we have long looked forward to the sequencing of the genome of the honey bee , for now we may uncover the genetic basis of divination : bees " have too the power of divination , so that they know in advance when rain or frost are coming " ( aelian , on animals i , 11 ) . unfortunately , the honey bee genome sequencing consortium ( hbgsc ) has not yet discovered the divination gene in the 236 megabases of the clonable bee genome . but much that is fascinating has been discovered , and this paper will be a landmark , not only in genomics , but also in bee research . honey bees have been exploited by humans for millennia , and their extraordinary behavior and biology have always intrigued and puzzled us . the achievement of sequencing the bee genome , by a team at the baylor college of medicine collaborating closely with the honey - bee research community , will provide an enormous boost to our understanding of some fascinating biology . the genome of the honey bee will inevitably be compared to that of the fruit fly drosophila melanogaster . inevitably , because so far we have the genomes of only two other orders - diptera ( drosophila ) and lepidoptera ( the silkworm bombyx mori ) - of the 30 or so orders of insects ( the honey bee belongs to the hymenoptera ) . members of three other orders - coleoptera ( beetles ) , anoplura ( lice ) and heteroptera ( bugs ) - will soon join this group . at a coarse level , the genomes of fly and bee are quite different : that of the bee is relatively at - rich , a fact that posed a technical problem to the sequencers , and , even more remarkably , the genes themselves are in regions that average 71% at ; in drosophila the genes are on average 56% at . the hbgsc suggests that this difference may be a consequence of cytosine methylation in the honey bee , as unlike drosophila , the bee genome contains members of all three known families of cytosine-5-methyltransferase genes ; indeed , it has two genes from the dnmt1 family of genes . the presumption is that high levels of cytosine methylation , which tend to repress gene expression , have led to the preferential selection of at - rich regions as a more favorable context for genes . if so , one might expect the bee genome to be deficient in the dinucleotide cpg ; the paradox is that this genome has the highest cpg over - representation ( by 1.67-fold ) of any known genome . although there is direct experimental evidence for some cpg methylation in honey bees , neither its extent , nor its significance , is yet known . another surprise of the bee genome is its complement of transposable elements , which comprise only 1% of the sequenced genome - in contrast to 5.3% of the euchromatic genome of d. melanogaster . even more surprising is that this 1% is almost entirely made up of members of the mariner family , which transpose by simple excision and reintegration . retrotransposable elements , a common feature of most metazoan genomes , are represented by only a small number of very degraded sequences . whether or not this is a consequence of the haploidy of male bees , as suggested by the hbgsc , is an open question . the other group in which retrotransposable elements are known to be absent are the fully parthenogenetic bdelloid rotifers ( see ) . like most hymenoptera , honey bees have an extraordinary sex - determining mechanism known as haplo - diploidy : females are normally diploid and a product of sexual congress ; males are haploid and develop parthenogenetically from unfertilized eggs . the study of the genetic basis of this mechanism of sex determination in honey bees had to await the development of artificial insemination ; otherwise it is impossible to do controlled crosses , a fact that , despite his efforts , defeated gregor mendel . whiting who , working with a more tractable hymenopteran , bracon hebetor , discovered this mechanism . there is a sex - determining locus with many alleles ; heterozygous zygotes develop as females , hemizygous or homozygous zygotes develop as males . this hypothesis was confirmed for honey bees by woyke   and the complementary sex determiner ( csd ) gene was cloned by beye and colleagues in 2003 . the product of csd is an rna - binding protein and it may , like the transformer protein in drosophila , control sex by determining the splicing pattern of the doublesex gene . population studies of the sequence of csd show that polymorphism of this gene , essential for sex determination , is maintained by balancing selection . the development of diploid honey - bee zygotes may follow one of two paths : to sterile workers who devote their lives to collecting nectar and pollen and taking care of the next generation ; or to queens who , after a brief mating flight , have a life of leisure laying eggs . the genome sequence of the honey bee will provide a valuable resource for the detailed analysis of differences in gene expression between these castes . early data from relatively small cdna libraries already indicate major differences in intermediary metabolism between workers and queens ( for example , see ) . the role of nutrition in determining caste development in honey bees has been known for over 200 years ( see ) , and wheeler et al . have used the official gene list from the hbgsp   to implicate the insulin - signaling pathway in this developmental decision . the rich behavioral repertoire of social bees compared to that of the diptera has often been invoked to explain the long - established observation that the hymenopteran brain has a dramatic expansion of the mushroom body region . this paired protocerebral structure has 170,000 intrinsic neurons ( called kenyon neurons ) per hemisphere in the adult honey bee , compared to a mere 2,500 in drosophila . in fact , about 15% of bee neurons are dedicated to the mushroom bodies compared to only around 1% in the fly , underscoring the enhanced role of these neural structures in bee behavior . the mushroom bodies have been much studied in drosophila , and appear particularly important for integrating sensory information , especially in the context of olfaction . making and strengthening connections between unconditioned and conditioned stimuli during olfactory learning is a major role of the mushroom bodies in drosophila , and so it seems reasonable to assume that much of the seemingly more complicated social behavior of apis may be mediated by this brain center . in support of this view is the observation that odorant receptors are among the gene families most over - represented in apis compared with the fly . thus we might guess that the duplication of odorant receptor genes provided a driving force for an exponential enlargement of the brain regions that deal with the extra demands of the huge increase in potential olfactory associations . this enhanced neural plasticity may have led to the retention in hymenoptera of genes such as mahya , which is also found in vertebrates but has been lost from diptera and lepidoptera . this gene encodes a secreted protein that is expressed in the bee mushroom bodies and antennal lobes , and in vertebrates is present in the olfactory bulb , the structure that shares the same function as antennal lobes in bees , namely the processing and integration of olfactory information . these observations provide an intriguing association between the presence of this gene , its anatomical site of expression , and species with higher cognitive functions . in contrast , the gene foraging ( for ) , which encodes a cgmp - dependent protein kinase ( pkg ) , is found in both flies and bees and , as its name suggests , is implicated in behavioral strategies for food searching in both organisms . in bees , for is expressed in the lamina of the optic lobes and also in a region of the mushroom bodies that receives visual information . nurse bees age to become foragers when levels of for rise significantly in these brain regions , and these ( now ) foraging worker bees become positively phototactic . they then leave the darkness of the hive to become bona fide foragers . in flies , however , ablation of the mushroom bodies in the larva does not affect food searching , so an additional level of regulation via these structures has clearly been recruited in the honey bee , further underscoring their critical neurogenic role at the interface between genome evolution and complex social behavior . the honey bee also misled one of us ( c.p.k . ) for several years about how one of the canonical circadian clock genes evolved . in 2000 , it was revealed that flies and moths have two ' timeless ' genes - the one first discovered and called timeless ( tim ) , which has a cardinal role in the 24-hour clock , and tim2 ( or timeout ) , which apparently was the only tim - like sequence found in mammals , nematodes , and other animals . thus it appeared that a relatively recent duplication had occurred in the ancestors of lepidoptera and diptera around 300 million years ago , and that tim had evolved rapidly to take on a dedicated circadian role . this view was further strengthened by the fact that mutations in tim2 in mammals or nematodes were lethal , whereas mutating tim in drosophila led to healthy , albeit arrhythmic , flies , revealing tim to be a dedicated ' behavioral ' rather than a ' developmental ' gene . as the years crept by , peeking at the emerging bee genome did not reveal tim , but did reveal tim2 - the ancestral form of tim . this was consistent with a scenario of a relatively recent duplication of tim2 to generate the clock - relevant tim in the ancestors of lepidoptera and diptera . this cosy story has been rudely demolished , however , as the tim sequences have recently been identified in the beetle tribolium and , even more surprisingly , in sea urchins . this puts back the date for the duplication of tim to pre - cambrian times . the genes that we presume encode the circadian clockworks of honey bees show a number of other interesting features , apart from tim evolution , in that their genes seem to be more mouse - like than fly - like . for example , in flies and mice , the clock ( clk ) and cycle ( cyc , also called bmal1 ) genes encode positive transcription factors that directly regulate the negative autoregulators encoded by period and tim . in flies , the abundance of clk mrna cycles with a circadian rhythm but cyc is expressed constitutively , whereas in the mammal , cyc cycles and clk does not . as if to highlight this species difference , the carboxy - terminal transactivation domain found in fly clk protein has been transposed to mouse cyc . flies also have a dedicated circadian photoreceptor , encoded by the cryptochrome ( cry ) gene , whereas mammals have two cry genes , which act as negative transcriptional regulators , not photoreceptors . nevertheless , the single copy of cry in the bee encodes sequences more reminiscent of the mammalian than the fly protein , suggesting that the bee cry protein also functions as a negative regulator , not a photoreceptor . in fact , lepidoptera have two copies of cry ; one acts as a negative regulator , the other probably acts as a photoreceptor . thus basal lineages probably had two types of cry and two types of tim , and different organisms appear to have mixed , matched and eliminated one or other copy of these two genes according to their needs . lepidoptera kept both types for each of their tim and cry genes , with both types of functions apparent for each gene . bees , on the other hand , have the stripped - down version , and have lost one copy of each gene , maintaining obligatory tim developmental , and non - photoreceptor cry function . most of us have , at one time or another , been stung by a honey bee . reading the account of the venoms predicted from the genome sequence   makes it quite clear why these stings are so painful : bee venom contains perhaps 20 different allergens including " several homologues of scorpion and snake venoms " . the domesticated european honey bee ( apis mellifera ligustica ) is not , thankfully , very aggressive , but the african a. mellifera scutellata , introduced to brazil by warwick kerr 40 years ago , is ( see bill hamilton 's amusing account of their attack ) . one of the consequences of the honey bee genome project is a very dense map of single - nucleotide polymorphisms ( snps ) , with nearly 5,500 snps already identified and mapped . these have already been used to study the four major groups of subspecies of a. mellifera , with the surprising result that the eastern ( a. mellifera ligustica ) and western ( a. mellifera mellifera ) european populations result from independent colonizations of europe by african populations . bee researchers , like their colleagues who work with drosophila , will now distinguish the bg ( before the genome ) and ag ( after the genome ) epochs . we can confidently predict that honey - bee research will now be even more vibrant and interesting than bg , with great consequences for both fundamental and applied biology . we both thank george weinstock ( baylor college of medicine ) for a preprint of the honey bee genome sequencing consortium 's paper and gene robinson ( university of illinois at urbana - champaign ) and richard gibbs ( baylor college of medicine ) for critical comments on our manuscript . we also thank diana wheeler ( university of arizona , tucson ) for a preprint of her paper .
the honey bee apis mellifera displays the most complex behavior of any insect . 
 this , and its utility 
 to humans , makes it a fascinating object of study for biologists . 
 such studies are now further enabled by the release of the honey - bee genome sequence .