Using the tools of genetic epidemiology to understand sex differences in neuropsychiatric disorders

Many neuropsychiatric disorders exhibit differences in prevalence, age of onset, symptoms or course of illness between males and females. For the most part, the origins of these differences are not well understood. In this article, we provide an overview of sex differences in psychiatric disorders including autism spectrum disorder (ASD), attention deficit/hyperactivity disorder (ADHD), anxiety, depression, alcohol and substance abuse, schizophrenia, eating disorders and risk of suicide. We discuss both genetic and nongenetic mechanisms that have been hypothesized to underlie these differences, including ascertainment bias, environmental stressors, X‐ or Y‐linked risk loci, and differential liability thresholds in males and females. We then review the use of twin, family and genome‐wide association approaches to study potential genetic mechanisms of sex differences and the extent to which these designs have been employed in studies of psychiatric disorders. We describe the utility of genetic epidemiologic study designs, including classical twin and family studies, large‐scale studies of population registries, derived recurrence risks, and molecular genetic analyses of genome‐wide variation that may enhance our understanding sex differences in neuropsychiatric disorders.     

Sex-different response in growth traits to resource heterogeneity explains male-biased sex ratio

In dioecious plants, differences in growth traits between sexes in a response to micro-environmental heterogeneity may affect sex ratio bias and spatial distributions. Here, we examined sex ratios, stem growth traits and spatial distribution patterns in the dioecious clonal shrub Aucuba japonica var. borealis, in stands with varying light intensities. We found that male stems were significantly more decumbent (lower height/length ratio) but female stems were upright (higher height/length ratio). Moreover, we found sex-different response in stem density (no. of stems per unit area) along a light intensity gradient; in males the stem density increased with increases in canopy openness, but not in females. The higher sensitivity of males in increasing stem density to light intensity correlated with male-biased sex ratio; fine-scale sex ratio was strongly male-biased as canopy openness increased. There were also differences between sexes in spatial distributions of stems. Spatial segregation of sexes and male patches occupying larger areas than female patches might result from vigorous growth of males under well-lit environments. In summary, females and males showed different growth responses to environmental variation, and this seemed to be one of possible causes for the sex-differential spatial distributions and locally biased sex ratios.     

Social Cognition,the Male Brain and the Autism Spectrum

Behavioral studies have shown that, at a population level, women perform better on tests of social cognition and empathy than men. Furthermore Autism Spectrum Disorders (ASDs), which are characterized by impairments in social functioning and empathy, occur more commonly in males than females. These findings have led to the hypothesis that differences in the functioning of the social brain between males and females contribute to the greater vulnerability of males to ASD and the suggestion that ASD may represent an extreme form of the male brain. Here we sought to investigate this hypothesis by determining: (i) whether males and females differ in social brain function, and (ii) whether any sex differences in social brain function are exaggerated in individuals with ASD. Using fMRI we show that males and females differ markedly in social brain function when making social decisions from faces (compared to simple sex judgements) especially when making decisions of an affective nature, with the greatest sex differences in social brain activation being in the inferior frontal cortex (IFC). We also demonstrate that this difference is exaggerated in individuals with ASD, who show an extreme male pattern of IFC function. These results show that males and females differ significantly in social brain function and support the view that sex differences in the social brain contribute to the greater vulnerability of males to ASDs.     

Detection of female mating status using chemical signals and cues

Males of many species choose their mate according to the female's reproductive status, and there is now increasing evidence that male fitness can depend on this discrimination. However, females will also aim to regulate their mating activity so as to maximize their own fitness. As such, both sexes may attempt to dictate the frequency and timing of female mating, reflecting the potentially different costs of female signaling to both sexes. Here, I review evidence that chemical cues and signals are used widely by males to discriminate between mated and unmated females, and explore the mechanisms by which female odour changes post‐mating. There is substantial empirical evidence that mated and unmated females differ in their chemical profile, and that this variation provides males with information on a female's mating status. Although there appears to be large variation among species regarding the mechanisms by which female odour is altered post‐mating, the transfer of male substances to females during or subsequent to copulation appear to play a major role. This transfer of substances by males may be part of their strategy to suppress reproduction by competing males, particularly in species where females mate more than once.     

Why Are Autism Spectrum Conditions More Prevalent in Males?

Autism Spectrum Conditions (ASC) are much more common in males, a bias that may offer clues to the etiology of this condition. Although the cause of this bias remains a mystery, we argue that it occurs because ASC is an extreme manifestation of the male brain. The extreme male brain (EMB) theory, first proposed in 1997, is an extension of the Empathizing-Systemizing (E-S) theory of typical sex differences that proposes that females on average have a stronger drive to empathize while males on average have a stronger drive to systemize. In this first major update since 2005, we describe some of the evidence relating to the EMB theory of ASC and consider how typical sex differences in brain structure may be relevant to ASC. One possible biological mechanism to account for the male bias is the effect of fetal testosterone (fT). We also consider alternative biological theories, the X and Y chromosome theories, and the reduced autosomal penetrance theory. None of these theories has yet been fully confirmed or refuted, though the weight of evidence in favor of the fT theory is growing from converging sources (longitudinal amniocentesis studies from pregnancy to age 10 years old, current hormone studies, and genetic association studies of SNPs in the sex steroid pathways). Ultimately, as these theories are not mutually exclusive and ASC is multi-factorial, they may help explain the male prevalence of ASC.     

Optimal Mate Searching Strategy in the Symbiotic Spider Crab Inachus phalangium (Decapoda)

The reproductive strategy of the symbiotic spider crab, Inachus phalangium was studied from 1981 to 1983 in the natural environment. Main study focus was the efficiency of males in search of mates. I. phalangium females are site-constant, and live in the protection of one anemone or group. Males travel frequently between anemones harbouring females due to spawn; they copulate and guard the females until spawning, after which the male leaves again. A male operates in a patrol area containing 3–8 anemone groups and up to 8 females, visiting each female in turn repeatedly just before it is due to spawn. Patrol areas of different males may overlap, with resulting competition to fertilize a female's next brood. Large males have higher reproductive success than small ones. Females live up to 8 months after the moult of puberty and hatch up to six broods, and males live up to 7 months as adults. A male could fertilize a calculated 26,000 eggs, whilst a female's reproductive potential is ca. 4,200 eggs. Mortality risks are higher for males than for females, probably because of increased predation while leaving the protection of anemones in order to visit females. Males learn the positions of anemones harbouring females in their patrol areas, and when these are due to spawn. This allows a male to travel with a target and arrive punctually to fertilize the next brood due in his circuit. I. phalangium is the first marine invertebrate reported to use a “schedule” of localities and times for visiting prespawning females. In this way males minimize searching time and mortality risk, and maximize the number of broods fertilized.     

Frequency of acrocentric association in abnormal sexual development in males and females

A significant difference (P less than 0.05) was observed in a chi 2 comparison of DD, GG and DG-DI associations between male hypogonads and females with primary amenorrhea. This difference increased still further (P less than 0.01) when only DD and GG associations were compared between males and females with abnormal sexual development (ASD). Similarly, when normal males and females were compared for DI, TRI, TETRA, DD vs GG and DG vs GG acrocentric chromosome associations, a significant difference (P less than 0.05) was again observed. The sex difference was also apparent in TRI and TETRA acrocentric associations both in abnormal and normal sexual development males and females. These results suggested that probably sex difference (may be hormonal) influences the number and/or type of acrocentric chromosomes involved in association between males and females with ASD and also between normal males and females.     

Constrained sex allocation in a parasitoid due to variation in male quality

The theory of constrained sex allocation posits that when a fraction of females in a haplodiploid population go unmated and thus produce only male offspring, mated females will evolve to lay a female-biased sex ratio. I examined evidence for constrained sex ratio evolution in the parasitic hymenopteran Uscana semifumipennis. Mated females in the laboratory produced more female-biased sex ratios than the sex ratio of adults hatching from field-collected eggs, consistent with constrained sex allocation theory. However, the male with whom a female mated affected her offspring sex ratio, even when sperm was successfully transferred, suggesting that constrained sex ratios can occur even in populations where all females succeed in mating. A positive relationship between sex ratio and fecundity indicates that females may become sperm-limited. Variation among males occurred even at low fecundity, however, suggesting that other factors may also be involved. Further, a quantitative genetic experiment found significant additive genetic variance in the population for the sex ratio of offspring produced by females. This has only rarely been demonstrated in a natural population of parasitoids, but is a necessary condition for sex ratio evolution. Finally, matings with larger males produced more female-biased offspring sex-ratios, suggesting positive selection on male size. Because the great majority of parasitic hymenoptera are monandrous, the finding of natural variation among males in their capacity to fertilize offspring, even after mating successfully, suggests that females may often be constrained in the sex allocation by inadequate number or quality of sperm transferred.     

Influence of male mating history on female reproductive success among monandrous Naryciinae (Lepidoptera: Psychidae)

1. Multiple male copulations can have detrimental effects on female fitness due to sperm limitation. 2. Monandrous Naryciinae females are immobile while the males are short‐lived and do not feed. Multiple male mating is therefore expected to lead to sperm limitation in females. Sperm limitation and male limitation are hypothesised as causes of the repeated evolution of parthenogenetic reproduction in the Psychidae. 3. In this study, the effects of multiple male mating on female reproduction are investigated in several species of Naryciinae by allowing males multiple copulations. The results for two species, Siederia listerella and Dahlica lichenella, are compared. The sex ratios of 53 natural populations are examined for indications of male limitation. 4. Previous copulations by the male increased the female's risk of remaining unfertilised. However, contrary to expectations, those unfertilised females were capable of successful re‐mating. 5. In S. listerella, the number of previous copulations of males negatively influenced female fitness. Females produced 30% fewer offspring if they mated with a previously mated male. In D. lichenella, the older the male and the lower its number of total lifetime copulations, the higher the female's reproductive success. 6. Only a fraction of the investigated populations had a female‐skewed sex ratio, but differences in development time between males and females could lead to reproductive asynchrony. 7. In conclusion, male mating history did not lead to strong sperm limitation in Naryciinae as had been suggested by their life history.     

FEMALE PREFERENCE FOR MALE COURTSHIP EFFORT CAN DRIVE THE EVOLUTION OF MALE MATE CHOICE

The evolution of male mate choice is constrained by costs of choice in species with a male‐biased operational sex ratio (OSR). Previous theoretical studies have shown that significant benefits of male choice are required, for example, by mating with more fecund females, in order for these costs to be offset and a male preference to spread. In a series of population genetic models we show the novel effect that male mating preference, expressed as a bias in courtship, can spread when females prefer, and thus are more likely to mate with, males who court more. We explore two female preference functions for levels of male courtship, one representing a threshold and the other a weighted female preference. The basic finding generally holds for both preference functions. However, the preference function greatly affects the spread of a male preference allele after the addition of competing males who can court more in total. Our results thus stress that a thorough understanding of the response of females to male courtship is a critical component to understanding male preference evolution in polygynous species.     

Sex ratios observed in 80 species of parrots

A number of potential evolutionary and physiological factors may be involved in avian sex ratio bias so that under certain conditions a sex ratio bias may favour males or females within a population. In addition different factors may be important in manipulating sex ratio bias through the different life stages. In this study sex ratio bias was examined in a total of 16 570 captive parrots, representing 80 species, many of which are endangered in the wild, using database records originating form commercial laboratories that offer genetic sexing. Within the species examined 72% showed a male bias this was significant in three species, when adjusted for multiple comparisons. This preliminary study is limited due to lack of data on the age of the individuals sampled. However, the large dataset do suggest that this phenomenon should be further considered by investigators working at a species level where such data can be collected.     

Male-biased sex ratios in broods of the cooperatively breeding bell miner Manorina melanophrys

We examined the sex ratios of adults and nestlings in the cooperatively breeding bell miner Manorina melanophrys . Males were over-represented among helpers (mean of 6.8 male helpers per nest compared to 0.3 female helpers). 58% of nestlings sampled were identified as male using a molecular genetic marker. This was a significant departure from parity, yet the magnitude of the bias varied between years. The beneficial and male-biased nature of helping behaviour in this species and the similar size of male and female nestlings suggest the net cost of raising males is lower than the cost of raising females. Consequently, the male-biased sex ratio of nestlings we observed is consistent with the predictions of the repayment hypothesis that females may bias the production of their young towards the more helpful sex. Difficulties of generating quantitative predictions from repayment models that can be tested in the field are discussed.     

Costs and benefits of giant sperm and sperm storage organs in Drosophila melanogaster

In Drosophila, long sperm are favoured in sperm competition based on the length of the female's primary sperm storage organ, the seminal receptacle (SR). This sperm–SR interaction, together with a genetic correlation between the traits, suggests that the coevolution of exaggerated sperm and SR lengths may be driven by Fisherian runaway selection. Here, we explore the costs and benefits of long sperm and SR genotypes, both in the sex that carries them and in the sex that does not. We measured male and female fitness in inbred lines of Drosophila melanogaster derived from four populations previously selected for long sperm, short sperm, long SRs or short SRs. We specifically asked: What are the costs and benefits of long sperm in males and long SRs in females? Furthermore, do genotypes that generate long sperm in males or long SRs in females impose a fitness cost on the opposite sex? Answers to these questions will address whether long sperm are an honest indicator of male fitness, male post‐copulatory success is associated with male precopulatory success, female choice benefits females or is costly, and intragenomic conflict could influence evolution of these traits. We found that both sexes have increased longevity in long sperm and long SR genotypes. Males, but not females, from long SR lines had higher fecundity. Our results suggest that sperm–SR coevolution is facilitated by both increased viability and indirect benefits of long sperm and SRs in both sexes.     

Biological factors underlying sex differences in neurological disorders

The prevalence, age of onset, pathophysiology, and symptomatology of many neurological and neuropsychiatric conditions differ significantly between males and females. Females suffer more from mood disorders such as depression and anxiety, whereas males are more susceptible to deficits in the dopamine system including Parkinson's disease (PD), attention-deficit hyperactivity disorder (ADHD), schizophrenia, and autism spectrum disorders (ASD). Until recently, these sex differences have been explained solely by the neuroprotective actions of sex hormones in females. Emerging evidence however indicates that the sex chromosome genes (i.e. X- and Y-linked genes) also contribute to brain sex differences. In particular, the Y-chromosome gene, SRY (Sex-determining Region on the Y chromosome) is an interesting candidate as it is expressed in dopamine-abundant brain regions, where it regulates dopamine biosynthesis and dopamine-mediated functions such as voluntary movement in males. Furthermore, SRY expression is dysregulated in a toxin-induced model of PD, suggesting a role for SRY in the pathogenesis of dopamine cells. Taken together, these studies highlight the importance of understanding the interplay between sex-specific hormones and sex-specific genes in healthy and diseased brain. In particular, better understanding of regulation and function of SRY in the male brain could provide entirely novel and important insights into genetic factors involved in the susceptibility of men to neurological disorders, as well as development of novel sex-specific therapies.     

Sex differences in juvenile mouse social behavior are influenced by sex chromosomes and social context

Play behavior in juvenile primates, rats and other species is sexually dimorphic, with males showing more play than females. In mice, sex differences in juvenile play have only been examined in out-bred CD-1 mice. In this strain, contrary to other animals, male mice display less play soliciting than females. Using an established same-sex dyadic interaction test, we examined play in in-bred C57BL/6J (B6) 21-day-old mice. When paired with non-siblings, males tended to be more social than females, spending more time exploring the test cage. Females displayed significantly more anogenital sniffing and solicited play more frequently than did males. To determine if the origin of the sex difference was sex chromosome genes or gonadal sex, next we used the four core genotype mouse. We found significant interactions between gonadal sex and genotype for several behaviors. Finally, we asked if sibling pairs (as compared to non-siblings) would display qualitatively or quantitatively different behavior. In fact, XX females paired with a sibling were more social and less exploratory or investigative, whereas XY males exhibited less investigative and play soliciting behaviors in tests with siblings. Many neurobehavioral disorders, like autism spectrum disorder (ASD), are sexually dimorphic in incidence and patients interact less than normal with other children. Our results suggest that sex chromosome genes interact with gonadal hormones to shape the development of juvenile social behavior, and that social context can drastically alter sex differences. These data may have relevance for understanding the etiology of sexually dimorphic disorders such as ASD.     

How Do Females’ Genetic Characteristics Influence Male Mate Preference in the Terrestrial Isopod Armadillidium vulgare?

Genetic diversity is a key factor that can influence mate choice in many species. We experimentally determined the influence of this factor on mate preference in the crustacean terrestrial isopod Armadillidium vulgare. This biological model is gregarious which could increase the risk of inbreeding by mating with closely related partners. Mechanisms of inbreeding avoidance during mate choice can thus be expected. Moreover, previous studies predict that males would be the choosy sex. We performed Y‐choice tests giving males the choice between two females presenting different levels of heterozygosity and genetic similarity to the male. Our results show potential inbreeding avoidance according to the genetic characteristics of females presented to males. The higher the variation in genetic similarity to the male between females is, the higher the preference of the male towards the most dissimilar female is. Hence, male preferences may only be detectable when the difference between females’ genetic characteristics is large enough. If heterozygosity is associated with fitness in A. vulgare (as in many organisms), the patterns of mate preference we observe may be adaptive.     

The operational sex ratio influences choosiness in a pipefish

If more females than males are available for mating in the breedingpopulation (i.e., the operational sex ratio, OSR, is femalebiased), males can afford to be choosy. In the pipefish (Syngnathustyphle) females compete for males, who are choosy. In natureOSRs are typically female biased, but may occasionally be malebiased. In a series of experiments, males were allowed to choosebetween a large and a small female under a perceived excessof either males or females. Under female bias, males preferredthe large female: they spent more time close to her than tothe small female; they courted the large female sooner thanthe small; and they tended to copulate sooner and more oftenwith the large female. Under male bias all these differencesvanished and males mated at random with respect to female size.Males reproduced at a faster rate under male than under femalebias because they received more eggs in their brood pouches.Thus, males switched from maximizing mate quality (i.e., beingchoosy) to minimizing the risk of not reproducing (i.e., beingquick) as the OSR became male biased.     

Male phenotypic quality influences offspring sex ratio in a polygynous ungulate

Evolutionary models of sex ratio adjustment applied to mammals have ignored that females may gain indirect genetic benefits from their mates. The differential allocation hypothesis (DAH) predicts that females bias the sex ratio of their offspring towards (more costly) males when breeding with an attractive male. We manipulated the number of available males during rut in a polygynous ungulate species, the reindeer (Rangifer tarandus), and found that a doubling of average male mass (and thus male attractiveness) in the breeding herd increased the proportion of male offspring from approximately 40 to 60%. Paternity analysis revealed indeed that males of high phenotypic quality sired more males, consistent with the DAH. This insight has consequences for proper management of large mammal populations. Our study suggests that harvesting, by generating a high proportion of young, small and unattractive mates, affects the secondary sex ratio due to differential allocation effects in females. Sustainable management needs to consider not only the direct demographic changes due to harvest mortality and selection, but also the components related to behavioural ecology and opportunities for female choice.     

Testing the ‘Extreme Female Brain’ Theory of Psychosis in Adults with Autism Spectrum Disorder with or without Co-Morbid Psychosis

Introduction

Males and females in the general population differ, on average, in their drive for empathizing (higher in females) and systemizing (higher in males). People with autism spectrum disorder (ASD) show a drive for systemizing over empathizing, irrespective of sex, which led to the conceptualisation of ASD as an ‘extreme of the typical male brain’. The opposite cognitive profile, an ‘extreme of the typical female brain’, has been proposed to be linked to conditions such as psychosis and mania/hypomania.

Methods

We compared an empathizing-over-systemizing bias (for short ‘empathizing bias’) in individuals with ASD, who had experienced psychotic illness (N = 64) and who had not (N = 71).

Results

There were overall differences in the distribution of cognitive style. Adults with ASD who had experienced psychosis were more likely to show an empathizing bias than adults with ASD who had no history of psychosis. This was modulated by IQ, and the group-difference was driven mainly by individuals with above-average IQ. In women with ASD and psychosis, the link between mania/hypomania and an empathizing bias was greater than in men with ASD.

Conclusions

The bias for empathizing over systemizing may be linked to the presence of psychosis in people with ASD. Further research is needed in a variety of clinical populations, to understand the role an empathizing bias may play in the development and manifestation of mental illness.     

Evolution of pseudo-arrhenotoky

In arrhenotokous arthropods, males arise from unfertilized eggs. Hence, by controlling the fertilization process mothers can adjust the sex ratio in their offspring. In pseudo-arrhenotokous phytoseiid mites, however, males are haploid, but arise from fertilized eggs. The haploid state is achieved through elimination of the paternal chromosome set during embryonic development. It is shown in this paper that phytoseiid females can control the sex ratio in their offspring and that this control seems as flexible as in arrhenotokous arthropods. As predicted by current evolutionary theory of sex allocation, sex ratios approached half males/half females under random mating, whereas a female bias was observed under sib-mating. The importance of these results for understanding the adaptive significance of pseudo-arrhenotoky is discussed. It is suggested that arrhenotoky is selected for when there is a substantial risk to the females of remaining unmated. When this risk of becoming a wall-flower is low, pseudo-arrhenotoky may evolve because it retains the possibility to reinstal lost genetic information in the maternally derived chromosome by using the paternal chromosome as a template for DNA-repair. The retention of the diploid state in males during embryonic development may thus have certain advantages. It is argued that pseudo-arrhenotoky may be an adaptive genetic system under certain conditions, and not an unstable system that readily reverts to diploidy or evolves towards arrhenotoky or thelytoky.