An international research team has mapped and compared the genomes of 29 mammals and found new regulatory elements in the human genome that govern how proteins are formed.

The researchers, led by Kerstin Lindblad-Toh of the Broad Institute in Cambridge, Mass. and Uppsala University in Sweden, said the findings help us understand how mutations in human genes give rise to diseases.

While the human genome was mapped a decade ago, deciphering its function has been more difficult. Humans have more than 20,000 genes and it has been difficult to find elements in the genome that determine when, where, and how genes produce proteins. So Lindblad-Toh and colleagues compared a large number of mammals, giving scientists a catalog of millions of regulatory elements found between and within genes.

“These elements are incredibly important in making us humans into the complex organisms that we are, even though our genes are rather similar to those of other vertebrates,” said Lindblad-Toh, scientific director of vertebrate genome biology at the Broad Institute and professor of comparative genomics at Uppsala University.

Human genes constitute only about 1.5 percent of the genome, whereas regulatory elements appear to take up about three times as much space. Early comparison studies of the human and mouse genomes led to the surprising discovery that the regulatory information that controls genes dwarfs the information in the genes themselves.

Dark matter

But these studies were indirect. Scientists could infer the existence of these regulatory sequences, but could find only a small fraction of them. These mysterious sequences have been referred to as the dark matter of the genome, analogous to the unseen matter and energy that make up most of the universe.

The researchers have now been able to show where a majority of these regulatory elements are located in the genome. By studying patterns in these elements, and combining this information with other types of genetic data, they have been able to understand how many of these regulatory elements function.

“The elements we find can have entirely different functions,” said Lindblad-Toh. “They can make different cell types use different versions of a certain gene, or can turn off a gene if the concentration of a certain compound is too high in a cell. Above all, we see that proteins that govern fetal development and the function of the nervous system have a huge number of regulatory elements.”

The new map helps pinpoint those mutations that are likely responsible for disease, as they have been preserved across millions of years of evolution, but are commonly disrupted in individuals that suffer from a given disease. Knowing the causal mutations and their likely functions can then help uncover the underlying disease mechanisms and reveal potential drug targets.

The regulatory elements that were found in this comparison between 29 mammals are important for many of our central functions, which are shared by placental mammals. However, the scientists were also looking for how these elements changed over time in various groups of mammals as they adapted to different living conditions.

“Among other things, we can see what parts of proteins and what regulatory elements changed rapidly in primates and humans. With the help of about a hundred other mammal species, we believe we will understand the function of every key base in the human genome and get a better understanding of how changes in genes made rodents into rodents and primates into primates,” said Lindblad-Toh.

Ref.: Kerstin Lindblad-Toh, et al., A high-resolution map of human evolutionary constraint using 29 mammals, Nature, 2011; [DOI: 10.1038/nature10530]