Key Points
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Differences between the brains of males and females are thought to arise largely through the actions of hormones secreted by the gonads. However, there is increasing evidence that X and Y chromosome-linked genes also act directly on the brain to cause sex-specific differences in both mammals and birds.
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The sex chromosomes have evolved under sex-specific selection processes, so that the Y chromosome would be expected to harbour male-benefit sexually antagonistic alleles. The X chromosome would be expected to contain both male-benefit genes and female-benefit genes.
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Because of the sex difference in the number of X chromosomes, mechanisms have evolved to compensate for the potential difference in dosage between expression of these genes in females and males. If dosage is not compensated, this could lead to sex-specific differences in gene expression.
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Genes that control sexual dimorphisms in the brain would be expected to be enriched on the sex chromosomes, because brain function is important for reproductive function and behaviour.
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The gonadal hormones can generate sexual dimorphisms in the brain, but sex differences can, in some cases, be detected before the gonads have differentiated. Further evidence for a direct role of the XX or XY genotype on the brain comes from mice in which the testis-determining Sry gene has been removed from the Y chromosome and replaced on an autosome. In this way, it is possible to generate 'female' mice with an XY− genotype, and 'male' mice with an XXSry genotype. The brains of XX mice differ in several respects from those of XY mice, regardless of the presence or absence of the Sry gene.
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Birds differ from mammals in that the female is heterogametic (with a Z and a W chromosome) and the male has two Z chromosomes. The forebrain song circuit shows marked sexual differentiation, which does not seem to be due solely to gonadal hormones, but rather might result from differences in neuronal sex chromosome genotype. Neuronal transplantation studies in quails also support a role for genetic sex in controlling sexual differentiation in the brain.
Abstract
In birds and mammals, differences in development between the sexes arise from the differential actions of genes that are encoded on the sex chromosomes. These genes are differentially represented in the cells of males and females, and have been selected for sex-specific roles. The brain is a sexually dimorphic organ and is also shaped by sex-specific selection pressures. Genes on the sex chromosomes probably determine the gender (sexually dimorphic phenotype) of the brain in two ways: by acting on the gonads to induce sex differences in levels of gonadal secretions that have sex-specific effects on the brain, and by acting in the brain itself to differentiate XX and XY brain cells.
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References
Arnold, A. P. & Gorski, R. A. Gonadal steroid induction of structural sex differences in the CNS. Ann. Rev. Neurosci. 7, 413–442 (1984).
Breedlove, S. M., Cooke, B. M. & Jordan, C. L. Orthodox view of brain sexual differentiation. Brain Behav. Evol. 54, 8–14 (1999).
Vallender, E. J. & Lahn, B. T. How mammalian sex chromosomes acquired their peculiar gene content. BioEssays 26, 159–169 (2004). Provides a good review of the reasons for the bias in gene content in the sex chromosomes.
Rice, W. R. Sex chromosomes and the evolution of sexual dimorphism. Evolution 38, 735–742 (1984).
Rice, W. R. Sexually antagonistic genes: experimental evidence. Science 256, 1436–1439 (1992).
Lahn, B. T. & Page, D. C. Functional coherence of the human Y chromosome. Science 278, 675–680 (1997).
Skaletsky, H. et al. The male-specific region of the human Y chromosome is a mosaic of discrete sequence classes. Nature 423, 825–837 (2003). This first map of the human Y chromosome led to remarkable conclusions about sex chromosome evolution.
Graves, J. A. M. The origin and function of the mammalian Y chromosome and Y-borne genes — an evolving understanding. BioEssays 17, 311–319 (1995).
Bull, J. J. Evolution of Sex Determining Mechanisms (Benjamin/Cummings, Menlo Park, California, 1983).
Charlesworth, B. The evolution of sex chromosomes. Science 251, 1030–1033 (1991).
Goodfellow, P. N. & Lovell-Badge, R. SRY and sex determination in mammals. Annu. Rev. Genet. 27, 71–92 (1993).
Graves, J. A. From brain determination to testis determination: evolution of the mammalian sex-determining gene. Reprod. Fertil. Dev. 13, 665–672 (2001).
Rice, W. R. Evolution of the Y sex chromosome in animals. BioScience 46, 331–343 (1996).
Burgoyne, P. S. The role of Y-encoded genes in mammalian spermatogenesis. Cell Dev. Biol. 9, 423–432 (1998).
Charlesworth, B. Genome analysis: more Drosophila Y chromosome genes. Curr. Biol. 11, R182–R184 (2001).
Delbridge, M. L. & Graves, J. A. Mammalian Y chromosome evolution and the male-specific functions of Y chromosome-borne genes. Rev. Reprod. 4, 101–109 (1999).
Jegalian, K. & Page, D. C. A proposed path by which genes common to mammalian X and Y chromosomes evolve to become X inactivated. Nature 394, 776–780 (1998).
Rice, W. R. Degeneration of a nonrecombining chromosome. Science 263, 230–232 (1994).
Cline, T. W. & Meyer, B. J. Vive la difference: males vs females in flies vs worms. Ann. Rev. Genet. 30, 637–702 (1996).
Lyon, M. F. X-chromosome inactivation. Curr. Biol. 9, R235–R237 (1999).
Tan, S. S. et al. Cell dispersion patterns in different cortical regions studied with an X-inactivated transgenic marker. Dev. 121, 1029–1039 (1995).
Bittner, R. E., Popoff, I., Shorny, S., Hoger, H. & Wachtler, F. Dystrophin expression in heterozygous mdx/+ mice indicates imprinting of X chromosome inactivation by parentoforigin, tissue, strain and position-dependent factors. Anat. Embryol. (Berl.) 195, 175–182 (1997).
Lingenfelter, P. A. et al. Escape from X inactivation of Smcx is preceded by silencing during mouse development. Nature Genet. 18, 212–213 (1998).
Carrel, L. & Willard, H. F. Heterogeneous gene expression from the inactive X chromosome: an X-linked gene that escapes X inactivation in some human cell lines but is inactivated in others. Proc. Natl Acad. Sci. USA 96, 7364–7369 (1999).
Carrel, L., Cottle, A. A., Goglin, K. C. & Willard, H. F. A first-generation X-inactivation profile of the human X chromosome. Proc. Natl Acad. Sci. USA 96, 14440–14444 (1999).
Brown, C. J. & Greally, J. M. A stain upon the silence: genes escaping X inactivation. Trends Genet. 19, 432–438 (2003).
Xu, J., Burgoyne, P. S. & Arnold, A. P. Sex differences in sex chromosome gene expression in mouse brain. Hum. Mol. Genet. 11, 1409–1419 (2002).
Gibson, J. R., Chippindale, A. K. & Rice, W. R. The X chromosome is a hot spot for sexually antagonistic fitness variation. Proc. R. Soc. Lond. B 269, 499–505 (2002).
Reinke, V. Sex and the genome. Nature Genet. 36, 548–549 (2004).
Hurst, L. D. Evolutionary genomics. Sex and the X. Nature 411, 149–150 (2001).
Wang, P. J., McCarrey, J. R., Yang, F. & Page, D. C. An abundance of X-linked genes expressed in spermatogonia. Nature Genet. 27, 422–426 (2001).
Zechner, U. et al. A high density of X-linked genes for general cognitive ability: a run-away process shaping human evolution? Trends Genet. 17, 697–701 (2001). This paper demonstrates the exceptional density on the X chromosome of genes that are essential for normal brain development, a finding that contributes to the speculation that sex differences in X gene expression could influence the brain.
Khil, P. P., Smirnova, N. A., Ramanienko, P. J. & Camerini-Otero, R. D. The mouse X chromosome in enriched for sex-biased genes not subject to selection by meiotic sex chromosome inactivation. Nature Genet. 36, 642–646 (2004).
Saifi, G. M. & Chandra, H. S. An apparent excess of sex- and reproduction-related genes on the human X chromosome. Proc. R Soc. Lond. B 266, 203–209 (1999).
Lercher, M. J., Urrutia, A. O. & Hurst, L. D. Evidence that the human X chromosome is enriched for male-specific but not female-specific genes. Mol. Biol. Evol. 20, 1113–1116 (2003).
Parisi, M. et al. Paucity of genes on the Drosophila X chromosome showing male-biased expression. Science 299, 697–700 (2003).
Reinke, V. et al. A global profile of germline gene expression in C. elegans. Mol. Cell 6, 605–616 (2000).
Arnold, A. P. & Burgoyne, P. S. Are XX and XY brain cells intrinsically different? Trend Endoc. Metab. 15, 6–11 (2004).
Tordjman, S. et al. Linkage between brain serotonin concentration and the sex-specific part of the Y-chromosome in mice. Neurosci. Lett. 183, 190–192 (1995).
Jutley, J. K. & Stewart, A. D. Genetic analysis of the Y-chromosome of the mouse: evidence for two loci affecting androgen metabolism. Genet. Res. 47, 29–34 (1986).
Maxson, S. C. Searching for candidate genes with effects on an agonistic behavior, offense, in mice. Behav. Genet. 26, 471–476 (1996).
Sluyter, F., Van Oortmerssen, G. A., De Ruiter, A. J. H. & Koolhaas, J. M. Aggression in wild house mice: current state of affairs. Behav. Genet. 26, 489–496 (1996).
Selmanoff, M. K., Goldman, B. D. & Ginsburg, B. E. Serum testosterone, agonistic behavior, and dominance in inbred strains of mice. Horm. Behav. 8, 107–119 (1977).
Selmanoff, M. K., Goldman, B. D., Maxson, S. C. & Ginsburg, B. E. Correlated effects of the Y-chromosome of mice on developmental changes in testosterone levels and intermale aggression. Life Sci. 20, 359–365 (1977).
Selmanoff, M. K., Goldman, B. D. & Ginsburg, B. E. Developmental changes in serum luteinizing hormone, follicle stimulating hormone and androgen levels in males of two inbred mouse strains. Endocrinol. 100, 122–127 (1977).
Lahr, G. et al. Transcription of the Y chromosomal gene, Sry, in adult mouse brain. Mol. Brain Res. 33, 179–182 (1995).
Mayer, A., Mosler, G., Just, W., Pilgrim, C. & Reisert, I. Developmental profile of Sry transcripts in mouse brain. Neurogenet. 3, 25–30 (2000).
Mayer, A., Lahr, G., Swaab, D. F., Pilgrim, C. & Reisert, I. The Y-chromosomal genes SRY and ZFY are transcribed in adult human brain. Neurogenetics 1, 281–288 (1998).
Clepet, C. et al. The human SRY transcript. Hum. Mol. Genet. 2, 2007–2012 (1993).
Harry, J., Koopman, P., Brennan, F., Graves, J. & Renfree, M. B. Widespread expression of the testis-determining gene SRY in a marsupial. Nature Genet. 11, 347–349 (1995).
Watanabe, M., Zinn, A. R., Page, D. C. & Nishimoto, T. Functional equivalence of human X- and Y-encoded isoforms of ribosomal protein S4 consistent with a role in Turner syndrome. Nature Genet. 4, 268–271 (1993).
Graves, J. A., Disteche, C. M. & Toder, R. Gene dosage in the evolution and function of mammalian sex chromosomes. Cytogenet. Cell Genet. 80, 94–103 (1998).
Agate, R. J., Choe, M. & Arnold, A. P. Sex differences in structure and expression of the sex chromosome genes CHD1Z and CHD1W in zebra finches. Mol. Biol. Evol. 21, 384–396 (2004).
Jacobs, G. H. A perspective on color vision in platyrrhine monkeys. Vision Res. 38, 3307–3313 (1998).
Hunt, D. M. et al. Molecular evolution of trichromacy in primates. Vision Res. 38, 3299–3306 (1998).
Morgan, M. J., Adam, A. & Mollon, J. D. Dichromats detect colour-camouflaged objects that are not detected by trichromats. Proc. R. Soc. Lond. B 248, 291–295 (1992).
Dulai, K. S., von Dornum, M., Mollon, J. D. & Hunt, D. M. The evolution of trichromatic color vision by opsin gene duplication in New World and Old World primates. Genome Res. 9, 629–638 (1999).
Surridge, A. K. & Mundy, N. I. Trans-specific evolution of opsin alleles and the maintenance of trichromatic colour vision in Callitrichine primates. Mol. Ecol. 11, 2157–2169 (2002).
Smallwood, P. M. et al. Genetically engineered mice with an additional class of cone photoreceptors: implications for the evolution of color vision. Proc. Natl Acad. Sci. USA 100, 11706–11711 (2003).
Jameson, K. A., Highnote, S. M. & Wasserman, L. M. Richer color experience in observers with multiple photopigment opsin genes. Psychonom. Bull. Rev. 8, 244–261 (2001). This paper provides evidence for a sex difference in colour perception in humans, caused by retinal mosaicism of X-linked photopigment genes.
Hedges, L. V. & Nowell, A. Sex differences in mental test scores, variability, and numbers of high-scoring individuals. Science 269, 41–45 (1995).
Dragich, J., Houwink-Manville, I. & Schanen, C. Rett syndrome: a surprising result of mutation in MECP2. Hum. Mol. Genet. 9, 2365–2375 (2000).
Thornhill, A. R. & Burgoyne, P. S. A paternally imprinted X chromosome retards the development of the early mouse embryo. Development 118, 171–174 (1993).
Arnold, A. P. in Hormones, Brain, and Behavior (eds Pfaff, D. W., Arnold, A. P., Etgen, A., Fahrbach, S. & Rubin, R.) 105–135 (Academic, San Diego, 2002).
Cooke, B., Hegstrom, C. D., Villeneuve, L. S. & Breedlove, S. M. Sexual differentiation of the vertebrate brain: principles and mechanisms. Front. Neuroendocrinol. 19, 323–362 (1998).
Forger, N. G., Hodges, L. L., Roberts, S. L. & Breedlove, S. M. Regulation of motoneuron death in the spinal nucleus of the bulbocavernosus. J. Neurobiol. 23, 1192–1203 (1992).
Burgoyne, P. S. A Y-chromosomal effect on blastocyst cell number in mice. Development 117, 341–345 (1993).
Burgoyne, P. S. et al. The genetic basis of XX–XY differences present before gonadal sex differentiation in the mouse. Phil. Trans. R. Soc. Lond. B 350, 253–260 (1995).
Renfree, M. B. & Short, R. V. Sex determination in marsupials: evidence for a marsupial-eutherian dichotomy. Phil. Trans. R. Soc. Lond. B 322, 41–53 (1988). This classic review and reference 70 highlight one of the most striking examples of a sexual dimorphism that is probably caused by dosage differences in X-linked genes.
Shaw, G., Harry, J. L., Whitworth, D. J. & Renfree, M. B. in Marsupial Biology Recent Research, New Perspectives (eds Saunders, N. & Hinds, L.) 132–141 (University of New South Wales Press Ltd, Sydney, Australia, 1997).
Dewing, P., Shi, T., Horvath, S. & Vilain, E. Sexually dimorphic gene expression in mouse brain precedes gonadal differentiation. Brain Res. Mol. Brain Res. 118, 82–90 (2003).
Pilgrim, Ch. & Reisert, I. Differences between male and female brains: developmental mechanisms and implications. Horm. Metab. Res. 24, 353–359 (1992).
Reisert, I. & Pilgrim, C. Sexual differentiation of monoaminergic neurons — genetic or epigenetic. Trends Neurosci. 14, 467–473 (1991).
Sah, V. P. et al. A subset of p53-deficient embryos exhibit exencephaly. Nature Genet. 10, 175–180 (1995).
Armstrong, J. F., Kaufman, M. H., Harrison, D. J. & Clarke, A. R. High-frequency developmental abnormalities in p53-deficient mice. Curr. Biol. 5, 931–936 (1995).
Cranston, A. et al. Female embryonic lethality in mice nullizygous for both Msh2 and p53. Nature Genet. 17, 114–118 (1997).
Juriloff, D. M. & Harris, M. J. Mouse models for neural tube closure defects. Hum. Mol. Genet. 9, 993–1000 (2000).
Lovell-Badge, R. & Robertson, E. XY female mice resulting from a heritable mutation in the primary testis-determining gene, Tdy. Development 109, 635–646 (1990).
Mahadevaiah, S. K. et al. Mouse homologues of the human AZF candidate gene RBM are expressed in spermatogonia and spermatids, and map to a Y chromosome deletion interval associated with a high incidence of sperm abnormalities. Hum. Mol. Genet. 7, 715–727 (1998).
De Vries, G. J. et al. A model system for study of sex chromosome effects on sexually dimorphic neural and behavioral traits. J. Neurosci. 22, 9005–9014 (2002). This paper provides evidence that confirms the importance of gonadal secretions in sexual differentiation of the brain, but describes a mouse model system in which the complement of sex chromosomes is made independent of the type of gonad, so that the role of each on brain phenotypes can be studied.
Markham, J. A. et al. Sex differences in mouse cortical thickness are independent of the complement of sex chromosomes. Neuroscience 116, 71–75 (2003).
Wagner, C. K. et al. Neonatal mice possessing an Sry transgene show a masculinized pattern of progesterone receptor expression in the brain independent of sex chromosome status. Endocrinology 145, 1046–1049 (2004).
Carruth, L. L., Reisert, I. & Arnold, A. P. Sex chromosome genes directly affect brain sexual differentiation. Nature Neurosci. 5, 933–934 (2002).
Isles, A. R., Davies, W., Burrmann, D., Burgoyne, P. S. & Wilkinson, L. S. Effects on fear reactivity in XO mice are due to haploinsufficiency of a non-PAR X gene: implications for emotional function in Turner's syndrome. Hum. Mol. Genet. 6 July 2004 [epub ahead of print].
Smith, C. A. & Sinclair, A. H. Sex determination: insights from the chicken. BioEssays 26, 120–132 (2004).
Hori, T., Asakawa, S., Itoh, Y., Shimizu, N. & Mizuno, S. Wpkci, encoding an altered form of PKCI, is conserved widely on the avian W chromosome and expressed in early female embryos: implication of its role in female sex determination. Mol. Biol. Cell 11, 3645–3660 (2000).
O'Neill, M. et al. ASW: a gene with conserved avian W-linkage and female specific expression in chick embryonic gonad. Devel. Genes Evol. 210, 243–249 (2000).
Reed, K. J. & Sinclair, A. H. FET-1: a novel W-linked, female specific gene up-regulated in the embryonic chicken ovary. Gene Expr. Patterns 2, 83–86 (2002).
Ceplitis, H. & Ellegren, H. Adaptive molecular evolution of HINTW, a female-specific gene in birds. Mol. Biol. Evol. 21, 249–254 (2004).
Smith, C. A., Katz, M. & Sinclair, A. H. DMRT1 is upregulated in the gonads during female-to-male sex reversal in ZW chicken embryos. Biol. Reprod. 68, 560–570 (2003).
Graves, J. A. Sex and death in birds: a model of dosage compensation that predicts lethality of sex chromosome aneuploids. Cytogenet. Genome Res. 101, 278–282 (2003).
Teranishi, M. et al. Transcripts of the MHM region on the chicken Z chromosome accumulate as non-coding RNA in the nucleus of female cells adjacent to the DMRT1 locus. Chrom. Res. 9, 147–165 (2001).
McQueen, H. A., McBride, D., Miele, G., Bird, A. P. & Clinton, M. Dosage compensation in birds. Curr. Biol. 11, 253–257 (2001).
Ellegren, H. Dosage compensation: do birds do it as well? Trends Genet. 18, 25–28 (2002).
Agate, R. J. et al. Neural not gonadal origin of brain sex differences in a gynandromorphic finch. Proc. Natl Acad. Sci. USA 100, 4873–4878 (2003).
Wade, J. Zebra finch sexual differentiation: the aromatization hypothesis revisited. Microsc. Res. Tech. 54, 354–363 (2001).
Arnold, A. P. Sexual differentiation of the Zebra Finch song system: positive evidence, negative evidence, null hypotheses, and a paradigm shift. J. Neurobiol. 33, 572–584 (1997).
Arnold, A. P. The gender of the voice within: the neural origin of sex differences in the brain. Curr. Opin. Neurobiol. 13, 759–764 (2003).
Holloway, C. C. & Clayton, D. F. Estrogen synthesis in the male brain triggers development of the avian song control pathway in vitro. Nature Neurosci. 4, 1–7 (2001). This paper provides important evidence for a sex difference in de novo oestrogen synthesis in the forebrain of the developing zebra finch, a difference that contributes to further sexual differentiation of the brain.
Dittrich, F., Feng, Y., Metzdorf, R. & Gahr, M. Estrogen-inducible, sex-specific expression of brain-derived neurotrophic factor mRNA in a forebrain song control nucleus of the juvenile zebra finch. Proc. Natl Acad. Sci. USA 96, 7986–7991 (1999).
Kim, Y. H., Perlman, W. R. & Arnold, A. P. Expression of androgen receptor mRNA in zebra finch song system: Developmental regulation by estrogen. J. Comp. Neurol. 469, 535–547 (2004).
Wade, J. & Arnold, A. P. Functional testicular tissue does not masculinize development of the zebra finch song system. Proc. Natl Acad. Sci. USA 93, 5264–5268 (1996).
Schlinger, B. A., Soma, K. K. & London, S. Neurosteroids and brain sexual differentiation. Trends Neurosci. 24, 429–431 (2001). An interesting review of the evidence for neural origin of hormones that contribute to sexual differentiation of the neural song circuit.
Amateau, S. K., Alt, J. J., Stamps, C. L. & McCarthy, M. M. Brain estradiol content in newborn rats: sex differences, regional heterogeneity, and possible de novo synthesis by the female telencephalon. Endocrinology 145, 2906–2917 (2004). This paper provides evidence that the postnatal male rat hippocampus has a higher level of oestradiol than the female hippocampus, possibly because of a sex difference in local synthesis of oestradiol, rather than sex differences in gonadal secretions.
Krets, O. et al. Hippocampal synapses depend on hippocampal estrogen synthesis. J. Neurosci. 24, 5913–5921 (2004).
Hojo, Y. et al. Adult male rat hippocampus synthesizes estradiol from pregnenolone by cytochromes P45017 alpha and P450 aromatase localized in neurons. Proc. Natl Acad. Sci. USA 101, 865–870 (2004).
Fester, L. et al. Hippocampal synapse formation depends on hippocampal estrogen synthesis. Acta Neuropathol. 106, 390 (2003).
Gahr, M. Male Japanese quails with female brains do not show male sexual behaviors. Proc. Natl Acad. Sci. USA 100, 7959–7964 (2003).
De Vries, G. J. Sex differences in adult and developing brains: compensation, compensation, compensation. Endocrinology 145, 1063–1068 (2004).
Acknowledgements
Thanks to Paul Burgoyne, Geert De Vries, Emilie Rissman, Robin Lovell-Badge, Amanda Swain, Eric Vilain, Robert Agate, Jun Xu, Xuqi Chen, Yuichiro Itoh, Barbara Finlay, Andrew Sinclair and Jennifer Graves for discussions of the ideas summarized here. Supported by the National Institutes of Health.
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DATABASES
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OMIM
FURTHER INFORMATION
Encyclopedia of Life Sciences
Glossary
- AUTOSOME
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Any chromosome in a cell that is not a sex chromosome.
- GYNANDROMPORPHIC
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Having both male and female morphological characteristics.
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Arnold, A. Sex chromosomes and brain gender. Nat Rev Neurosci 5, 701–708 (2004). https://doi.org/10.1038/nrn1494
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DOI: https://doi.org/10.1038/nrn1494
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