September 2007

The Nation Reviewed

Ticked off

By Ashley Hay
Illustration by Jeff Fisher.

The unlikely combination of a small seaside village in Crete and an Adelaide-born Kylie Minogue look-alike would not have suggested, to the casual observer, news from the frontiers of science. But in the northern summer Dr Catherine Hill of Purdue University, Indiana, announced to the Third International Meeting on Molecular and Population Biology of Mosquitoes, held at Kolymbari’s Orthodox Academy, that sequencing of the world’s first tick genome had been completed.

Clocking in at 2x109 base pairs (each pair forms a double helix of DNA), it’s two-thirds the size of the human genome. To finish sequencing a genome, Hill says later, is one of the few “woo-hoo moments” one gets in science. Not that the project is anywhere near over: in many ways, its real work can now begin.

Hill, 35, completed her PhD on diseases endured by lice - as opposed to diseases transmitted by them - in 1998 at the University of Adelaide. She then switched blood-sucking parasites to work with ticks as part of a post-doctoral position with a pharmaceutical company in the US. But she’s democratic in her attention to vampiric spongers: she works with mosquitoes too, and left that role to work in the laboratory behind the sequencing of the world’s first mosquito genome, just as that project got underway. It was, she says, an “addictive scenario. I saw what the release of that genomic information did for the mosquito community, and the way it revolutionised everything by giving us a better understanding of mosquitoes’ biology.”

All of which got her thinking about other parasites. If mosquitoes are “the world’s number-one vector in terms of human disease and mortality”, then ticks come in second. And, given that these two creatures last shared an ancestor about 500 million years ago (ticks are more closely related to spiders, scorpions and horseshoe crabs), “the tick genome would let us study a whole other branch of the evolutionary tree, and the only other group of blood-fed vectors apart from the mosquitoes. We’d look for some similarities between the two, but we’d also expect to find some big differences.”

When the US National Institute of Allergy and Infectious Diseases called for sequencing projects in 2004, Hill saw an opportunity for a tick genome to fill “a gaping hole in our knowledge”. She and her collaborators submitted their proposal that March, were funded in April and began work in May - “much faster than usual,” she says, “although actual sequencing didn’t start until 2005. We had to grow our ticks, get their DNA; we’d spent a lot of time thinking about which species to use.” Their choice, Ixodes scapularis, is the most important tick in the US, responsible for the transmission of Lyme disease, human babesiosis (a malaria-like infection) and human anaplasmosis (a form of cattle fever).

In Hill’s terms, sequencing a genome is “like taking a completed jigsaw puzzle, breaking it into its pieces and trying to remake it, or” - she pauses - “it’s more than that. It’s like taking a book, chopping it into words and bits of sentences, and trying to put them back together again. Parts of it are easy to work out and parts of it aren’t.” The end of sequencing means that all the pieces of the jigsaw, or all the book’s phrases, have been turned face-up to show what they are and perhaps how sections of them might fit together. Then the assembly and annotation, the decoding of what sits where and what each gene might do, can begin. “Once all the pieces of the genome have been sequenced, we start looking for genes that are interesting or genes that we already know from other genomes - from humans or fruit flies or mosquitoes - and that kind of investigation can go on forever.”

Things both expected and unexpected appear. Ticks stay attached to their hosts much longer than do mosquitoes, so the researchers expected to find mechanisms that let them achieve this undetected - and they did. On the unexpected side was “just how messy this genome would be, and how much of it would be made of repeated material: around 70% is moderately or highly repetitive. It must provide some kind of structural benefit or perform some regulatory function. In nature things aren’t designed to have anything extraneous, so why would you replicate all that DNA if it didn’t confer some kind of advantage?”

Fruit flies have given their genome what Hill calls “a bit of a spring-clean, throwing out everything they don’t need - and they’re recent arrivals on the evolutionary tree. But then, plants like wheat, corn and maize that are thought to have evolved more recently have bigger genomes. And we know that another tick, Rhipicephalus microplus, has an even bigger genome again - around three times the size of Ixodes scapularis, and twice the size of the human genome - and it’s evolved more recently too. These things are following a trend towards genetic obesity, but we don’t know what regulates the size of genomes or why so many ticks have such big ones.” Hill looks out to the horizon. “If there was such a thing as a genome genie,” she says, “Rhipicephalus would definitely be on my wish list.”

It was Francis S Collins, the leader of the first publicly funded human sequencing project, who talked about “human snobbery” and genome size. “Early on,” Hill explains, “people assumed that bigger, more complicated organisms would have more genes and more DNA. The first multi-cellular organism sequenced, a roundworm, had a tiny genome, so that seemed to bear out the theory; but it turned out to have about 18,000 genes. Then we started seeing that in insects. Fruit flies and mosquitoes have around 15,000 genes each; humans have only 30,000. Now scientists are getting better at not making those assumptions, and we’re starting to understand that there’s much more to genomes than just genes.”

Back on the evolutionary tree, there’s evidence that hard ticks - the ticks of most concern in terms of public health and veterinary issues - evolved in the piece of Gondwanaland that became Australia. “We think this because of the funny lineage of the main Australian tick, Ixodes holocyclus,” says Hill. “It’s a wacky little thing, and nasty too. It injects toxins during its blood-feeding which can cause paralysis or kill small animals. Sequencing Ixodes holocyclus to compare to the American tick would be great, because the more genomes you can align in a group, the more you can understand about how new species form and evolve.”

In the meantime, all that information about Ixodes scapularis will go out into the world so that, as Hill puts it, “the community can ask their favourite questions: Does ticks’ saliva have any possible vaccine candidates? What genes are involved in their resistance to insecticides? Like female mosquitoes, female ticks need to feed on blood to reproduce and this can quadruple their body size. How do they get rid of the water and ions and only use what they need?”

That’s the thing about science: any answer only generates more questions. “People think that if we sequence an organism’s genome, we can unravel its mysteries,” says Hill. “They don’t understand that it’s really only the beginning. There are no easy answers; only very slow unravelling and very small steps. In the end, this project has the same importance as all genome projects: it gives us a much better understanding of biology.” An assembly of the genome will be publicly released in a month, although a second, improved version could take several years to appear.

Hill’s eyes light up when discussing the tiny animals. “You know,” she says, “ticks are really cool. They don’t have antennae like mosquitoes; their smell receptors are on their feet. So they crawl up blades of grass and move their legs around like they’re doing a Mexican wave at the cricket. They’re trying to smell ammonia and CO2, trying to detect interruptions to heat or light, which would tell them a host is nearby.”

And her personal favourite? Catherine Hill looks out across the clear, calm water of the Aegean Sea. “Well,” she says at last, “they’re all kind of cute ... I like them all; but I like my mosquitoes too. I wouldn’t want to favour one over the others.”

Ashley Hay

Ashley Hay won last year’s Bragg UNSW Prize for Science Writing. Her last novel, The Railwayman’s Wife, won the Foundation for Australian Literary Studies’ Colin Roderick Award and the People’s Choice category in the NSW Premier’s Literary Awards. Her new novel, A Hundred Small Lessons, will be published this April. She lives in Brisbane.

September 2007

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