Download Do the constraints of human speciation cause

Cytogenet Cell Genet 91:300–302 (2000)
Do the constraints of human speciation cause
expression of the same set of genes in brain,
testis, and placenta?
M. Wilda,a D. Bächner,b U. Zechner,c H. Kehrer-Sawatzki,a W. Vogela and
H. Hameistera
a Abteilung
Humangenetik, Universität Ulm, Ulm;
für Zellbiochemie und Klinische Neurobiologie, Universitätskrankenhaus Eppendorf, Hamburg; and
c Abteilung Innere Medizin I, Universität Ulm, Ulm (Germany)
b Institut
Dedicated to Professor Dr. Ulrich Wolf on the occasion of his retirement.
Abstract. Evolution appears to be especially rapid during
speciation, and the genes involved in speciation should be evident in species such as humans that have recently speciated or
are presently in the process of speciation. Haldane’s rule is that
when one sex is sterile or inviable in interspecific F1 hybrids, it
is usually the heterogametic sex. For mammals, this implicates
genes on the X chromosome as those particularly responsible
for speciation. A preponderance of sex- and reproduction-related genes on the X chromosome has been shown repeatedly, but
also mental retardation genes are more frequent on the X chromosome. We argue that brain, testis, and placenta are those
organs most responsible for human speciation. Furthermore,
the high degree of complexity of the vertebrate genome demands coordinate evolution of new characters. This coordination is best attained when the same set of genes is redeployed
for these new characters in the brain, testis, and placenta.
The “biological species concept” (Mayr, 1942) defines a species as an interbreeding population that is reproductively isolated from coexisting other populations. Reproduction barriers
may be active prior to mating (pre-mating effect genes) or after
mating (post-mating effect genes) (Coyne, 1992). Speciation
genes are best studied by backcross analysis of interspecific
hybrids, and, consequently, the post-mating effect genes have
attained much interest in the past (e.g., Davis and Wu, 1996).
Post-mating genetic systems act on fertility and on the number
of offspring that will reach their reproductive age. Fertility
genes are expressed in the testis and observed in their default
state as sterility factors. The genes associated with survival of
the offspring manifest themselves as developmental genes in
the embryo itself and as placental growth factors, which guide
the nutritional supply of the offspring.
The mapping of speciation genes has revealed one general
rule: there is an apparent excess of sex- and reproduction-related genes on the X chromosome (Hurst and Randerson, 1999;
Saifi and Chandra, 1999). As a consequence of this disproportionality, it is the heterogametic sex which suffers most from
sterility and inviability. This is the basis of Haldane’s rule, one
of the general rules in biology: when only one sex is sterile or
inviable in the offspring of interspecies crosses, it is nearly
always the heterogametic sex (Haldane, 1922).
Taking into account the incidence of male sterility or hypofertility in humans, as it becomes obvious in a genetic counseling setting, and the change in the male:female ratio at fertilization (140:100) compared to that at birth (106:100), it is obvious
that the aforementioned post-mating speciation systems are
active in humans up to the present time.
Concerning the pre-mating effect genes, which are obviously
active during human evolution too, the choice of a suitable
mate is the most relevant selection factor. In mammals and in
humans, it is mainly the female’s choice with whom she will
Received 27 July 2000; revision accepted 4 September 2000.
Request reprints from Dr. H. Hameister, Abteilung Humangenetik,
Universität Ulm, Albert-Einstein-Allee 11, D–89070 Ulm (Germany);
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e-mail: [email protected]
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produce offspring (Miller, 1997, 2000). The characters influencing this choice are best studied by the pattern they leave
behind in the genome, i.e., which trait shows a high preponderance to map on the X chromosome.
There is an excess of males among the mentally retarded
(25 % to 30 %), particularly when moderate mental retardation
(MR) is considered (Penrose, 1938). X-linked mental retardation (XLMR) has a prevalence of 1 in every 600 males in the
general population (Herbst and Miller, 1980). During biannual
workshops, new and already known entities are listed (Lubs et
al., 1999). The disproportionate effect of the X chromosome on
mental performance is reflected by the last listing of 178 entities. Mental performance directs human behavior, and it is not
surprising that this is the most attractive character for female
mate choice in humans.
Many of the X-chromosome MR traits are also associated
with urogenital anomalies. Macroscopically visible structural
or endocrine malfunction (hypogonadism) has been observed
in 22 syndromic XLMRs of 68 XLMRs investigated (Lubs et
al., 1999). The fertility state is difficult to prove in mentally
handicapped male patients, but from the pattern of gene
expression, it must be expected that several further XLMR syndromes are combined with sterility or subfertility.
In many instances it has been shown that genes with a differential spatial and temporal expression pattern during development are expressed at the same time in brain and testis (e.g.,
Schmitt et al., 1995). In particular, the high percentage of genes
that are expressed in the mature testis has found extensive
interest in the past (Wolgemuth and Watrin, 1991; Eddy and
O’Brien, 1998). A biological explanation may assign the expression of so many genes in the testis to the exchange of histones
against the more tightly packing protamines (P. Burgoyne, personal communication). But according to this interpretation, the
pattern should be almost the same for all genes. This is definitely not the case. Therefore, one has to give priority to another
explanation for the high percentage of genes specifically expressed in the mature testis, combined with the coincidence of
their specific expression in the brain (the “brains and balls”
phrase). In this context, the nature of the genes in question is of
further interest.
XLMR traits are differentiated into syndromes in which
MR occurs together with other easily recognizable symptoms
and in non-syndromic or unspecific MR, where MR is the only
symptom (Lubs et al., 1999). From a more biologic/developmental point of view, it seems more appropriate to differentiate
between (1) entities of MR due to metabolic defects (including
defects in mitochondrial genes), (2) entities of MR due to developmental defects which lead to obvious brain malformation,
and (3) other, unspecific forms of MR with a grossly normal
brain structure (Allen et al., 1998). Especially interesting are the
genes responsible for the last, the unspecific form of MR.
Recent reviews show that in these entities mutations have been
found in genes which encode for very important proteins that
are active in universally used basic signaling cascades in the cell
(Chelly, 1999; Gècz and Mulley, 2000; Toniolo and D’Adamo,
2000). Several of these genes interfere with the MAPK pathway, which regulates basic cellular processes such as transcriptional reprogramming, differentiation, proliferation, and cyto-
Fig. 1. An example of a putative speciation gene expressed simultaneously in brain, testis, and placenta. RNA in situ hybridizations with an FMR1specific gene probe on tissue sections from different mouse organs. For methods, see Bächner et al. (1993). Left, bright-field illumination; right, darkfield illumination. (A, B) Placenta of a day 14.5 post coitum (pc) embryo;
(C, D) mature testis of an 8-wk-old male; (E, F) horizontal section through the
brain of a day 14.5 pc embryo; (G, H) horizontal section through the nasal
cavities of a day 14.5 pc embryo. Dg = dentate gyrus; dec = decidua; lab =
labyrinth; lp = lamina propria; ne = nasal epithelium; pyl = pyramidal cell
layer; se = ductuli seminiferi; spl = splanchnopleure; spo = spongiotrophoblast; umb = umbilical cord.
skeleton organization responsible for cell movement and
changes in cell shape, such as dendrite outgrowth in neuronal
cells.
It is intriguing to hypothesize that the speciation process
that only very recently led to humans redeploys already existing
genes that have proven to be functional in several pathways
before. This is a scenario that was envisaged long ago by Jacob
(1977). Evolution to higher complexity means acquisition of
pleiotropy: the same genes get redeployed to different functions
within a network of epistatic interactions (Duboule and Wil-
Cytogenet Cell Genet 91:300–302 (2000)
301
kins, 1998; Wolf, 1999). This hypothesis is corroborated by the
recent finding that the number of human genes has to be reconsidered and is certainly much lower than it was expected (The
Chromosome 21 Mapping and Sequencing Consortium, 2000;
Pennisi, 2000). There are no human-specific genes. However,
human-specific functions of otherwise well-conserved genes,
together with human-specific expression patterns of these
genes, must be assumed. Furthermore, speciation seems to
recruit always the same genes for the functions in question in
brain, testis, and placenta. Here we argue that this is a stringent
necessity due to the constraints of the speciation process.
(1) Even at the evolutionary state of the early vertebrate, the
genome was well balanced and had reached a high degree of
complexity. No gross additions (or deletions) of genes have
occurred since that time (Wakefield and Graves, 1996). The
evolution of a new level of organization is due to coordinated
changes in many different organ systems. These changes must
coordinate with an already well-balanced genome. These
changes cannot evolve independently to maximize only a single
function, but must co-evolve with other characters in a way that
the many developmental interactions among them do not
decrease fitness (Strickberger, 2000). This is most easily attained when the same genes are redeployed simultaneously for
all speciation systems. (2) The development of a new character
during speciation has to be intimately correlated with reproductive isolation to not become diluted at once. Again, this is
most easily attained when the same genes are responsible for
speciation and isolation. We have argued before that human
evolution ameliorates particularly brain function. Therefore,
the same genes responsible for enhanced brain function are also
functional in testis (the “brains and balls” phrase).
A prominent example for specific and coordinate expression in brain, testis, and placenta is given in Fig. 1. Here, the
expression pattern is shown for the FMR1 gene, which belongs
to the third group of unspecific MR entities, according to the
definition given above. The FMR1 gene product interferes with
RNA metabolism (Siomi et al., 1993) and is expressed in a specific pattern throughout the whole embryo (Bächner et al.,
1993). As shown in Fig. 1, FMR1 is highly and specifically
expressed in brain, testis, and placenta.
It is fascinating to realize that now we have available the
tools to prove the hypothesis that speciation recruits the same
set of tissue-specific genes that are active in those organs important for speciation. This often-repeated recruitment mechanism may explain the high percentage of genes expressed in
brain, testis, and placenta. Furthermore, a detailed analysis of
the expression pattern will reveal what structures and, therefore, with which functions human evolution proceeds. This is
expected to be especially interesting with respect to brain function. As an example, the expression of FMR1 in the hippocampus and dentate gyrus suggests that FMR1 may have a special
role in learning and memory (Bliss and Collingridge, 1993;
Tsien et al., 1996). Further analysis of unspecific MR genes in
the same manner will provide insights into one of the most fascinating evolutionary processes in the last 7 million years.
References
Allen KM, Gleeson JG, Bagrodia S, Partington MW,
MacMillan JC, Cerione RA, Mulley JC, Walsh CA:
PAK3 mutation in nonsyndromic X-linked mental
retardation. Nature Genet 20:25–30 (1998).
Bächner D, Manca A, Steinbach P, Wöhrle D, Just W,
Vogel W, Hameister H, Poustka A: Enhanced expression of the murine FMR1 gene during germ
cell proliferation suggests a special function in both
the male and the female gonad. Hum molec Genet
2:2043–2050 (1993).
Bliss TVP, Collingridge GL: A synaptic model of memory: long-term potentiation in the hippocampus.
Nature 361:31–39 (1993).
Chelly J: Breakthroughs in molecular and cellular
mechanisms underlying X-linked mental retardation. Hum molec Genet 8:1833–1838 (1999).
Coyne JA: Genetics and speciation. Nature 355:511–
515 (1992).
Davis AW, Wu CI: The broom of the sorcerer’s apprentice: the fine structure of a chromosomal region
causing reproductive isolation between two sibling
species of Drosophila. Genetics 143:1287–1298
(1996).
Duboule D, Wilkins AS: The evolution of “bricolage.”
Trends Genet 14:54–59 (1998).
Eddy EM, O’Brien DA: Gene expression during mammalian meiosis. Curr Top dev Biol 37:141 (1998).
Gécz J, Mulley J: Genes for cognitive function: developments on the X. Genome Res 10:157–163
(2000).
302
Haldane JBS: Sex-ratio and unisexual sterility in hybrid
animals. J Genet 21:101–109 (1922).
Herbst DS, Miller JR: Non-specific X-linked mental
retardation. II The frequency in British Columbia.
Am J med Genet 28:378–382 (1980).
Hurst LD, Randerson JP: An eXceptional chromosome. Trends Genet 15:383–385 (1999).
Jacob F: Evolution and tinkering. Science 196:1161–
1166 (1977).
Lubs H, Chiurazzi P, Arena J, Schwartz C, Tranebjaerg
L, Neri G: XLMR genes: update 1998. Am J med
Genet 83:237–247 (1999).
Mayr E: Systematics and the Origin of Species (Columbia University Press, New York 1942).
Miller GF: Mate choice: from sexual cues to cognitive
adaptions. Ciba Found Symp 208:71–82 (1997).
Miller GF: Mental traits as fitness indicators: expanding evolutionary psychology’s adaptationism. Ann
NY Acad Sci 907:62–74 (2000).
Pennisi E: And the gene number is ...? Science 288:
1146–1147 (2000).
Penrose LS: A clinical and genetic study of 1280 cases
of mental defects (The Colchester Survey). MRC
Special Report 229 (Her Majesty’s Stationery Office, London 1938).
Saifi GM, Chandra HS: An apparent excess of sex- and
reproduction-related genes on the human X-chromosome. Proc R Soc, Lond B 266:203–209
(1999).
Cytogenet Cell Genet 91:300–302 (2000)
Schmitt I, Bächner D, Megow D, Henklein P, Hameister H, Epplen JT, Riess O: Expression of the Huntington disease gene in rodents: cloning of the rat
homologue and evidence for downregulation in
non-neuronal tissues during development. Hum
molec Genet 4:1173–1182 (1995).
Siomi H, Siomi MC, Nussbaum RL, Dreyfuss G: The
protein product of the fragile X gene, FMR1, has
characteristics of an RNA binding protein. Cell 74:
291–298 (1993).
Strickberger MW: Evolution, 3rd Ed (Jones and Bartlett Publishing, Sudbury 2000).
The Chromosome 21 Mapping and Sequencing Consortium: The DNA sequence of human chromosome 21. Nature 405:311–319 (2000).
Toniolo D, D’Adamo P: X-linked non-specific mental
retardation. Curr Opin Genet Dev 10:280–285
(2000).
Tsien JZ, Huerta PT, Tonegawa S: The essential role of
hippocampal CA 1 NMDA receptor-dependent
synaptic plasticity in spatial memory. Cell 87:
1327–1338 (1996).
Wakefiled MJ, Graves JAM: Comparative maps of vertebrates. Mammal Genome 7:715–716 (1996).
Wolf U: Sex-determining genes as a model of the evolutionary origin of pleiotropy. Fourth International
Symposion on Genetics, Health and Disease, 1–4
December 1998, Amritsar, India.
Wolgemuth DJ, Watrin F: List of cloned mouse genes
with specific expression pattern during spermatogenesis. Mamm Genome 1:283–288 (1991).