Malaria is caused by injection of Plasmodium parasites into the hu- man bloodstream via the bites of infected mosquitoes. This simple description overlooks a fantastic biological complexity: Some 60
anopheline mosquito species can serve as
vectors for five distinct species of
Plasmodium that produce varying
levels of illness in many animal species. Comparative genomic studies
may shed light on the mechanisms
whereby Anopheles gambiae specifically target humans, why the mosquitoes can tolerate P. falciparum
infection, and how the parasite has
adapted to this lifestyle. In this issue, Neafsey et al. [(1), page 43] and
Fontaine et al. [(2), page 42] analyze
the genome sequences of 16 species
of anopheline mosquitoes and reveal a complex pattern of evolution
that defies the classic concept of a
Sequencing of multiple related species has revealed many attributes of the
evolutionary pressures faced by those
species ( 3–6). For example, multiple genome alignments can show which genes
are most conserved and which evolve the
fastest. In general, Anopheles genomes appear to evolve faster than do Drosophila
genomes, perhaps because the former depend on hosts that may provide opportunities for coevolutionary arms races. This is
especially evident in the families of closely
related genes that formed from the duplication of a single original gene. Fontaine
et al. show that the 16 Anopheles species
gain and lose such gene family members
at five times the rate of the 12 sequenced
Anopheles genomics also sheds light on
the genes involved in the specialization of
An. gambiae on human hosts. Olfactory
and gustatory receptors help the mosqui-
toes to identify and be attracted to hosts.
Although these gene families are gener-
ally highly conserved across Anopheles ge-
nomes, An. gambiae shows a remarkable
gain of 12 olfactory receptors, suggesting
a possible role for these genes in guiding
human host preference [as seen in Aedes
mosquitoes ( 7)]. Many of the olfactory and
gustatory receptors also display acceler-
ated protein evolution, consistent with re-
sponse to positive natural selection. Future
studies should test the adaptive benefit of
specific odorant chemicals and the specific
associations between odorant chemicals
and odorant receptors.
The genome sequences generated by
Neafsey et al. provide the opportunity to investigate whether the observed evolutionary
patterns in sequence divergences between
the 16 mosquito species are consistent with
a single phylogenetic tree. That the
Anopheles phylogeny might be complex has been
suspected since the first An. gambiae genome was sequenced ( 8) from a lab strain
that included two distinct subtypes [today
recognized as two separate species, An.
gambiae and An. coluzzi ( 9)]. The observations that these two species readily hybridize and also have largely overlapping ranges
suggest that there might be gene flow between them. Despite this, the Anopheles
phylogeny has generally been described by a
species tree, constructed from the informa-
Conundrum of jumbled
By Andrew G. Clark1,2 and
Philipp W. Messer2
Multiple Anopheles mosquito genome sequences reveal
extreme levels of mixing
1Department of Molecular Biology and Genetics, Cornell
University, Ithaca, NY 14853, USA. 2Department of Biological
Statistics and Computational Biology, Cornell University,
Ithaca, NY 14853, USA. E-mail: firstname.lastname@example.org
matic wound to the epidermis. However,
there is likely a healthy amount of dermal
fat and an unhealthy amount. Zhang et al.
address this in part by studying a high-fat
diet. Interestingly, induction of adipogenesis in mice through a high-fat diet also
increased the production of cathelicidin
by the proliferating adipocytes. However,
mice harboring disabling mutations in the
receptor for leptin—a hormone produced
by fat cells that suppresses food intake—
gain weight and develop type 2 diabetes,
but are more susceptible to S. aureus infection ( 10). Likewise, in humans, obesity
has been associated with an increased
risk of skin and soft tissue infection ( 11).
One possible explanation for this discrepancy is that insulin resistance or other aspects of metabolic syndrome perturb the
identified by Zhang et al. Thus, signaling
by adipose-derived hormones that control
energy expenditure (adipokines) could influence the expression of cathelicidin. This
antimicrobial peptide also is posttransla-tionally cleaved to its active form, a process
that that may also be influenced by obesity
and metabolic syndrome.
The mechanism underlying the recognition of S. aureus by adipocytes remains
unclear, although it likely involves toll-like receptor 2 (TLR2). Adipocytes express
many members of the toll-like receptor
family, including TLR2 ( 9, 12), which recognizes lipopeptides produced by bacteria.
This may be an operative pathway that
controls cathelicidin production. Moreover, a TLR2-ZFP423-PPAR-γ-cathelicidin
pathway might be augmented pharmacologically by PPAR-γ agonists, thereby
increasing host resistance to infection in
susceptible individuals such as those with
diabetes and metabolic syndrome. ■
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J. F. A. acknowledges support from NIH grant R01HL107380;
J.K.K. is supported by NIH grant R37HL079142.