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XXYY males, however, are also at an increased risk. Comparing the incidence of ASC across different sex aneuploidies does not suggest a simple dosage effect; since the ASC frequently occurs in the context of clear learning disabilities, it could simply be secondary to the latter.

Finally, the X chromosome could affect ASC risk through parentally imprinted genes. Genomic imprinting refers to a process by which genetic effects are influenced according to whether the genes are transmitted through the father or the mother. Ordinarily, this would not result in sex differences, but it will if the imprinting affects the X chromosome. It has been suggested that an imprinted X-locus may explain sex differences in social and communicative skills and the male vulnerability to ASC. This theory was inspired by the finding that, in individuals with TS, social problems are greater when the single X is maternal in origin. Typical females always inherit an X chromosome from both parents, but typical males always have only a maternal X. Creswell and Skuse [27] reported 5 cases of ASC from an unselected sample of 150 subjects with TS. All of the affected cases were X^m or had a structurally abnormal paternal X. While this was an exciting finding, it should be kept in mind that 77% of TS females are X^m, while only 23% are X^p, meaning that by chance alone one would expect to find ASC in association with X^m more often than with X^p. In addition, all of the ASC cases in that report had low verbal IQ scores despite the fact that intelligence is usually in the average range in TS, raising the possibility that the ASC was secondary to intellectual disability.

It is also notable that some of the ASC cases had a structurally abnormal paternal X. TS individuals with small ring X chromosomes often have a severe phenotype that is not typical of TS and includes intellectual disability. In these individuals, the loss of the XIST gene, which is involved in causing X-inactivation, may allow for normally inactivated genes to be expressed, resulting in functional disomy. Finally, the presence of residual Y chromosome sequences in a subset of cells in the brain could explain the greater vulnerability of X^m TS females to social dysfunction, but this hypothesis is untestable without access to brain tissue. Bruining et al. [28] examined whether parent-of-origin of the X chromosomes relates to autistic traits in individuals with Klinefelter syndrome (XXY). The hypothesis of Creswell and Skuse [27] would suggest that X^m X^mY males show more autistic traits than X^m X^pY males, but this was not the case for Autism Diagnostic Interview-Revised (ADI-R) core domain scores.

      The Y Chromosome and Autism Spectrum Conditions

Male-limited expression of genes on the Y chromosome can also produce biased sex ratios. This possibility has attracted very little research attention. Such genes should be located in the nonrecombining region of the Y chromosome. SRY (the sex-determining gene) is expressed in the medial rostral hypothalamus, as well as the frontal and temporal regions of the human brain. In vitro assays suggest that SRY can increase transcription of tyrosine hydroxylase (the rate-limiting enzyme in dopamine biosynthesis). In addition, the knockdown of SRY expression in the substantia nigra of the rat decreases tyrosine hydroxylase expression [see 4 for review]. SRY may also regulate monoamine oxidase A (MAO-A) [4] and brain β-endorphin levels [29]. Other Y-linked genes known to be expressed in the human brain include ZFY and PCDH11Y. A small candidate gene study failed to find associations between variants in PCDH11Y and autism, while ZFY and SRY have not been specifically investigated. Comparison of Y chromosome haplotype groups between cases and controls represents an alternative strategy for identifying Y chromosome effects. Two such studies have been conducted with regard to ASC – one was positive and one was negative [see 4 for review].

      As noted previously, XYY and XXYY males are at an increased risk for ASC, which would be compatible with a role for the Y chromosome. However, it should be noted that an increased risk for ASC may also be present in individuals with Klinefelter syndrome (XXY) which could implicate a pseudoautosomal locus on the sex chromosomes in the etiology of ASC, but this would not necessarily help explain the male bias (as pseudoautosomal regions should act like nonsex chromosomes). Y chromosome effects certainly merit additional research attention, but current evidence is insufficient to determine whether this mechanism could explain the sex bias in ASC.

      Outstanding Issues: Alternative Biological Mechanisms Resulting in Biased Sex Ratios

      There are also a number of other mechanisms which can produce biased sex ratios which have received almost no research attention in relation to ASC, including parental manipulation of the sex ratio, the immunoreactive theory of selective male affliction, and the effects of müllerian inhibiting substance (MIS).

      Parental Manipulation of the Sex Ratio

It has been argued that, whenever a particular environment results in males experiencing greater reproductive success than females (or vice versa), the possibility exists for the evolution of parental mechanisms which vary the sex ratio accordingly [30]. Thus, if autistic traits are more detrimental to women in terms of reproductive fitness (resulting in a decreased number of offspring) as compared to men, parents carrying genes for autistic traits could be under selection to produce sons. While we are not aware of any studies directly comparing the reproductive success of men and women with ASC or their relatives, women with ASC have been reported to have poorer peer relationships compared to males with ASC in adolescence. Also relevant to this hypothesis, it has recently been reported that there is an excess of males in the siblings of children with autism [31] (e.g. the parents of children with ASC produced more sons than daughters).

      The Immunoreactive Theory of Selective Male Affliction

This is a theory that posits that male-specific antigens from male fetuses may enter the maternal circulation and activate the mother’s immune system. The mother then produces antibodies to the male antigen which cross the placental barrier and enter the fetal brain, where they alter brain development [32]. A maternal immune response could also alter brain development through transplacental transfer of proinflammatory cytokines (a different product of the immune system) and an altered hormonal milieu caused by immune system-mediated enlargement of the placenta. Animal research indicates that the immune system of pregnant females does recognize and react to fetal male-specific antigens, male fetuses are more antigenic to human mothers than female fetuses, and male-specific antigens are strongly represented on the surface of brain cells. Relevant to this hypothesis is the observation that mothers of children with ASC show an aberrant immune response to their child’s lymphocytes [33].

      Müllerian Inhibiting Substance

MIS is another hormone produced by the testes. In the developing embryo it causes regression of the Müllerian ducts (which in females develop into the fallopian tube, uterus, and upper portion of the vagina). MIS has been observed to support the survival and differentiation of embryonic motor neurons in vitro [34], which raises the possibility that circulating MIS during embryonic development could play a role in sexual differentiation of the brain and the vulnerability to male-biased neurodevelopmental disorders.

      Outstanding Issues: Sex Differences in Symptomatology

Due to the highly biased

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