item edited had anomalies in a part of the anterior brain that is involved in memory formation, as well as in epilepsy. “Normally it looks like a blade, but in these mice, the blade was wavy,” says Dickel.

She suggests that the resulting cognitive defects would endanger mice in nature. Therefore, variations in these ultraconserved regions would not spread through a population, since the affected individuals would have less success in reproduction than those who were not affected.

Future studies could 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-preserved sequences remain unknown, Bejerano is confident that they will also be essential. But it remains perplexed by the level of conservation, up to 100%, in some of the sequences because biology often tolerates minor variations. “The mysteries are still on the table,” says Bejerano.

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