ScienceThe Loom

To Bee

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To sequence the human genome, scientists established a network of laboratories, equipped with robots that could analyze DNA day and night. Once they began to finish up the human genome a few years ago, they began to wonder what species to sequence next. With millions of species to choose from, they could only pick a handful that would give the biggest bang for the buck. Squabbling ensued, with different coalitions of scientists lobbied for different species. Some argued successfully for medically important species, such as the mosquito that carries malaria. Others made the case for chimpanzees, to help them pinpoint that genes that make us uniquely human. And in 2002, a team of scientists made the case for the humble honeybee.

Why spend millions on the honeybee? For one thing, honeybees are commercially valuable. They make honey, and they pollinate crops. But the honeybee lobby also argued that there were much deeper reasons to sequence its genome. Honeybees lives in societies that rival our own in size and complexity. A single hive may contain as many as 80,000 bees, which together build the hive, gather food, and feed the next generation of bees. They gather nectar from flowers, and they find flowers by merging many sources of information including the position of the sun and the subtle nuances of a flower’s scent. When they come back to their hive, they waggle out a dance to indicate where other honeybees can find the flowers. They manage all this with only a million neurons in their head–a thousandth the number we have.

Only some of the bees in a hive search for food. Each hive is divided up into castes, such as foragers, sterile female worker bees who tend to the larvae, male drones who mate with the queen, and the queen herself. These different kinds of honeybees might well seem like they belong to different species. The queen lives ten times longer than her workers, churning out 2,000 eggs a day. Yet the genetic information for building all of these bees is stored in the same genome. Each bee’s fate is determined as it develops. All bee larvae are initially fed a substance called royal jelly, secreted from the heads of the workers. It’s a rich source of vitamins and other nutrients. It also influences how a bee develops. After three days, almost all the larvae get switched to a diet of honey. Only the queens in the making continue to get the royal jelly. Sequencing the honeybee genome could allow scientists to begin to piece together the way genes can help give rise to a complex animal society.

The scientists got the green light, and four years later, we now have the honeybee genome–and much, much more. Today, three separate journals–Nature, Science, and Genome Research–are simultaneously publishing 18 papers on the genome and what it tells us about what it means to be a bee. The genome is 236 million base pairs long (less than a tenth our own), and contains over 10,000 genes (we have less than 20,000).

But what do all those genes do? To make sense of a genome, the first thing scientists do is figure out its evolutionary history.

The honeybee genome is the product of billions of years of evolution, as is the genome of every other living species. Humans and honeybees share a common ancestor that has been estimated to have lived 600 million years ago. While our ancestors evolved into fish and then moved on land, the honeybee’s ancestors evolved into crustacean-like ocean-dwelling animals, some of which moved ashore and became insects. Early lineages of flying insects had fixed wings, represented today by dragonflies. The ancestors of honeybees evolved folded wings, and one lineage of the folded-wing insects evolved larvae about 300 million years ago. This lineage gave rise to many of the most common insects today, including beetles, ants, flies, mosquitoes, wasps, and bees.

In one of the papers published in Genome Research, scientists reconstructed part of this evolutionary tree by comparing the honeybee genome to the other larvae-producing insect genomes now sequenced–Anopheles gambiae, the malaria mosquito; Dropsophila melanogaster, the fruit fly that geneticists have studied for a century; and Bombyx mori, the silkworm. The fruit fly, mosquito, and silkworm all share a common ancestor that the honeybee does not. In other words, the honeybee’s ancestors branched off first. At first, the bee lineage did not produce bees. The closest relatives of bees are wasps–in fact, previous studies have indicated that bees evolved from a group of predatory wasps that gave up a life of killing for a life of flower-grazing. And in the current issue of Science, researchers published details of a “pre-bee” stuck in a blog block of amber 100 million years ago. While it has a number of features found only today on bees–a brush on its hindlegs for cleaning pollen of its forelegs, for example–it also has spurs on its legs and other distinctive features found today only on the wasps most closely related to bees.

Those early bees probably took advantage of the growing diversity of flowering plants at the time. They gave rise to thousands of descendant species, some of which were solitary and others that lived in colonies. Honeybees are a relatively young cluster of species that emerged in the past few million years. A study published today in Science uses the genome to place the origin of honeybees in Africa. They spread in a series of waves into Europe and Asia. Colonists brought European honeybees several times to the New World. The aggressive African honeybees that have been moving through the United States in recent decades may seem like weird alien invaders, but they actually belong to the oldest lineage of honeybees on Earth.

Many of the scientists publishing papers today compare the honeybee genome to those of other insects in order to pinpoint genes that are distinctively honeybee. One of the most striking group of these honeybee genes are the ones that encode receptors the bees use to sense odors. The common ancestor of mosquitos, fruit flies, and honeybees had a basic set of odor receptor genes, and modified versions of those genes can be found in all three species. But mutations could accidentally duplicate those genes, making extra copies which could later mutate to detect new odors. In the honeybee lineage, gene duplication has produced many more genes for smelling than in other insects. Scientists tallied 170 olfactory genes, compared to just 62 in flies. Given how important smell is to bees to detecting particular flowers and learning which ones have valuable nectar, this explosion of genes makes sense.

Just as striking is the low number of genes honeybees have for tasting. Insects have receptors on their tongues, known as gustatory genes. Honeybees have only 10 gustatory genes, compared to 68 in the fly. Again, the flower-grazing life of bees may account for this difference. Fruit flies and many other insects have an antagonistic relationship with plants. They devour the leaves and steams and seeds of the plants, depriving the plants of reproductive success. The plants have evolved lots of toxins in their tissues to repel the insects, driving the evolution of sophisticated taste in the insects so that they can avoid poisonous food. Bees, on the other hand, are in a friendly relationship with flowers, which depend on them to spread their pollen. Nectar lacks toxins altogether. Once a bee has settled on the right flower, it has little reason to fear the food it finds. And while many other insects must find food as larvae (think caterpillars munching tomato leaves), bees grow up in hives, delivered safe nectar by their aunts.

Royal jelly is a unique feature of honeybees, and the honeybee genome has allowed scientists to trace its origins. Honeybees use ten genes to produce royal jelly, and they all show clear evidence of having descended from a single gene called yellow-e3. Yellow-e3 belongs to a family of genes found in insects as well as in other groups of species such as fungi and bacteria. The yellow genes were among the first ever to be studied by geneticists in the early 1900s. In fruit flies, yellow genes play many roles, and seem espcially important for sex. They allow males to extend their wings in courtship and also give the males their yellow pigment in their eyes–hence the name. One of these genes, yellow e-3, became duplicated and the copy took on a new function–probably serving as a source of food for larvae.

In the new paper on royal jelly, scientists suggest that the early royal jelly genes may have created proteins that were rich in nitrogen or sulfur, two nutrients that can limit the growth of bees. In addition to producing royal jelly, however, royal jelly genes also appear to have taken on new functions in honeybees. They are active throughout the development of a honeybee, not just when a worker needs to feed larvae. It’s possible that they help to determine the caste to which a bee will ultimately belong.

One of the biggest surprises of the honeybee genome project is how much like humans they are–at least compared to other insects. Fruit flies and mosquitoes have undergone a much faster rate of evolution than honeybees. In addition, they have also lost many genes that honeybees and other animals–including humans–have preserved. The genome team idenfitied that 762 genes in the honeybee that are also found in mammals but have been lost in flies. (This is the nice thing about studying genomes: there’s nowhere for missing genes to hide. If they’re gone, they’re gone.)

The similarities between honeybees and humans go beyond retained genes, however. Many of their genes work much like ours. The honeybee’s body clock, for example, uses the same system of genes we do, while fruit flies use a different set. It appears that the common ancestor of insects and humans had two systems of genes for telling time. Fruit flies lost one system, while honeybees and vertebrates lost the other.

Another similarity between us and honeybees is in the way our cells control their genes. They cap certain genes with clusters of atoms called methyl groups that can switch genes on or off. Methylation, as this process is known, allows our cells to silence parasitic stretches of DNA that would otherwise make new copies of themsleves and insert them willy-nilly in our genomes. Scientists have long been struck by the fact that fruit flies use almost no methylation. It turns out that honeybees methylate their DNA, using versions of the same genes we use.

It’s likely, then, that the common ancestor of insects and us methylated its DNA too. But it didn’t methylate to control parasitic DNA. Honeybees have lots of parasitic DNA in their genome, but it’s not methylated. One intriguing possibility is that the original function of methylation was to allow mothers and fathers to shut off their copies of genes in their offspring (I write about this more here). In our lineage, methylation also took on a new function, as a way to control parasitic DNA. In the insect lineage, honeybees may have retained its original use. In fruit flies, the genes disappeared completely.

I was surprised while reading these papers to learn that Gregor Mendel tried to breed honeybees. Having discovered rules of heredity with peas, he hoped to create healthier honeybee hybrids. But the odd mating habits of honeybees–the queen only mates with males as they swarm away from an old hive–proved impossible for him to control. He supposedly did manage to create one hybrid strain of bees, but it was so nasty that it had to be destroyed. Mendel’s work with peas would be neglected for years after his death. Genetics was reborn in 1900, and fruit flies became the model for animal genetics. They are far easier to breed than honeybees–just stuff old bananas in a milk bottle and you’re on your way.

Only now does it turn out that fruit flies were a rather freakish species to pick. Honeybees–for all their royal-jelly-slathered weirdness–are a lot more like other animals, including us.

[Note: I’ll post links to the papers as soon as they are posted]

Update: The NIH has a portal for all the honeybee papers, plus press coverage here.