To Bee

i-36ec44cabe57b84a8050962136527bf7-honeybee.jpgTo 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.


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Just a quirk of history - I heard when the honey bee genome project got a green light from Gene Robinson in person. He was here giving a talk. I can't wait for papers to go online - you bet I'll review the clock one at least!

Did they map the genome from each differnt bee caste? Perhaps co-habitational speciation has occurred at some point in the bees ancestry. Only the stud drones and the queen reproduce. Foragers do not and the females are sterile, a classic hybrid malignancy.

My Ph.D. advisor is an entomologist, and another member of my graduate committee is a molecular biologist (but not an insect guy) with a longtime interest in DNA methylation. The latter has always suspected that we'd find DNA methylation in insects, while the former once told me "Most of the time when people say 'Insects do X', they really mean 'Drosophila do X'." Both have certainly been vindicated!

As for breeding honeybees: The way to do it is via artificial insemination. The apparatus even includes a little gadget for holding the sting out of the way!

they waggle out a dance to indicate where other honeybees can find the flowers

I thought this was, uh, contentious? I remember reading something that made von Frisch's experiments seem pretty badly flawed.

we have less than 20,000

That's the first estimate I've seen below 20K; how'd you come up with it?

I'm not saying you're wrong -- no hard numbers available, after all, and not exactly my field -- it's just that every other estimate I've seen has been "20-25K" or "even fewer than the 35K guess from a couple of years ago", or some other formulation that refuses to go below 20K.

More interesting bee information:

* all bees in a colony are the daughters (workers) and sons (drones) of the queen. Workers graduate through a series of tasks as they age, starting with caring for brood in the center of the hive, and progressing until they fly out of the hive to forage. Drones do no work, do not gather food, have no sting, and are useful only for mating. However, they die when they mate, and if they don't mate, the workers will kick them out of the hive at the end of summer. No boys allowed during winter.

* The queen has one mating flight, in which she will mate with up to a dozen drones. This lasts her the rest of her life - usually several years. The queen may lay up to 2000 eggs a day in the summer, and she selects the sex of an egg by fertilizing it (female) or not (male). Hence, drones are haploid and have no father.

* This also gives rise to multiple lineages of half-sister workers, with the same mother but different fathers. It is thought that multiple lineages provide different qualities to the hive. One may be particularly good at grooming, which promotes disease resistance.
Others may excel at regulating the hive temperature (bees spread water on the comb and fan it when the hive gets too hot, creating their own evaporative cooling). The hive is better equipped to surive as a result.

* Here in the southern US, the multiple lineages may give an edge to the africanized ("killer") bee. Guard bees release an alarm odor to alert the hive to danger; africanized bees release much more alarm odor, and (as a result) their hives put up a much greater defensive response. The problem is, if a queen mated with a dozen drones, even if eleven of those drones are european (hence relatively non-defensive), the single resulting lineage of africanized workers in the hive will so stir up their sisters that the hive will behave like an africanized hive - even though 90%+ of the bees are not african!

* Honeybees are not native to the Americas. In reference to africanized honeybees, we speak of our european honeybees as the "native" population, but really they're not - they are imports, too.

* The queen starts laying eggs again in the middle of winter, growing the worker population in anticipation of the first nectar flows of spring. This gives honeybees a significant advantage over,
for example, bumblebees, where just the queen survives over the winter, and colony growth only takes off late in the spring.

* 1 pound of honey = 25,000 bee flight miles. The average worker will produce less than a tablespoon of honey in her entire life.

By beekeeper (not verified) on 25 Oct 2006 #permalink

Bill--Bee dancing is well-accepted and actively researched. See here for example.

As for human genes, I got the less-than-20,000 figure from David Haussler at UCSD. That's a current estimate, though.

Wow, awesome stuff.

Has anybody sequenced the ant genome yet? Or termites, for that matter? It should be fascinating to see how those two, also being social insects, compare with the honeybees. In particular, aren't ants derived from essentially the same branch of the evolutionary tree as bees and wasps? I have to wonder how it is that worker ants lose their wings while the queens and drones keep them. Obviously, that's not strictly determined by genetics, but I wonder how that difference arises in ants when all bees keep their wings.

Carl Zimmer wrote:

As for human genes, I got the less-than-20,000 figure from David Haussler at UCSD. That's a current estimate, though.

Actually, David Haussler is at UCSC, where the assembly of the public version of the human genome was done....

And in the current issue of Science, researchers published details of a "pre-bee" stuck in a blog of amber 100 million years ago.

Freudian slip? Don't you mean block? ;-)

PS. You can delete this. It doesn't need to be posted.

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.

I assume that when you write "fruit flies" you mean Drosophila (rather than true fruit flies, tephritids). Drosophila (for the most part) feed on rotting fruit, so I doubt there is much of an antogonistic relationship between these flies and their hosts. Also, many insect larvae mature where the mother oviposits, so they don't need to find a host.

Of course, the signature of a past selective environment may be retained in the genome. If the ancestor of Drosophila destroyed healthy plants, then you might see evidence of that in the genome.

"Insects have receptors on their tongues, known as gustatory genes." paragraph 10, line 2
The genes code for the receptors, they aren't the receptors.

Very cool piece! I'll have yo come by more often.

Bill--Bee dancing is well-accepted and actively researched.

As I recall, the contention wasn't over bee dancing per se; it was whether the "round dance" and "waggle dance" were separate behaviors or ends of a spectrum of behaviors. There's a relevant abstract from a recent international social-insects research meeting at this URL:

Has anybody sequenced the ant genome yet? Or termites, for that matter?

This would be interesting, because while bees, ants, and wasps are closely related taxa within the order Hymenoptera, termites (Isoptera) are quite distant -- they're much more closely related to the cockroaches and mantids. They're so different, in fact, that unlike Hymenoptera, the termites don't even have complete metamorphosis. Termites are also full diploids, and both sexes are represented among their non-reproductive castes.

It would be very cool if homologous genes contributed to the social behaviors in both lineages. It would also be interesting to look at close relatives that are not social. There are lots of solitary bees and wasps (though no known solitary ants). All termites are social as well, but related orders aren't. (Hmmm -- cockroach genome project, anyone?)

Of course all the castes have the same genome, two copies of the chromosomes in the females and one in the males (haplodiploid sex determination). It's the expression of the genes that makes divergent phenotypes for different castes and for different life stages of the workers.

But as a matter of fact, I was told that drones were the actual DNA source. You get more DNA than you would from grinding up a single queen, but as they're all from unfertilized eggs, their DNA is still all the queen's.

Polymorphism between the queen's two sets of chromosomes (randomly recombined and passed on to each drone) was more of a challenge for the bee than for other insects because of how sex determination works. You can't produce a completely inbred queen honeybee. You have to be heterozygous for the sex-determination gene in order to be female. So you end up male if you're haploid (homozygous because you've only one copy) or overly inbred (homozygous because your copies are identical). Oh, and the diploid males are killed by the nursery bees.

By Paul Havlak (not verified) on 26 Oct 2006 #permalink

Very interesting article! One nitpick though...

"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."

the bees that are invading the US aren't really african bees, they're africanized honey bees. They're a hybrid between african and european honeybees, so I wouldn't say that africanized honey bees belong to the oldest lineage of honeybees on earth, but the youngest.

I do have one question... How did metamorphosis evolve? Seems like a pretty hard thing to evolve (which is maybe why only insects have it?)

Just a note, maybe someone else could elaborate on it -
While proper honeybees are not native to the Americas, there are native species of eusocial stingless bees that do produce (some really great) honey. Unfortunately, the cultivation of these bees in Central and South America is waning due to the spread of European and Africanized bees.

Has anyone looked into the genetic differences of these bees and the other Hymenoptera (or other insect orders)?

Thanks for a great article on the bee genome papers. In addition to the Nature, Science, and Genome Research articles, there are a set of companion papers in Insect Molecular Biology and several others elsewhere. There's a website at NCBI trying to keep track of all this and the coverage - which is where I found your piece -

In answer to a couple of the queries you got, indeed several groups are trying to motivate for an ant genome, or two. The imported Argentinian fire ant in the southern United States is perhaps the strongest candidate right now, but others would be good too. Termites on the other hand have a genome that is far too large for current sequencing costs and methods, but soon might come within reach with radical new sequencing methods being developed.

Comparisons of stingless and honey bees are being made, but genomic level comparisons are just starting. Gene Robinson's lab in the Department of Entomology at the University of Illinois at Urbana-Champaign, which is also my home, and several other groups are working hard to use evolutionary approaches to really get at the genetic underpinnings of bee sociality. More distantly, there is a wasp genome sequence underway that will help somewhat with these evolutionary comparisons.

The evolution of insect metamorphism is even harder, although various aspects of it have been studied for decades (e.g. the hormonal regulation), and again, new insect genomes like those underway on insects that do not metamorphose, e.g. the pea aphid and the human body louse, will help here.

It is correct that Drosophila are not true fruit flies (the tephritid flies that attack intact fruit), nevertheless the larvae and adults are exposed to lots of nasty chemicals in the rotting fruit they occupy, and we speculate in the Nature paper and our companion paper in Genome Research that in comparison bees have less need of gustatory receptors to detect all these nasty chemicals, given their mutualistic relationship with plants.

By Hugh Robertson (not verified) on 27 Oct 2006 #permalink

"Another similarity between us and honeybees is in the way our cells control their genes."

I had to read that five times before I connected 'their' to 'cells' instead of 'honeybees'.

Joshua commented:

"Has anybody sequenced the ant genome yet? Or termites, for that matter? It should be fascinating to see how those two, also being social insects, compare with the honeybees. In particular, aren't ants derived from essentially the same branch of the evolutionary tree as bees and wasps?"

The social wasps, the bees, and the ants are from separate lineages of the Hymenoptera. Most bee species are solitary anyway, as are their closest relatives in the Sphecoid wasps. Social wasps and ants are in the Vespoidea, a separate radiation, and it appears that within the vespoids the ants and social wasps aren't that closely-related anyway. So we're looking at multiple independent acquisitions of sociality in the Hymenoptera.

An ant genome would be nice, and at least one group has recently proposed attempting the Argentine ant, although I don't know how they fared with the funding agencies.

"* all bees in a colony are the daughters (workers) and sons (drones) of the queen."

Quick note: I've heard that a foraging bee is welcome at most any hive it returns to. Ths is why you put your weakest hives on the outside edge of the table, or even away from the other hives: some foragers will return to the closest hive that will have them, building the weak hive's numbers.

By e.carlson (not verified) on 01 Nov 2006 #permalink

Fascinating post, Carl! Excellent, informative comments! Wow!

By David B. Benson (not verified) on 03 Nov 2006 #permalink

Mr. Zimmer:

I find bees (and ants) fascinating. You might be interested in this post from last year where I discuss a clip involving bees and giant hornets (Unlike their Asian counterparts, the bees we know and love have no defense against the hornets.)

Also, you might be interested in this discussion of bee castes.

By Robert O'Brien (not verified) on 18 Nov 2006 #permalink

"do have one question... How did metamorphosis evolve? Seems like a pretty hard thing to evolve (which is maybe why only insects have it?)"
I seem to remember that it has been suggested vertabrates evovled from some ancestral species, the larval form of which had a notochord, the adult did not. If that counts as metamorphosis, then its not just insects. Sea slugs i think do something similar

Virtually every critter goes through considerable change during the course of development from (the equivalent of) a single-celled individual to a small "colony" of cells to some sort of larger, more "complex" critter with differentiated cell and tissue types and one (or more) body plans/locomotion schemes.

While we may not have formal larval, nymph, juvenile, and adult phases, even humans go through phases ranging from a one-celled free-floating eukaryotic existence to a small implanted parasitic critter to a tadpole-esque swimmer in an internal solution to an increasingly-confined hairless tetrapodal larva and so on...before eventually morphing into an independent partially-haired, sexually-mature, free-roaming, air-breathing biped.

As some of Carl's posts have shown, even algae, fungae, and some very simple animals (choanoflagellates?) can undergo substantial reorganization in response to changes in the available nutrition, predation, etc. Fluctuating and unpredictable environmental challenges presumably drove the evolution of multicellular plants and animals in the first place.

In the course of this growth and development, the challenges and opportunities to which even a fairly-generalized multi-celled critter is exposed (even if we just envision some sort of larger and larger blob of cells) are bound to change.

"Formal" metamorphosis is indeed interesting, and no doubt the evolutionary explanations for it will surprise us from time to time as scientists continue to tackle one question after another and as the explanations themselves become more and more refined, detailed, and illuminating.

But it does not seem to me that, in general terms, it should be surprising that the different environments and selection pressures to which critters are exposed as they grow and differentiate during life should, at times, result in radically different strategies, phenotypes, and adaptations...

By Steviepinhead (not verified) on 07 Dec 2006 #permalink