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Researchers Compare 29 Mammalian Genomes, Build Map of Evolutionary Constraint

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By comparing related genomes, researchers can pinpoint which areas change and which stay relatively similar across organisms, allowing for a more complete genomic interpretation. In a study published in Nature in October, an international team of researchers — including scientists from the Broad Institute, Washington University in St. Louis, and Baylor College of Medicine — reported a comparison of 29 mammalian genomes, 20 of which had never been published before, and described a new high-resolution map of human evolutionary constraint using the information gleaned from the comparison.

"Our initial comparative studies with four yeasts, four mammals, and 12 flies showed how much discovery power there was in annotating functional elements by comparing genomes, and that this power increases with more species," says senior author and MIT professor Manolis Kellis. "So the rationale for this study was that by comparing 29 mammals, we should be able to discover the functional elements encoded in the human genome at a much higher resolution than previously possible."

This study gave researchers the ability to pinpoint regions of regulatory control in the genome, he adds, which could not have been found without the comparisons with other mammalian genomes. "Imagine you have a letter from a friend and it's been sitting in a drawer for many years. You now look back at it through a new light, and you realize that every third letter spells a completely different message," Kellis says. "We had that realization — genes that we very much know the function of, and we had known for a while, it turns out are encoding additional regulatory elements."

The study's results suggest that one out of every four human genes has one of these overlapping functional elements. "The whole principle relies on what we call evolutionary signatures: if you look at any one species, the letters are effectively static and silent. But if you look at many species, you can see how these letters are changing, and their dynamics bring them new meaning," Kellis says. "The patterns of change are in fact dictated by the selective pressures acting on these elements, and result in distinct evolutionary signatures for each type of function."

Kellis was also surprised by the "sheer magnitude" of constraint present in the genome — the new map revealed about 2.6 million additional, previously undetected elements in non-coding regions of the genome, which may make it easier for researchers to find disease-causing variations. "This global map of functional elements that we've produced allows us to now go back to groups of variants that are all together associated with a disease, and recognize which ones disrupt evolutionarily-conserved functional elements," Kellis says. "So it frequently allows us to go from a whole region of association to a single nucleotide predicted to be disruptive, and predict the possible underlying molecular mechanism."

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