Digital reconstruction of ancient chromosomes reveals surprises about mammalian evolution

Humans have 46 chromosomes. Dogs have 78. And a small South American rodent called the red viscacha has a whopping 104. Geneticists have marveled at the chromosomal diversity among mammals for decades, and now, they may know how it happened. A new digital reconstruction of the chromosomes of the ancestor of all placental mammals reveals that these tightly packed structures of DNA and proteins have become scrambled over time—a finding that may help pinpoint possible problem sites in our genomes that underlie cancer and other disease.

The work "helps us to understand how chromosomes have changed over time, which chromosome rearrangements may have led to the formation of new species, and what might be driving chromosomal rearrangements," says Janine Deakin, a geneticist at the University of Canberra who was not involved with the work. "This was a very elegant study."

There are three kinds of mammals: egg-laying monotremes such as the platypus, marsupials like kangaroos and opossums, and the majority—placental, or eutherian, mammals—including humans and about 4400 other mammal species. The earliest members of this larger group were mouse-sized, lived in trees, and ate insects about 105 million years ago. To figure out how chromosomes of placental mammals have changed over time, researchers need to know what those early eutherians started with. And that required putting some complicated puzzle pieces back together.

To do that, Harris Lewin, an evolutionary geneticist at the University of California, Davis, and colleagues compared 19 genomes of various mammals at different spots in the eutherian family tree, including several primates. But genomes usually don’t reveal how an animal’s DNA is distributed into chromosomes—they just give you the DNA sequence.

So team member Jaebum Kim, now at Konkuk University in Seoul, and colleagues wrote a sophisticated computer program that was able to reconstruct the original eutherian chromosomes based on what parts of the chromosomes are together today in those 19 species. The researchers came up with 21 pairs of ancestral eutherian chromosomes, they report today in the Proceedings of the National Academy of Sciences .

A few of those chromosomes have stayed intact—with their genes in the same order—over the past 105 million years, at least in orangutans and humans. "I find the stability of some of the ancestral chromosomes remarkable," Deakin says.

But many have broken apart, swapping places between and within chromosomes, Kim, Lewin, and their colleagues found. These exchanges "are the footprints of changing the order of the packaging of 22,000 vertebrate genes," says Stephen O'Brien, a geneticist at Saint Petersburg State University in Russia who was not involved with the work.

All told, the scientists found 162 break points—places where a chromosome broke open so the DNA between those points could move around. They found that this chromosome scrambling varied over time and from mammal group to mammal group. "The big surprise is how the chromosomes evolved differently in different lineages, Lewin says. "It's one of the most splendid examples” of stepwise changes that led to the evolution of new species, he says.

This new study shows that as mammals evolved early on, the rate at which chromosomes broke apart was stable, and relatively low, with eight per 10 million years. But 65 million years ago, the rate jumped, averaging 20 per 10 million years in primates other than the orangutan. So the orangutan chromosome setup looks the most like the ancient ancestor revealed by Kim’s team, with eight ancient chromosomes intact. Humans have five such chromosomes and mice have just one.

The researchers also showed that ancestral chromosome 20 is completely conserved in primates, but very much changed in goats and cows because of rearrangements within chromosomes. Rat chromosomes, too, are very different than the early eutherian’s, but for a different reason: Their chromosomes swapped pieces between chromosomes rather than within a given chromosome.

Lewin thinks sections of repetitive bases—the “letters” that make up DNA—tend to make chromosomes susceptible to scrambling. Goats and cows, as well as rodents, had many so-called retrotransposons—rogue invading DNA—and many rearrangements, whereas primates have far fewer of both.

In some ways, the implications of the many chromosomal changes suggested by the new analysis is obvious—just look how different an ant-eater is from a whale. But in other ways, researchers have much to learn about exactly how chromosomal changes influence the course of evolution. The changes were clearly advantageous and perpetuated through time in different mammalian groups, Lewin says.

Though O'Brien says he's impressed with this study's detail, he's holding out for more comprehensive comparisons, wherein the genomes of many more than 19 species are matched up. "That is what is really required” to get a full history of our chromosomes, he says. “Until that scale is achieved, we will still be poking around in the dark matter of evolutionary processes."

That work is coming, says Lewin, as a project at the Broad Institute in Cambridge, Massachusetts, is sequencing 150 more mammals. And with those genomes, as well as the genomes of marsupials and monotremes, he and his collaborators plan to tackle the ancestral genome of the first mammal next, which lived about 185 million years ago. "I'm looking forward to seeing this analysis expanded to include a detailed look at all mammals,” Deakin says.

Meanwhile, these break points may help guide researchers trying to understand disease. "There are a score of medical syndromes involving chromosome rearrangements," says O’Brien, and there may be others not yet discovered.