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Sex chromosomes XX XO XX XY XX XY
Current Biology
environmental stimuli. Perhaps photoperiod, as seen in some sexual phenotype (e.g., ZZ female
the best-known examples of ESD populations of the brackish water bearded dragons and XX male
involve temperature-dependent shrimp, Gammarus duebeni, where skinks). Similarly, infection by the
sex determination, or TSD, where males are produced on long days and symbiotic bacterium Wolbachia can
temperature during a critical window females are produced on short days. override GSD in a variety of insects,
of embryonic development influences The traditional view that divides and depletion of oocytes can cause
the sex of the offspring. A common sex-determining mechanisms female-to-male sex reversal in some
TSD pattern, seen in alligators and strictly into GSD and ESD is being fish species (e.g., Oryzias and Danio).
crocodiles and some turtle and challenged by evidence that both GSD and ESD may be better viewed,
lizard species, for example, involves GSD and ESD can coexist in the therefore, as extreme points along a
females developing at both low and same species. Sex determination continuum, with sex determination
high incubation temperatures while in two lizard species exemplifies being more influenced by genetic
males are produced at intermediate the false dichotomy between GSD factors in some species and by
temperatures. Other environmental and ESD. The bearded dragon environmental factors in others.
variables that can act as sex- Pogona vitticeps and the skink Categorizing GSD species
determining mechanisms include: Bassiana duperreyi both possess simply into male and female
the proximity of conspecifics, as is sex chromosomes — ZZ/ZW and heterogamety obscures surprising
found in the echiurid marine worm, XX/XY systems, respectively — yet variation in the underlying genetic
Bonellia viridis, where planktonic genotypic sex can be overridden at mechanisms. A comparison of the
larvae that settle in isolation become extreme incubation temperatures, male heterogametic systems of
females whereas larvae that settle resulting in individuals with a mice, roundworms and fruit flies
near females become males; and mismatch between genotype and illustrates this point (Figure 1). The
Magazine
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were identifying the major players examined where it is clear that alleles of sex-determining genes in
controlling sex in these organisms. Dmrt1 or a paralog does not act as worms. In each case sex reversal
Surprisingly, there was initially a sex-linked sex-determining gene, required intervention during
no overlap among these model although Dmrt1 still plays a crucial embryonic development and did
systems — though many of the genes role in male gonadal differentiation not alter phenotypic sex after
controlling sex in flies or roundworms and maintenance in these species. that time (although in flies sexual
were conserved, their sex-determining phenotypes can be altered as late
roles were not. Thus, sex- Acquiring and evolving sexual traits as the pupal stage). It came as a
determination pathways seemed to Sexual selection and other selective surprise, therefore, when it was
lack shared components, unlike many pressures cause sexually dimorphic shown recently that deleting either of
other major developmental regulatory traits to evolve rapidly. Thus, even two sex-specific mouse transcription
pathways, a near heresy in the age of dramatic dimorphisms in one species factors — forkhead box L2 (Foxl2) in
model organisms. Until the late 1990s, may be very different or absent in females or Dmrt1 in males — could
a molecular geneticist therefore related species. Recent work, mainly cause gonadal cells to reprogram
could be excused for viewing sex in fruit flies, has helped reveal how their sex, even in adults. Thus, sex is
determination much as Darwin initially dimorphic traits arise and adapt determined early but not irreversibly,
viewed the peacock’s tail. during evolution. Two distinct and Foxl2 and Dmrt1 lie at the
A measure of resolution came when mechanisms, both involving the heart of two opposed maintenance
the downstream male regulator male activity of dsx, have been described. networks that uphold the initial sex
abnormal 3 (mab-3) was cloned from The first involves the ability of dsx to determination decision.
C. elegans and found to be related to regulate downstream transcriptional
the insect dsx gene. dsx and mab-3 targets and relies on variation in the The future
share a novel DNA-binding motif, the presence or location of DSX binding Several decades of intensive
DM domain, which was subsequently sites in cis-regulatory elements. genetic investigation have
found in many metazoan sexual In abdominal pigmentation, which provided a detailed view of how
regulators, most notably Dmrt1 in is present in males but reduced in sex is determined in several model
vertebrates. Dmrt1 is expressed females, changes in DSX binding organisms, including what triggers
in the embryonic gonad of all sites have altered the ability of DSX sex determination, what gene
vertebrates examined and Dmrt1 or a to repress the two bric a brac (bab) networks respond to the trigger, and
close paralog has been shown to be genes, and thereby promote strong how downstream genes integrate
essential for testicular differentiation pigmentation in the male posterior sex and pattern to promote sexual
in mammals, birds, and fish. Thus, at abdomen. The second mechanism differentiation, and have begun to
least one family of regulators acting involves changes in the expression illustrate how sex determination
at the interface of sex determination pattern of dsx itself. Although dsx and sexual dimorphism can evolve.
and sexual differentiation does controls most dimorphic traits, it is New technologies, including
appear to be deeply conserved. not actually expressed in all cells, so inexpensive high-throughput DNA
Studies of Dmrt1 in vertebrates that in effect some cells ‘know’ their sequencing, RNAi, and other reverse-
also have suggested that simple sex and some do not. This feature has genetic strategies, herald rapid
gene mutations can drive transitions been exploited in the evolution of sex future progress in our understanding
between sex-determining combs, male-specific sensory bristles of sex determination and its
mechanisms in nature, much like used in mating that are found on the evolution, making it easier to perform
those created by Hodgkin in C. first pair of legs in some Drosophila genetic mapping in non-model
elegans in the laboratory. In three species. Sex combs develop as a organisms, to identify and study the
different vertebrate groups it result of the joint expression of the function of sex-biased regulatory
appears that a new sex‑determining male-specific dsx isoform and the networks, and to compare sex
mechanism resulted from a different HOX gene sex combs reduced (Scr) chromosomes across species. A
mutational event affecting Dmrt1: the and are present only in species that detailed understanding of how
avian ZZ/ZW system likely arose from have evolved an appropriate dsx transitions among sex-determining
a recessive loss-of-function mutation expression domain in the foreleg. mechanisms can occur is currently
in Dmrt1; in the medaka fish (Oryzias lacking, although several theoretical
latipes) a new XX/XY system evolved Staying committed models provide testable hypotheses
due to a dominant gain-of-function Sexual dimorphisms arise about how such transitions might be
mutation of Dmrt1 in which the new throughout much of development accomplished. Fine-scale phylogeny-
Dmrt1 allele — Dmy — functions in most species and thus sex based studies will be one way
analogously to Sry in mammals; and presumably is determined early. forward and will identify many new
the African clawed frog (Xenopus A wide range of experimental models to study. Sex maintenance
laevis) ZZ/ZW system likely arose approaches have confirmed that is another emerging field of study.
from a truncation that generated a this is so, including experiments While we now know that Dmrt1 and
dominant-negative ovary‑determining involving surgical removal of Foxl2 are required for maintaining the
dmrt1 allele — dm‑w — that blocks the fetal gonad and conditional sex of postnatal gonads in mice, we
the masculinizing activity of the deletion of sex determination know little of the gene networks in
autosomal dmrt1 gene. Therian genes in mammals, temperature which they function nor whether sex
mammals and stickleback fish are shifts in reptiles with TSD, and maintenance occurs in other animals.
the only vertebrate groups so far temperature shifts using conditional Darwin’s theories provided the
Current Biology Vol 22 No 8
R262
foundation for modern studies of how in the medical leech (Hirudo medicinalis)
and why sexual dimorphisms arose Correspondences viruses remain detectable in the blood
and evolved; with the advent of new meal for up to 27 weeks, indicating viral
technologies the near future will nucleic acid survival [4,5]. To examine
certainly provide deeper insights into Screening mammal whether PCR amplifiable mammalian
the molecular basis of these
processes.
biodiversity using DNA persists in ingested blood, we
fed 26 medical leeches (Hirudo spp.)
Further reading
DNA from leeches freshly drawn goat (Capra hircus)
blood (Supplemental information) then
Bull, J.J. (1983). Evolution of Sex Determining
sequentially killed them over 141 days.
Mechanisms. (Menlo Park, California: Ida Bærholm Schnell1,2,†,
Benjamin Cummings Publishing Company, Following extraction of total DNA, a
Inc.) Philip Francis Thomsen2,†,
goat-specific quantitative PCR assay
Darwin, C. (1871). The Descent of Man and Nicholas Wilkinson3,
Selection in Relation to Sex. (London: John demonstrated mitochondrial DNA
Morten Rasmussen2,
Murray.) (mtDNA) survival in all leeches, thus
Dewing, P., Shi, T., Horvath, S., and Vilain, E. Lars R.D. Jensen1, Eske Willerslev2,
persistence of goat DNA, for at least
(2003). Sexually dimorphic gene expression in Mads F. Bertelsen1,
mouse brain precedes gonadal differentiation. 4 months (Figure 1A; Supplemental
Mol. Brain. Res. 118, 82–90. and M. Thomas P. Gilbert2,*
information).
Graves, J.A.M. (2008). Weird animal genomes
and the evolution of vertebrate sex and sex We subsequently applied the
chromosomes. Annu. Rev. Genet. 42, 565–586. With nearly one quarter of mammalian method to monitor terrestrial
Herpin, A., and Schartl, M. (2011). Dmrt1 genes
at the crossroads: a widespread and central
species threatened, an accurate mammal biodiversity in a challenging
class of sexual development factors in fish. description of their distribution and environment. Haemadipsa spp. leeches
FEBS J. 278, 1010–1019. conservation status is needed [1]. were collected in a densely forested
Hodgkin, J. (2002). Exploring the envelope:
systematic alteration in the sex-determination For rare, shy or cryptic species, biotope in the Central Annamite region
system of the nematode Caenorhabditis existing monitoring methods are of Vietnam (Figure 1B; Supplemental
elegans. Genetics 162, 767–780.
Hosken, D.J., and House, C.M. (2011). Sexual
often prohibitively expensive or information), in which five new mammal
selection. Curr. Biol. 21, R62–R65. unreliable. The problem is particularly species have recently been discovered.
Matson, C.K., Murphy, M.W., Sarver, A.L., acute in tropical forests, where a Despite the interest these discoveries
Griswold, M.D., Bardwell, V.J., and
Zarkower, D. (2011). DMRT1 prevents female disproportionate number of species have generated, including adoption of
reprogramming in the postnatal mammalian are listed by IUCN as ‘data deficient’ the saola (Pseudoryx nghetinhensis) as
testis. Nature 476, 101–104.
Matson, C.K., and Zarkower, D. (2012). Sex and
[2], due to the difficulty of monitoring a regional flagship species by the World
the singular DM domain: insights into sexual with conventional approaches. Wildlife Fund, all attempts to develop
regulation, avolution and plasticity. Nat. Rev. This presents serious obstacles to standardised survey and monitoring
Genet. 13, 163–174.
Quinn, A.E., Georges, A., Sarre, S.D., Guarino, conservation management. We, here, techniques for these species have
F., Ezaz, T., and Graves, J.A.M. (2007). describe a new screening tool, the failed.
Temperature sex reversal implies sex gene
dosage in a reptile. Science 316, 411.
analysis of mammalian DNA extracted Remarkably, 21 out of 25 leeches
Robinett, C.C., Vaughan, A.G., Knapp, J.M., and from haematophagous leeches. By tested yielded mammalian mtDNA
Baker, B.S. (2010). Sex and the single cell. II. demonstrating that PCR amplifiable sequences, representing six species
There is a time and place for sex. PLoS Biol.
8, e1000365. mammalian blood DNA survives for spanning three orders — Artiodactyla,
Sekido, R., and Lovell-Badge, R. (2009). Sex at least four months post feeding in Carnivora and Lagomorpha (Figure
determination and SRY: down to a wink and a
nudge. Trends Genet. 25, 19–29.
haematophagous Hirudo spp. leeches, 1B; Supplemental information). We
Tanaka, K., Barmina, O., Sanders, L.E., Arbeitman, we hypothesise that most wild caught deliberately chose PCR assays that
M.N., and Kopp, A. (2011). Evolution of adult leeches will contain DNA traces of are unable to PCR amplify human
sex-specific traits through changes in HOX-
dependent doublesex expression. PLoS Biol. their last blood meal. We subsequently DNA in order to prevent false positives
9, e1001131. demonstrate the efficacy of the method, derived from human contamination
Uhlenhaut, N.H., Jakob, S., Anlag, K., Eisenberger,
T., Sekido, R., Kress, J., Treier, A.-C.,
by testing it in situ using terrestrial of the leeches at time of sampling
Klugmann, C., Klasen, C., Holter, N.I., et al. Haemadipsa spp. leeches caught (Supplemental information). Therefore,
(2009). Somatic sex reprogramming of adult in a tropical Vietnamese rainforest it is possible that human DNA is
ovaries to testes by FOXL2 ablation. Cell 139,
1130–1142. setting, and identify cryptic, rare and present in the four samples that failed
Veitia, R.A. (2010). FOXL2 versus SOX9: a lifelong newly discovered mammalian species. to yield an amplicon; thus, the value
‘‘battle of the sexes’’. Bioessays 32, 375–380.
Williams, T.M., and Carroll, S.B. (2009). Genetic
We propose that DNA from leeches is a conservative estimate of the
and molecular insights into the development represents a quick, cost-effective and blood-meal-derived mammalian DNA
and evolution of sexual dimorphism. Nat. Rev. standardised way to obtain basic data prevalence in the leeches. Although
Genet. 10, 797–804.
Williams, T.M., Selegue, J.E., Werner, T., Gompel, on mammalian biodiversity and species multiple clones were sequenced per
N., Kopp, A., and Carroll, S.B. (2008). The occupancy, facilitating efficient use of amplicon, no leech yielded sequences
regulation and evolution of a genetic switch
controlling sexually dimorphic traits in
limited conservation resources. from more than one species, suggesting
Drosophila. Cell 134, 610–623. An emerging tool for assessing that rapid decline in blood meal DNA
Zhao, D., McBride, D., Nandi, S., McQueen, H.A., mammalian biodiversity is the profiling concentration over time (Supplemental
McGrew, M.J., Hocking, P.M., Lewis, P.D.,
Sang, H.M., and Clinton, M. (2010). Somatic of DNA extracted from micropredators. information) will render DNA levels
sex identity is cell autonomous in the chicken. In addition to ticks and mosquitoes [2], derived from a new feeding to be
Nature 464, 237–242.
haematophagous leeches represent greatly higher than those from previous
promising candidates as, following feedings. Two of the detected species
Department of Genetics, Cell Biology, and
Development, University of Minnesota, feeding, they store concentrated blood have been recently described, the
Minneapolis, MN 55455, USA. for several months [3]. Furthermore, Truong Son muntjac (Muntiacus
E-mail: zarko001@umn.edu several studies have demonstrated that truongsonensis, one leech) and