Chemical on-off switches for genes may help explain why large mammals live longer

When it comes to how long a mammal can live, a bigger body is usually better: The typical mouse life span is less than 4 years, whereas a bowhead whale may make it to 211. But within a species, this relationship can flip: Large dog breeds tend to have shorter life spans than smaller canines.

Now, a massive analysis of chemical marks spread along the genomes of about 200 mammalian species has hinted at a novel explanation for this canine curiosity—and yielded a bounty of data for understanding mammalian differences in life span, average weight, and other traits.

The analysis looked at a DNA modification called methylation, which can control whether genes are turned on or off. The patterns of methylation the team found add a new layer of information to better understood differences in the DNA sequences of genes themselves, the authors say. “It’s kind of a gold mine for people who either want to study what is unique about a certain species or conversely what is shared,” says aging researcher Steve Horvath of the University of California, Los Angeles, who leads a team that described the methylation results this week online at the annual meeting of the American Society of Human Genetics (ASHG).

Others welcome the new findings. “Why different species age at different rates is both a fascinating and important question,” says aging researcher Vardhman Rakyan of Queen Mary University of London. This resource “could be the starting point for other important studies in the field of mammalian aging.”

Methylation is one of several so-called epigenetic marks, referring to changes in DNA or its protein packaging that influence how genes are expressed without altering the heritable sequence of bases that make up DNA. In DNA methylation, a molecule called a methyl group attaches to a base, usually cytosine. Horvath is known for showing that patterns of these methyl groups change as a person ages, and for creating an “epigenetic clock” that uses a DNA sample to estimate a person’s age within 3.6 years.

In a new project, Horvath teamed up with more than 100 other labs to look at these epigenetic marks across mammalian species. The Mammalian Methylation Consortium gathered thousands of blood and other tissue samples from more than 200 mammals, from shrews to elephants, and scanned their DNA using a chip that looks for the presence of a methyl group at about 36,000 cytosines along stretches of DNA shared across mammals. They used the data to devise an epigenetic clock that can be used to estimate the age of any living mammal from a DNA sample. This clock turned up some new genes that may govern aging, first author Ake Lu reports in a poster at the ASHG meeting this week and a January preprint.

The consortium also wondered whether other individual or species-specific traits could be tied to DNA methylation. To explore this, computational biologist Amin Haghani, a postdoc in Horvath’s lab, first simply looked for methylation patterns. He found 55 clusters of methylated cytosines—between 33 and 1864 sites per cluster—many of which turned out to correlate with species-specific traits such as maximum life span, average adult weight, and age at sexual maturity. And others matched up with individual traits, such as age, sex, and tissue type.

The team also showed, in work reported in a poster and a March preprint, that evolutionary trees constructed using cytosine methylation largely mirror phylogenies based on their gene sequences. “This is really interesting because it shows our DNA methylation is tracking evolution,” Haghani says.

The genes switched on or off by the methylated bases near them may help control that trait—for example, the life span methylation cluster may govern stem cell genes important early in development, the team proposes. “Chances are, these cytosine sites are part of pathways or cell types that are important,” Horvath says.

Haghani’s analysis also revealed a cluster correlated with longer life span and larger size in most mammals was linked to longer life but smaller size in dog breeds—in line with that known paradoxical relationship. This life span–related cluster includes genes in a molecular pathway for fat disposition. The finding may mesh with a recent report that the blood of large breeds contains relatively high levels of a fat molecule that can damage neurons, the team found.

“Maybe that’s part of the aging process in dogs. They are losing the ability to protect neurons and deteriorating,” says dog genetics researcher and study co-author Elaine Ostrander of the National Human Genome Research Institute. The methylation study suggests experiments that “we wouldn’t have known to do,” she says, such as looking at whether altered fat deposition somehow protects against other harmful effects of the physiology of big dogs.

Not all epigenetics researchers are surprised by the consortium’s findings. It’s logical that methylation patterns track with evolution because the process itself is controlled by genes with evolving sequences, says plant epigenomics researcher Frank Johannes of the Technical University of Munich. Horvath’s trees are “a molecular readout … of genetic diversity,” says Johannes, who notes that similar “phyloepigenetic” trees were constructed for plants 10 years ago. Still, he says, the new study offers “a large resource for comparative epigenomics.”

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