It has been known as “the world’s most harmful meal,” a fish whose inside organs are laced with one of many deadliest toxins on Earth. Specialised eating places in Japan and some different locations serve fastidiously ready fugu flesh as an costly delicacy, partly due to this dangerous thrill.
However Byrappa Venkatesh was drawn to the fugu for a completely completely different motive: It has the smallest genome of any vertebrate. That high quality was gold again within the 1990s, when geneticists have been nonetheless racing to sequence the human genome or that of every other vertebrate: Fugu supplied a shortcut to the end line. The puffer was nonetheless a slog, although. It price Venkatesh and his colleagues 9 years of arduous work and about $10 million, and, ultimately, the human genome venture nosed them out, simply barely, as the primary vertebrate genome ever accomplished.
The venture kindled a ardour for fish genomics that has propelled Venkatesh ever since. With good motive: Fish are essentially the most numerous group of vertebrates on the planet. They dwell in deep ocean, in acid waters and in Antarctic seas beneath the freezing level of blood. Their our bodies vary from eely, jawless lampreys to flattened flounders to large, lumpish ocean sunfish. Some lay eggs, some bear dwell younger, and in seahorses, it’s the males that turn into pregnant. In brief, fish are a geneticist’s dream. “They present so many variations,” says Venkatesh. “If there’s any adaptation in any vertebrate, it ought to be there in fish.”
Within the years since finishing the fugu genome in 2002, Venkatesh — recognized universally as Venki — has sequenced the genomes of greater than a dozen fishes, from sharks to the living-fossil coelacanth to his private favourite, the seahorse. “He’s been a champion, in a really mild-mannered however persistent means, for a very long time,” says Richard Durbin, a genomicist on the College of Cambridge. “He’s one of many focal individuals for evolutionary fish genomics.”
Venkatesh has seen an infinite progress in sequencing energy and expertise for the reason that early days of fugu. Right this moment, producing a high-quality genome sequence from scratch takes simply two months’ work and about $30,000. “No one predicted it will occur so quick,” he says. “You may sequence any genome now.”
And you’ll sequence numerous them. Venkatesh, based mostly at Singapore’s Institute of Molecular and Cell Biology, helps lead a consortium with huge ambitions to sequence a whole bunch of vertebrate genomes by the tip of this decade, almost half of them fish, en path to finally finishing sequences of each residing vertebrate, and extra.
A Scholar Takes the Bait
Regardless of his present prominence in genomics, Venkatesh got here to the sector nearly accidentally. Born in Bangalore, India, to a scientific household — his father was a veterinarian — he selected to review fisheries in college as a result of it appeared like enjoyable. “I believed I might go diving and have a good time,” he remembers.
He by no means did be taught to dive. As a substitute, after a couple of years as a fisheries biologist in India, he headed off to Singapore for graduate college, the place he studied the hormonal regulation of being pregnant in guppies.
Whereas there, he met Sydney Brenner of the College of Cambridge, one of many founders of molecular biology. Brenner wished to be first to sequence an entire vertebrate genome and chosen fugu for its tiny genome. He was in search of scientists to work with him on the venture and noticed one thing particular in Venkatesh. “He mentioned I ought to go be part of him in Cambridge,” says Venkatesh. “I had little or no molecular biology background at the moment, however he mentioned it will be good for me.” Off he went to Cambridge, as the one fish professional on Brenner’s crew.
In 1992, after Brenner left Cambridge for California, Venkatesh returned to Singapore to take up a job on the institute, bringing the fugu genome venture with him. (Ultimately Brenner, too, moved to Singapore, the place he established his personal lab subsequent door to his protege’s. Now age 91, he nonetheless lives in Singapore and the 2 meet weekly for a drink or dinner.)
The fugu genome gave geneticists a beneficial level of comparability to the human genome. They discovered that, regardless of its small measurement — simply one-eighth the dimensions of the human genome — the fugu has roughly the identical complement of genes, and the on-off switches that management them, as people do. To achieve its slimline state, fugu appears to have misplaced lots of the lengthy, baffling stretches of DNA of unknown perform — typically known as junk DNA — that litter most genomes. That made the fugu genome a useful instrument for separating the human genomic wheat from the chaff and particularly for figuring out the essential regulatory switches, says Venkatesh. He later confirmed that the fugu’s regulatory switches are so much like their mammalian counterparts that they’ll typically be swapped with out lack of perform.
Dipping Into the Shark Tank
Recent from that success, Venkatesh turned his consideration to different fish genomes. His first objective was to sequence a shark. Sharks lack bony skeletons, which signifies that they’re an early department within the evolutionary tree of vertebrates. Evaluating their genes with these of bony fishes can thus shed new mild on the evolution of upper fishes and their descendants, together with people.
However Venkatesh confronted an enormous downside. Most sharks have enormous genomes, far bigger than these of people, so that they have been tough to sequence with the expertise of the day. After two years of rummaging by way of the genomes of assorted shark species, he discovered the answer: the elephant shark, whose genome is just a couple of third the dimensions of our personal. “It’s the fugu among the many sharks,” he says. That one, he might deal with.
The sequencing, accomplished in 2007, revealed that the elephant shark is a residing genomic fossil — it has modified much less from its ancestral state than every other vertebrate recognized. “It’s like a display screen shot of the previous, how our ancestors appeared,” says Venkatesh. “That makes it a really helpful mannequin for inspecting what modifications have occurred.”
Extra genomes adopted shortly, together with these of the deep-sea coelacanth (one of many closest residing relations of terrestrial vertebrates) in 2013, the noticed gar (a primitive bony fish) in 2015, and the large ocean sunfish and the distinctively formed seahorse in 2016. Different analysis teams joined the hunt, in order that by early 2018, Venkatesh might record 60 bony fish genomes accomplished by varied labs world wide.
On the molecular degree, fish change into rather more numerous than land vertebrates. A while early of their evolution, bony fishes underwent a duplication of their whole genome. This freed up “spare” copies of genes for evolutionary tinkering with out risking lack of the unique gene perform. This will clarify why bony fish genomes have advanced extra quickly than these of their terrestrial cousins.
The Huge Catch
Although Venkatesh finds fish fascinating in their very own proper, there’s a bigger prize in play as nicely. People and fish share many of the similar molecular constructing blocks — their complement of genes — however deploy them in numerous methods. “You may take a pile of bricks and make a cathedral, you can also make a bridge, you can also make a villa, or you can also make a highway. The query is, what are the controlling mechanisms that take these bricks and make them into what you may see? That’s the large query,” says Edward Wiley, an ichthyologist on the College of Kansas. As a result of fish fluctuate a lot in physique kind, they make a super take a look at mattress to work out a lot of these controls, with huge potential payoffs for our understanding of all vertebrates, together with people.
These and different genome research are actually coalescing into a scientific effort to sequence the best potential range of vertebrate life. Venkatesh is among the leaders of this consortium, often known as Genome 10Ok, and is taking part in a key position in figuring out which fish to incorporate. “Venki has been in on fish genomics for the reason that starting. When G10Ok was shaped, it was pure that they might ask him to be answerable for the fishes,” says Wiley who, with Venkatesh, cochairs the hassle’s fish part.
As its title suggests, G10Ok started with the objective of sequencing 10,000 vertebrate genomes, largely in a rudimentary trend. Since then, although, the group has refocused on high quality over amount: sequencing at the very least one genome from each main group, or order, of vertebrates — some 260 in all — utilizing the most recent, high-precision sequencing expertise. The primary hundred genomes ought to roll off the road throughout the subsequent 12 months, and the total set of 260 ought to be completed by 2020, says Erich Jarvis, a genomic neurobiologist at Rockefeller College in New York Metropolis, who chairs the venture. After that, the group has an much more formidable objective: to sequence the genomes of each one of many 60,000-plus vertebrate species.
The expertise is advancing so quick that a couple of genome biologists are speaking of the last word objective: sequencing the genome of each species on Earth. The plan shouldn’t be as far-fetched because it sounds. “There are one thing on the order of a million-and-a-half named species,” says Durbin. “We’ve in all probability sequenced on the order of a thousand. So there’s a thousandfold enchancment to make. Usually, sequencing applied sciences are bettering twofold a 12 months. On that scale, within the subsequent decade we’re going to have the ability to discover the genomes of every little thing.”
If geneticists get anyplace near that objective, present strategies of sorting, evaluating and understanding genomes won’t address the large mass of knowledge, says Gene Myers, a bioinformatician on the Max Planck Institute for Molecular Cell Biology and Genetics in Dresden, Germany. However Myers is optimistic that researchers, in time, will resolve that downside, simply as they realized to deal with the once-daunting knowledge administration problem posed by the human genome. “Assembly these challenges is the enjoyable half,” he says. “I wish to be overwhelmed and determine it out.”
Working Away on DNA
Genome researchers will need assistance on one other entrance, too, Venkatesh notes. Spelling out the genome of a species and choosing out the genes it comprises is comparatively straightforward. Figuring out precisely what every gene really does — and the way variations in DNA sequence throughout the gene alter that — could be a a lot greater problem that includes loads of detailed lab work. “You may sequence a genome in two months, however understanding the purposeful facet of even one variant takes two years. We have to compensate for the purposeful research.”
If geneticists can clear these hurdles — and if the consortium can discover the funding to do the work — having an entire set of genomes might open entire new avenues of analysis. “Upon getting the blueprints of all vertebrates on the planet, you’re going to have the ability to tackle questions that you might by no means tackle,” says Jarvis. Evolutionary biologists might observe the genetic modifications that underpin speciation — how a single cichlid species advanced into a whole bunch in Africa’s Lake Malawi, for instance. Conservation biologists might extra simply determine genetically distinct populations of threatened species or nonintrusively monitor their distribution from traces of DNA left within the setting. Sometime, they can perceive the genetic the reason why some species are uncommon, and maybe even resurrect extinct species from their genome sequences.
Human geneticists will get their payoff, too. With an entire set of genomes, they may reconstruct the evolutionary historical past of our personal genome and hint the origin and performance of each gene and on-off swap. “As soon as we have now the whole sequences, we are able to begin asking the query of how they’re regulated, and the way that regulation or misregulation impacts human well being,” says Venkatesh, who has already begun exploring the genomic foundation of some uncommon human ailments. “That is what I’d love to do in ten years, if I’m nonetheless round.”