快猫短视频

BY APRIL, the human genome will be in the can 鈥� spelled out to almost the last letter, polished and completely wrapped up. A scientific triumph for sure, but one that will leave a yawning void. The vast sequencing factories, built to chew through those 3 billion letters of DNA faster than anyone thought possible, will still be hungry. What genome should we feed them next?

There is no shortage of candidates, but surprisingly few clear answers. Biologists cannot reach agreement about which organisms are most deserving. 鈥淭his has come up quickly on all of us, because we鈥檝e all been focusing on the human genome for a number of years and have deferred thinking much beyond that,鈥� says George Weinstock, co-director of one of the world鈥檚 largest sequencing centres, at Baylor College of Medicine in Houston, Texas. Senior officials at other sequencing centres echo his uncertainty about what to do next.

So which species should be first in line? The obvious answers 鈥� the lab workhorses mouse, fruit fly, nematode worm, thale cress, yeast, rat, African clawed frog, pufferfish and zebra fish 鈥� have already been completed or soon will be. And while hundreds of microbial genomes are crying out to be sequenced, the world鈥檚 powerhouses also want some meatier projects.

Ask any group of biologists, and you will find there is no shortage of candidates. Ornithologists tend to rally behind the chicken. Livestock researchers support the cow. Biomedical types throw their weight behind the chimp or the dog. Developmental biologists champion the sea urchin, behaviourists the honeybee, agrobiologists maize. Comparative geneticists, meanwhile, support any representative of a group that has not been sequenced before, such as the kangaroo. Each one is worthy in its own way.

Tough decisions

There are several big sequencing centres scattered around the world: at Baylor College of Medicine in Texas and Washington University in St Louis, Missouri, the Whitehead Institute in Massachusetts, the US Department of Energy鈥檚 Joint Genome Institute in Walnut Creek, California, Britain鈥檚 Sanger Institute in Cambridge, various centres in Japan, and non-profit ones such as The Institute for Genomic Research in Maryland. Yet taken even together they only have the capacity to polish off one or two large genomes per year. Someone, somewhere has some tough decisions to take.

Up to now only one big hitter has started formally canvassing biologists鈥� opinions and setting priorities. Researchers who wish to champion a particular species of animal, fungus or protozoan can submit proposals to a panel at the US National Human Genome Research Institute (NHGRI) in Bethesda, Maryland, which funds Baylor, Washington and the Whitehead. The panel meets three times a year to sift through their suggestions and assign each genome a high, moderate or low priority based on its practical value and feasibility.

So what makes a strong proposal? Most of the people making the decisions agree on a few basic principles. Top of the list is that the organism must be of practical importance. Genomes don鈥檛 come cheap: even moderate-sized ones such as the chicken, at 1.2 billion DNA letters, will cost tens of millions of dollars. That doesn鈥檛 allow much scope for indulging academic curiosity. 鈥淵ou need an immediate application,鈥� says Jane Rogers, who heads the sequencing division at the Sanger Institute.

That may tip the balance in favour of the dog, which is often used in studies of human cancer and some forms of blindness, among other ailments. Established research favourites such as the sea urchin Strongylocentrotus purpuratus, which is used to study development, and the protozoans Tetrahymena and Oxytricha, which have unusual chromosome structure, also score well here, as do crops, livestock, pests and disease-causing fungi. Less utilitarian species also rate highly if they shed light on how the human genome evolved. Chimps fall into this category.

The second main criterion is how hard the task will be. Some species of obvious practical importance fall at this hurdle. Maize, for example, has a genome riddled with thousands of repeats of the same sequence. 鈥淭he genome is basically a huge sea of repetitive sequences, and floating in that sea are islands of genes,鈥� says Jane Silverthorne, director of the plant genome research programme for the US National Science Foundation. Because geneticists sequence a genome by chopping it up haphazardly, sequencing each fragment and then reassembling the whole by piecing together overlapping bits, these repetitions make it almost impossible to work out which bits go where.

鈥淲e don鈥檛 even know what a typical corn gene looks like yet. Before embarking on a huge sequencing project we really need to know what we are doing,鈥� says Silverthorne.

All else being equal, a short genome should be favoured over a long one and a well-understood organism over a little-studied one. Likewise, an organism for which all the groundwork for sequencing has already been laid 鈥� that is, whose chromosomes have been mapped by identifying marker genes to help keep sequencers oriented 鈥� is more likely to get the nod than one in which the preliminary work has yet to be done.

鈥淚t doesn鈥檛 rule out an organism if those resources are not available, but it鈥檚 obviously a stronger position to be in,鈥� says Jane Peterson, who directs the comparative genomics program at the NHGRI. (Most women high in the genomics hierarchy seem to be named Jane.)

Top priorities

At its first two meetings this year, the NHGRI panel assigned high priority to nine proposals: chicken, chimp, cow, dog, honeybee, sea urchin, Tetrahymena, Oxytricha and a group of 15 fungi chosen to represent their kingdom. The rhesus macaque and the single-celled protozoan Trichoplax won the consolation prize of being assigned moderate priority. Several others were assigned low priority, but the NHGRI is not divulging what they were. The results of the panel鈥檚 third meeting will be announced early next year.

Even those species that won the panel鈥檚 approval will not necessarily be sequenced straight away, as all three major centres funded by the NHGRI are still tied up finishing off the human, mouse and rat genomes. But whenever one needs a new project it will select one of the organisms in the high-priority bin.

In practice, though, the final choice comes down to what is ready to go. Some of the high-priority genomes are not yet fully funded, and for several the basic mapping is incomplete. So the race as been whittled down to a list of five candidates.

Washington University plans to start with the chicken, Baylor the bee and the sea urchin, while the Whitehead Institute has already begun sequencing some of the 15 fungi. Washington and the Whitehead, meanwhile, will collaborate on the chimp.

In other words, the genomes to be sequenced have pretty much chosen themselves. 鈥淪o far those decisions have been automatic,鈥� says Weinstock. 鈥淲e haven鈥檛 got to the point yet where there is more sequencing than we can do right now so we have to make a decision. I would love to be in that position, but it鈥檚 not that way.鈥�

But competition is sure to hot up. Some of the strongest candidates have not even entered the NHGRI鈥檚 ranking competition. It can take years to form a consortium of researchers, develop a sequencing plan, and write a proposal for a particular species. The bigger the genome and the more important the organism, the harder this can be. Several contenders, including the pig, cat, baboon and silkworm, have yet to be put before the panel.

And the NHGRI is not the only game in town. Lobby groups will soon start looking towards other sequencing centres with their own idea of what is important. The Sanger Institute, for example, is funded mostly by the Wellcome Trust. And as this is a biomedical foundation, it is likely to lean towards animals and microbes of biomedical importance, Rogers predicts.

One day, sequencing an organism鈥檚 genome could become routine. 鈥淚f the cost came down orders of magnitude, that鈥檚 the first thing you would do 鈥� generate a sequence for an organism 鈥� and that would be the backbone of your research,鈥� says Rogers.

But until sequencing a genome becomes as mundane a task as ordering a microscope or a centrifuge, the world鈥檚 big sequencers are going to have to get used to being lobbied by creatures great and small.