How humans evolved a starch-digesting superpower long before farming?

Most modern humans carry multiple copies of this salivary amylase gene, called AMY1. Some populations—typically those who eat lots of starch, whether grains or tubers—have even more copies, supercharging their production of the amylase enzyme and allowing them to wring more calories from starchy food. But when our ancestors first acquired these copies, and why exactly the gene is so prone to duplication, has been a mystery.

The Nature and Science papers disagree by hundreds of thousands of years about just when the gene first duplicated. But both track the gene’s later evolution in fine detail, revealing how the rise of agriculture coincided with a pronounced jump in the number of AMY1 copies in some populations. And both studies shine light on the mechanism, showing why the genes were so prone to duplicating themselves in the first place.

“This is such elegant work,” says Christina Warinner, a Harvard University biomolecular archaeologist who has found evidence indicating ancient humans, including Neanderthals, consumed starches. “It details at a mechanistic level how this happens specifically for amylase genes, [and also] has broader implications in general for evolution.”

In 2007, bioanthropologist George Perry, then at Arizona State University, and colleagues identified the link between eating lots of starchy foods and having more copies of AMY1 in populations around the world. Perry, now at Pennsylvania State University, hypothesized that when humans began to grow wheat, yams, and other starchy crops, people with more copies of AMY1 absorbed more energy-rich sugars in every bite—and had more surviving children.

But the genomic technology of the time wasn’t powerful enough to confirm this scenario. Scientists could only sequence small fragments of DNA at a time, leaving them effectively blind to labyrinthine stretches of DNA populated by multiple copies of genes. “The methods I used were extremely crude,” Perry recalls. “These [new] papers are … able to look at this in much more depth.”AdvertisementToday, researchers can sequence bigger chunks of DNA and so reveal multiple copies of genes in their locations on a chromosome. In last month’s Nature paper, a team led by integrative biologist Peter Sudmant at the University of California, Berkeley reported that humans around the world have up to 11 copies of AMY1 per chromosome as well as between zero and four copies per chromosome of one of two other genes that produce amylase in the pancreas. The team also looked at ancient genomes from three Neanderthals and one Denisovan, and found no sign that these extinct human cousins had multiple copies of the genes.

Sudmant and colleagues then analyzed genomes from 519 ancient Eurasians who lived starting 12,000 years ago, at the dawn of agriculture on the continent. The average number of copies of AMY1 rose from four to more than seven about 5000 years ago, and the fraction of people who had at least one duplicated salivary or pancreatic amylase gene also rose dramatically.

By counting slight differences in DNA regions flanking the duplicated genes to determine how long ago they split apart, Sudmant and colleagues built a family tree of the salivary gene and dated its branches. They estimate the gene was first duplicated at least 279,000 years ago, and was later duplicated and deleted many times, giving rise to a variety of copy numbers in modern humans. “Before our species left Africa, there were already higher copy numbers of amylase,” Sudmant says. “Those … were later selected” when starchy farming diets made them favorable.

Today in Science, a team led by University at Buffalo anthropological genomicist Omer Gokcumen reported a similar surge in AMY1 copies in European farmers over the past 4000 years, confirming a potential link to agriculture. But they also found AMY1 duplications in three of six Neanderthal genomes and one Denisovan genome. They conclude the gene was first duplicated much earlier than Sudmant’s group estimated: before modern humans’ split from those close cousins, which some estimates put as early as 800,000 years ago. But the researchers caution it’s also possible that the initial duplication, which resulted in three copies of AMY1 on a single chromosome, took place later, in modern humans. Neanderthals and Denisovans could then have picked up the DNA segment through interbreeding or evolved multiple copies independently.

Runyang Nicolas Lou, a postdoc in Sudmant’s lab, says his group only analyzed ancient genomes that had been more completely sequenced, to rule out contamination from modern DNA. “That’s mainly why our results differ,” he says.  

Gokcumen’s team also spelled out how AMY1 copies itself so prolifically. Once the initial three-copy version, or haplotype, emerged, they report, the arrangement of gene copies on the chromosomes allowed DNA from two different copies to cross over and repeat itself, duplicating—or sometimes deleting—two copies of the genes. “The moment we have the three-copy haplotype, it’s the steppingstone for the evolution of this locus—we can either go up by two [copies] or we can go down by two,” explains Charikleia Karageorgiou, a postdoc in Gokcumen’s lab and co-author on the paper. “From that point on, everything changes.”

Diyendo Massilani, a geneticist at Yale University, says the “very exciting” papers should spur ancient DNA researchers to think more about how structural variation in genomes—as opposed to differences between genes—has influenced selection.

Warinner thinks similar mechanisms could explain other instances of gene copy number variation, such as seen in Huntington disease. And understanding the evolution of AMY1 may help solve other amylase mysteries. “There are still a lot of unknowns here, but we finally have more pieces to this puzzle than before,” she says.

-From <SCIENCE>

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