Biologists propose to sequence the DNA of all life on Earth

Can biologists sequence the genomes of all the plants and the animals in the world, including this greater bird of paradise in Indonesia?

When it comes to genome sequencing, visionaries like to throw around big numbers: There’s the UK Biobank, for example, which promises to decipher the genomes of 500,000 individuals, or Iceland’s effort to study the genomes of its entire human population. Yesterday, at a meeting here organized by the Smithsonian Initiative on Biodiversity Genomics and the Shenzhen, China–based sequencing powerhouse BGI, a small group of researchers upped the ante even more, announcing their intent
to, eventually, sequence “all life on Earth.”

Their plan, which does not yet have funding dedicated to it specifically but could cost at least several billions of dollars, has been dubbed the Earth Bio Genome Project (EBP). Harris Lewin, an evolutionary geneticist at the University of California, Davis, who is part of the group that came up with this vision 2 years ago, says the EBP would take a first step toward its audacious goal by focusing on eukaryotes—the group of organisms that includes all plants, animals, and single-celled organisms such as amoebas.



That strategy, and the EBP’s overall concept, found a receptive audience at BioGenomics2017, a gathering this week of conservationists, evolutionary biologists, systematisms, and other biologists interested in applying genomics to their work. “This is a grand idea,” says Oliver Ryder, a conservation biologist at the San Diego Zoo Institute for Conservation Research in California. “If we really want to understand how life evolved, genome biology is going to be part of that.”

Ryder and others drew parallels between the EBP and the Human Genome Project, which began as an ambitious, controversial, and, at the time, technically impossible proposal more than 30 years ago. That earlier effort eventually led not only to the sequencing of the first human genome, but also to entirely new DNA technologies that are at the center of many medical frontiers and the basis for a $20 billion industry. “People have learned from the human genome experience that [sequencing] is a tremendous advance in biology,” Lewin says.

Many details about the EBP are still being worked out. But as currently proposed, the first step would be to sequence in great detail the DNA of a member of each eukaryotic family (about 9000 in all) to create reference genomes on par or better than the reference human genome. Next would come sequencing to a lesser degree a species from each of the 150,000 to 200,000 genera. Finally, EBP participants would get rough genomes of the 1.5 million remaining known eukaryotic species. These lower resolution genomes could be improved as needed by comparing them with the family references or by doing more sequencing, says EBP co-organizer Gene Robinson, a behavioral genomics researcher and director of the Carl R. Woese Institute for Genomic Biology at the University of Illinois in Urbana.



The entire eukaryotic effort would likely cost about the same as it did to sequence that first human genome, estimate Lewin, Robinson, and EBP co-organizer John Kress, an evolutionary biologist at the Smithsonian National Museum of Natural History here. It took about $2.7 billion to read and order the 3 billion bases composing the human genome, about $4.8 billion in today’s dollars.

With a comparable amount of support, the EBP’s eukaryotic work might be done in a decade, its organizers suggest. Such optimism arises from ever-decreasing DNA sequencing costs—one meeting presenter from Complete Genomics, based in Mountain View, California, says his company plans to be able to roughly sequence whole eukaryotic genomes for about $100 within a year—and improvements in sequencing technology that make possible higher quality genomes, at reasonable prices. “It became apparent to me that at a certain point, it would be possible to sequence all life on Earth,” Lewin says. Although some may find the multibillion-dollar price tag hard to justify for researchers not studying humans, the fundamentals of matter, or the mysteries of the universe, the EBP has a head start, thanks to the work of several research communities pursuing their own ambitious sequencing projects.

These include the Genome 10K Project, which seeks to sequence 10,000 vertebrate genomes, one from each genus; i5K, an effort to decipher 5000 arthropods; and B10K, which expects to generate genomes for all 10,500 bird species. The EBP would help coordinate, compile, and perhaps fund these efforts. “The [EBP] concept is a community of communities,” Lewin says. There are also sequencing commitments from giants in the genomics field, such as China’s BGI, and the Wellcome Trust Sanger Institute in the United Kingdom. But at a planning meeting this week, it became clear that significant challenges await the EBP, even beyond funding. Although researchers from Brazil, China, and the United Kingdom said their nations are eager to participate in some way, the 20 people in attendance emphasized the need for the effort to be more international, with developing countries, particularly those with high biodiversity, helping shape the project’s final form.



They proposed that the EBP could help develop sequencing and other technological experts and capabilities in those regions. The Global Genome Biodiversity Network, which is compiling lists and images of specimens at museums and other biorepositories around the world, could supply much of the DNA needed, but even broader participation is important, says Thomas Gilbert, an evolutionary biologist at the Natural History Museum of Denmark in Copenhagen.

The planning group also stressed the need to develop standards to ensure high-quality genome sequences and to preserve associated information for each organism sequenced such as where it was collected and what it looked like. Getting DNA samples from the wild may ultimately be the biggest challenge—and the biggest cost, several people noted. Not all museum specimens yield DNA preserved well enough for high-quality genomes. Even recently collected and frozen plant and animal specimens are not always handled correctly for preserving their DNA, says Guojie Zhang, an evolutionary biologist at BGI and the University of Copenhagen. And the lack of standards could undermine the project’s ultimate utility, notes Erich Jarvis, a neurobiologist at The Rockefeller University in New York City: “We could spend money on an effort for all species on the planet, but we could generate a lot of crap.”



But Lewin is optimistic that won’t happen. After he outlined the EBP in the closing talk at BioGenomics2017, he was surrounded by researchers eager to know what they could do to help. “It’s good to try to bring together the tribes,” says Jose Lopez, a biologist from Nova Southeastern University in Fort Lauderdale, Florida, whose “tribe” has mounted “GIGA,” a project to sequence 7000 marine invertebrates. “It’s a big endeavor. We need lots of expertise and lots of people who can contribute.”

Source: Elizabeth Pennisi

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Scientists engineer animals with ancient genes to test causes of evolution

A transgenic fruit fly engineered to carry the alcohol dehydrogenase gene as it existed about 4 million years ago. Thousands of these 'ancestralized' flies were bred and studied for their ability to metabolize alcohol and to survive on an.

Scientists at the University of Chicago have created the first genetically modified animals containing reconstructed ancient genes, which they used to test the evolutionary effects of genetic changes that happened in the deep past on the animals' biology and fitness.

The research, published early online in Nature Ecology & Evolution on Jan. 13, is a major step forward for efforts to study the genetic basis of adaptation and evolution. The specific findings, involving the fruit fly's ability to break down alcohol in rotting fruit, overturn a widely-held hypothesis about the molecular causes of one of evolutionary biology's classic cases of adaptation.



"One of the major goals of modern evolutionary biology is to identify the genes that caused species to adapt to new environments, but it's been hard to do that directly, because we've had no way to test the effects of ancient genes on animal biology," said Mo Siddiq, a graduate student in the Department of Ecology and Evolution at the University of Chicago, one of the study's lead scientists.

"We realized we could overcome this problem by combining two recently developed methods—statistical reconstruction of ancient gene sequences and engineering of transgenic animals," he said.

Until recently, most studies of molecular adaptation have analyzed gene sequences to identify "signatures of selection"—patterns suggesting that a gene changed so quickly during its evolution that selection is likely to have been the cause. The evidence from this approach is only circumstantial, however, because genes can evolve quickly for many reasons, such as chance, fluctuations in population size, or selection for functions unrelated to the environmental conditions to which the organism is thought to have adapted.

Siddiq and his advisor, Joe Thornton, PhD, professor of ecology and evolution and human genetics at the University of Chicago, wanted to directly test the effects of a gene's evolution on adaptation. Thornton has pioneered methods for reconstructing ancestral genes—statistically determining their sequences from large databases of present-day sequences, then synthesizing them and experimentally studying their molecular properties in the laboratory. This strategy has yielded major insights into the mechanisms by which biochemical functions evolve.

Thornton and Siddiq reasoned that by combining ancestral gene reconstruction with techniques for engineering transgenic animals, they could study how genetic changes that occurred in the deep past affected whole organisms-their development, physiology, and even their fitness.



"This strategy of engineering 'ancestralized animals' could be applied to many evolutionary questions," Thornton said. "For the first test case, we chose a classic example of adaptation-how fruit flies evolved the ability to survive the high alcohol concentrations found in rotting fruit. We found that the accepted wisdom about the molecular causes of the flies' evolution is simply wrong."

The fruit fly Drosophila melanogaster is one of the most studied organisms in genetics and evolution. In the wild, D. melanogaster lives in alcohol-rich rotting fruit, tolerating far higher alcohol concentrations than its closest relatives, which live on other food sources. Twenty-five years ago at the University of Chicago, biologists Martin Kreitman and John McDonald invented a new statistical method for finding signatures of selection, which remains to this day one of the most widely used methods in molecular evolution. They demonstrated it on the alcohol dehydrogenase (Adh) gene—the gene for the enzyme that breaks down alcohol inside cells—from this group of flies. Adh had a strong signature of selection, and it was already known that D. melanogaster flies break down alcohol faster than their relatives. So, the idea that the Adh enzyme was the cause of the fruit fly's adaptation to ethanol became the first accepted case of a specific gene that mediated adaptive evolution of a species.

Siddiq and Thornton realized that this hypothesis could be tested directly using the new technologies. Siddiq first inferred the sequences of ancient Adh genes from just before and just after D. melanogaster evolved its ethanol tolerance, some two to four million years ago. He synthesized these genes biochemically, expressed them, and used biochemical methods to measure their ability to break down alcohol in a test tube.



The results were surprising: the genetic changes that occurred during the evolution of D. melanogaster had no detectable effect on the protein's function.
Working with collaborators David Loehlin at the University of Wisconsin and Kristi

Montooth at the University of Nebraska, Siddiq then created and characterized transgenic flies containing the reconstructed ancestral forms of Adh. They bred thousands of these "ancestralized" flies, tested how quickly they could break down alcohol, and how well the larvae and adult flies survived when raised on food with high alcohol content. Surprisingly, the transgenic flies carrying the more recent Adh were no better at metabolizing alcohol than flies carrying the more ancient form of Adh. Even more strikingly, they were no better able to grow or survive on increasing alcohol concentrations. Thus, none of the predictions of the classic version of the story were fulfilled. There is no doubt that D. melanogaster did adapt to high-alcohol food sources during its evolution, but not because of changes in the Adh enzyme.

"The Adh story was accepted because the ecology, physiology, and the statistical signature of selection all pointed in the same direction. But three lines of circumstantial evidence don't make an airtight case," Thornton said. "That's why we wanted to test the hypothesis directly, now that we finally have the means to do so."

Siddiq and Thornton hope that the strategy of making ancestralized transgenic will become the gold standard in the field to decisively determine the historical changes in genes to their changes on organisms' biology and fitness.

For his part, Kreitman, who is still a professor of ecology and evolution at UChicago, has been supportive of the new research, helping advise Siddiq on the project and sharing his vast knowledge about molecular evolution and Drosophila genetics.



"From the beginning, Marty was excited about our experiments, and he was just as supportive when our results overturned well-known conclusions based on his past work," Siddiq said. "I think that's extremely inspiring."

Source: University of Chicago, Medical Center

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