Review
The genetics of sex differences in brain and behavior

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Abstract

Biological differences between men and women contribute to many sex-specific illnesses and disorders. Historically, it was argued that such differences were largely, if not exclusively, due to gonadal hormone secretions. However, emerging research has shown that some differences are mediated by mechanisms other than the action of these hormone secretions and in particular by products of genes located on the X and Y chromosomes, which we refer to as direct genetic effects. This paper reviews the evidence for direct genetic effects in behavioral and brain sex differences. We highlight the ‘four core genotypes’ model and sex differences in the midbrain dopaminergic system, specifically focusing on the role of Sry. We also discuss novel research being done on unique populations including people attracted to the same sex and people with a cross-gender identity. As science continues to advance our understanding of biological sex differences, a new field is emerging that is aimed at better addressing the needs of both sexes: gender-based biology and medicine. Ultimately, the study of the biological basis for sex differences will improve healthcare for both men and women.

Introduction

Men and women are different in many ways. These differences include both biological phenotypes [e.g. 191] and psychological traits [e.g. 200]. Some of these differences are influenced by environmental factors [1], [340]. Yet, there are fundamental differences between the sexes that are rooted in biology.

Of particular interest are sex differences that have been identified in the brain. Although the brains of men and women are highly similar, they show consistent differences that have important implications for each sex. That is, brain sex differences uniquely affect biochemical processes, may contribute to the susceptibility to specific diseases, and may influence specific behaviors. Such biological differences should never be used to justify discrimination or sexism. However, we believe that a thorough understanding of these differences can inform researchers and clinicians so that they can better address important issues. Two examples include how genetic sex can lead to differences between the sexes in the etiology and the progression of disease and how differences in neural development may result in differences in cognition and behavior.

In this paper, we will review sex differences in brain and behavior that are not due to the action of hormones secreted by the gonads—which has been the dominant mechanism associated with such differences—but to what we term ‘direct genetic effects.’ These are effects that arise from the expression of X and Y genes within non-gonadal cells and result in sex differences in the functions of those cells. First, we will highlight some sex differences at the biological level and at the psychological level. Then, we will review the ‘classic’ view that dominated the field of sex differences—that most sex differences, especially those concerned with reproductive physiology and behavior, were due to the action of hormones produced by the gonads. Next, we will present the emerging view that ‘direct genetic effects’ play an important role as well. Finally, we will discuss novel approaches to studying sex differences by focusing on unique groups of individuals: people with sex-chromosome variations (e.g., Klinefelter Syndrome and Turner Syndrome), people with genetic mutations in the sexual development pathway, people with an atypical sexual-orientation, and people who experience a cross-gender identity.

Section snippets

Biological sex differences

There are many biological differences between males and females that are beyond the obvious differences at a gross, macro level (e.g., height, weight, and external genitalia). Specifically, there are several important physiological differences that have critical implications including the susceptibility to different diseases and the ability to metabolize different medications. In this section we will highlight some sex differences in neuroanatomy and neurochemistry.

Psychological and behavioral sex differences

In addition to biological differences, men and women differ in many psychological and behavioral aspects. For instance, men perform better on specific visuospatial aspects (e.g., mental rotation) compared to women; and women perform better on specific verbal tasks (e.g., verbal fluency) compared to men [155]. Furthermore, there is a large sex difference in sexual interests and behaviors, such as interest in casual sex, interest in multiple sex partners, and interest in visual-sexual stimuli

The classical view on sex differences

Researchers have examined what contributes to the differences we see between males and females. Certainly for humans, social environments influence some of these differences. For instance, social stratifications (e.g., social class and the distribution of social power) and social rules (e.g., customs and traditions) may affect the ability of people to access educational resources or to engage in certain behaviors [156], [339]. However, social factors alone do not explain all differences seen

An expanded view on sex differences

In light of scientific findings such as the ones presented above (the zebra finch and the tammar wallaby), the field of sex differences has now come to encompass studies that examine gonadal hormone as well as genetic origins of these differences. One of the most significant challenges in studying the establishment of sex differences in animal models has been the difficulty in separating gonadal sex from chromosomal sex. These two parameters almost always correlate in an animal.

In the following

Novel approaches to studying sex differences

Traditional animal models have played an invaluable role in advancing our understanding of sex differences. In particular, scientists are able to conduct experimental manipulations that would be unethical on human subjects. However, research on specific groups of people has addressed some complex questions. In this section, we focus on research conducted on four such groups: people with sex-chromosome variations, people with genetic mutations of the sexual development pathway, people attracted

Conclusion

There are many differences between men and women. In this review, we have focused on brain sex differences because of the role that they play in people’s health and behavior. Historically, it was believed that such differences were solely due to gonadal hormone secretions. Yet, emerging research is also implicating direct genetic effects.

The next challenge will be to first elucidate the molecular mechanisms by which these direct genetic effects on sex differences arise. One way to address this

Acknowledgment

This work was funded in part by the National Institutes of Health (1R01MH075046).

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    These authors contributed equally to this work.

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