Advanced Search Abstract The X-chromosome has played a crucial role in the development of sexually selected characteristics for over million years. During that time it has accumulated a disproportionate number of genes concerned with mental functions. Evidence is emerging, from studies of both humans and mice, for a general influence upon intelligence as indicated by the large number of X-linked mental retardation syndromes.
In addition, there is evidence for relatively specific effects of X-linked genes on social—cognition and emotional regulation. Sexually dimorphic processes could be influenced by several mechanisms.
First, a small number of X-linked genes are apparently expressed differently in male and female brains in mouse models. Secondly, many human X-linked genes outside the X—Y pairing pseudoautosomal regions escape X-inactivation. To date, little is known about the process but clues can be gleaned from the study of X-monosomic females who are haploinsufficient for expression of all non-inactivated genes relative to 46,XX females. Finally, from studies of both X-monosomic humans 45,X and mice 39,X , we are learning more about the influences of X-linked imprinted genes upon brain structure and function.
Surprising specificity of effects has been described in both species, and identification of candidate genes cannot now be far off. There are estimated to be genes on the X-chromosome Ensembl version Why should there be such a concentration on this particular chromosome 1? In particular, males are more likely than females to be influenced by haplotypes that are associated with exceptionally high abilities. For an equivalent reason, they are also more likely to show deficits in mental abilities than females because of the impact of deleterious mutations carried in haploid state.
The hypothesis offers an explanation for the higher male variance in many aspects of cognitive performance 3. Genes on the X-chromosome not only influence general intelligence, but also have relatively specific effects on social—cognition and emotional regulation.
Subsequently, another family has been identified with similar phenotypic associations 6. We, therefore, have a potential explanation for the male preponderance of mental retardation in general, and for isolated heritable cases of autism in males, in particular.
But, we are still some way from understanding the wider male predisposition to a range of neurodevelopmental disorders including reading disabilities 7 , Asperger syndrome, which may be 10 times as common in males as in females 8 and attention deficit hyperactivity disorder 9.
This review shall consider the accumulating evidence that there are several genetic and epigenetic mechanisms that could influence the role of X-linked genes in sexual dimorphism, not only in humans but also in mice, and thus potentially in other mammalian species too.
Mechanisms of sexual dimorphism involving X-linked genes Genes on the X- and Y-chromosomes are of particular importance in the development of differences between the sexes, a fact that might at first sight appear self evident, because the mechanism for mammalian sex-specific differentiation involves the Y-linked gene SRY, but nature is not so transparent The Y-chromosome does indeed contain a substantial proportion of genes that are involved in spermatogenesis 11 , We might reasonably suppose these are on the Y-chromosome because this is evolution's way of ensuring they are expressed only in males.
Surprisingly, many genes involved in spermatogenesis in mice are X-linked 13 and are expressed exclusively in males.
How has this extraordinary situation evolved? Hurst 10 proposes that an X-linked locus is at least three times more likely to be involved in sexual development than is a locus on an autosomal chromosome, especially if that locus is advantageous to males.
Accordingly, the X-chromosome could function as a filter for sexually antagonistic alleles. As the male-advantageous allele frequency increases on the X-chromosome, the proportion of females who are homozygous for that allele which is disadvantageous to them will also increase. Accordingly, deleterious gene-function will become suppressed in females. Logically, we should not be surprised to find a male-biased expression of X-linked genes in clearly sexually dimorphic processes such as spermatogenesis.
The same mechanism may apply to specific higher cognitive functions, if they are associated with some male advantage in adaptation 1. Similarly, if there are mutations in such specialized genes associated with impaired function, these will be manifested more commonly in males than in females.
Skewed patterns of X-inactivation may arise, which will influence the expression of recessive X-linked disease mutations in females. Skewing could also influence expression patterns of common allelic variants in genes that are subject to X-inactivation. There is some limited and controversial evidence to suggest that skewing of X-inactivation normally becomes greater with advancing age, but the implications of that observation if true are unknown.
The potential impact of Y-linked genes on sexual dimorphism is limited, because few different proteins are encoded by the Y-chromosome 12 , All three have human homologues, but their role in human neural development is presently unclear, although worthy of investigation Fig. These regions contain relatively few genes about 12 and are known as pseudoautosomal PAR.
Both X and Y copies are expressed in normal males and females 16 , with presumed dosage equivalence. This is baffling at first sight, because X-inactivation must have evolved for the purpose of ensuring dosage equality in sex chromosome expressed genes between males and females of the species. Because the escapees are interspersed among genes that are subject to X-inactivation, they must be protected in some way. We do not currently know why or how this occurs although there are recent intriguing leads Non-inactivated genes on the X-chromosome that lack a Y-homologue are potential candidates for sexual dimorphism 16 , It should be possible to learn more about their functions in humans by studying females who have but a single X-chromosome and who would, therefore, be haploinsufficient for their products.
The fact that the condition, known clinically as Turner syndrome, is associated with a phenotype results from two main influences. First, there is haploinsufficiency for genes that are normally expressed from both X-chromosomes in females. They fall into two classes: Secondly, because non-inactivated genes contribute to the development and maintenance of ovarian tissues 22 , there is early degeneration of the ovaries and consequent estrogen insufficiency.
Other features include a high arched palate, neck webbing, broad chest, as well as characteristic cardiac and renal anomalies, but the genetic basis for such anomalies is not known.
Textbook descriptions of Turner syndrome often exaggerate the severity of the associated physical anomalies because, until recently, most cases were identified in middle childhood and later-diagnosed cases tend to have more severe phenotypes Occasionally, milder cases are not detected until adulthood—but these are likely to be mosaics rather than purely X-monosomic—about one-half of phenotypic Turner syndrome patients have detectable mosaicism for a second cell line.
This additional cell line may contain a normal 46,XX karyotype in which case the phenotypic features of the syndrome are ameliorated , some structural anomaly of the X-chromosome or, rarely, a partial Y-chromosome lacking critical elements essential for the development of the male phenotype.
In terms of cognitive development, girls with Turner syndrome have normal verbal intelligence, but they are deficient in terms of visuospatial abilities [such as the ability to complete a jigsaw puzzle 25 ]. They also usually have difficulties in arithmetical abilities and may lack even a basic concept of number 26 , implying dosage-sensitive X-linked genes are also involved in numerical cognitive skills and spatial intelligence.
The condition is associated with a substantially increased risk of autism at least times Focussed studies have demonstrated profound face and emotion recognition deficits in a minority 30 , as well as difficulties in the interpretation of direction of other's eye gaze and line of sight The nature and severity of these social—cognitive deficits points to an anomaly in the functioning of neural centres which, for many, is as severe as that reported in cases of bilateral amygdalectomy No genes that contribute to the cognitive or behavioural disorders of Turner syndrome have yet been identified.
Recent research has, however, led to the delineation of a critical region on proximal Xp where a cluster of genes escapes X-inactivation 34 , in which one or more candidate genes appear to be located. There were also increases in grey matter volume in the orbitofrontal cortex bilaterally, close to a region that is implicated in emotional learning. Intriguingly, the increase in amygdala size was even greater than the relative difference normally found between males and females 36 , This implied that sexually dimorphic processes could be involved.
Patients were selected who had variably sized deletions of the short arm of the X-chromosome, some of whom had the brain structural and functional deficits of X-monosomy. Mapping deletion size against phenotype, we identified a genetic locus 4. Within this region lie a number of plausible candidate genes Fig. These include Usp9x, which escapes X-inactivation in humans as well as in mice 15 , and the monoamine oxidase genes MAOA and MAOB , which play an important role in psychiatric adjustment 38 , MAOB enzymatic activity can be measured in platelets.
We found expression was even lower in 45,X females than in normal males 35 indicating the MAOB gene may escape X-inactivation and thus be haploinsufficient in both males and X-monosomic females. This may arise because expression is exclusively from the paternally inherited X-chromosome and thus only in females. Alternatively, expression could be exclusively from the maternally inherited X-chromosome and would be sexually dimorphic if the gene concerned was subject to X-inactivation.
X-linked imprinting could also protect females from deleterious allelic variants of autosomal genes that influence the functions of the social brain Sexual dimorphism in the processing social perceptions and emotional responsiveness 42 , 43 , involves amygdala-related neural circuitry Although there is no simple correlation between individual social—cognitive variables and the parental origin of the single X-chromosome in X-monosomy, more complex relationships between such variables exist, which indicate the role of X-linked imprinting in social adjustment is rather more subtle than was at first suspected.
Previous work had demonstrated X-linked imprinting effects on the volumes of the superior temporal gyrus 46 , as well as on occipital white matter and cerebellar grey matter Using both a hand-traced region of interest approach and VBM, 45,Xm women were shown to possess a significantly larger adjusted right hippocampal volume than 45,Xp subjects personal communication , possibly explaining a prior finding that 45,Xp females have poorer visual memory than 45,Xm females, despite their better social adjustment Dysfunction of the caudate nucleus could lead to abnormal executive function with impaired working memory, planning ability, set-shifting and social cooperation Maternally expressed X-linked genes might, therefore, influence hippocampal development, and paternally expressed genes influence the normal development of the caudate nucleus and thalamus in females.
It used to be thought that the X-monosomic mouse was not a good model for Turner syndrome human X-monosomy because they are fertile and do not have gross phenotypic anomalies in terms of growth or cognitive abilities. On the other hand, there are subtle differences in their behaviour, indicating that dosage-sensitive X-linked genes do influence cognitive and emotional processing in ways that are reminiscent of X-monosomic human females. The behaviour was not influenced by the stage of the oestrus cycle, locomotor activity, response to novelty or the parental origin of the single X-chromosome.
This hypothesis was not supported: Males were also less competent at the task than normal females. The Y-maze, a visual, non-spatial, serial reversal-learning paradigm was used, in which mice were trained to go down one of two goal arms to collect a foodstuff reinforcer. The arm containing the food might be either light or dark. The same authors have compared neural gene expression in the two sets of monosomic mice by microarray analysis to reveal a potentially maternally expressed X-linked imprinted candidate gene, the characterisation of which is ongoing Studies are currently underway to discover whether functionally similar genes on the human X-chromosome are also subject to parent-of-origin specific expression in a study of X-monosomic females.
For reasons that are not yet understood, there is an excess proportion of genes on the X-chromosome that are associated with the development of intelligence, with no obvious links to other significant biological functions. Recent work has suggested that, in the critical Xp11 region that harbours a large number of such XMLR genes 59 , there may be others specialized for abilities such as social intelligence too.
Perhaps subtle polymorphic variations in genes that, when non-functional, lead to serious learning difficulties can have relatively specific modulating influences on intellectual or social abilities A key implication of these findings is that male and female brains may differ not only because of their contrasting genetic constitutions, but also because of their sex-steroid environments, and that differences in cognitive and social abilities between the sexes could be directly linked to the influence of X-chromosome genes.
Recently, we have learned that there is remarkable traffic, in terms of retrotransposition of genes in both directions, between the X-chromosome and the autosomes; sexual antagonism and sex-biased gene expression may be explicable in terms of this remarkable phenomenon A particularly exciting possibility is that genes which are involved in relatively subtle influences upon behaviour in rodents 54 have evolved to modulate human social responses too or were acquiring new cognition-related functions in primates View large Download slide Figure 1.
Relative positions of genes discussed, where known orthologies exist on mouse and human X-chromosomes. Physical distances are shown as marked. Approximate mouse and human map positions from: Confirmatory positions from Ensembl www. Images adapted from Ensembl.
View large Download slide Figure 2.