Precision medicine requires understanding how both sex and gender influence health

Stachenfeld, Nina S.; Mazure, Carolyn M.

doi:10.1016/j.cell.2022.04.012

Cited by 17 publications

(8 citation statements)

References 14 publications

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“…However, a growing body of evidence from traditionally under-represented populations suggests that in fact sex and gender disparities in many diseases are more variable than previously believed (Abarca-Gómez et al, 2017;Mills et al, 2020;Reynolds et al, 2020;Zhou et al, 2017). The results of the present study imply that our understanding of sex-linked risk factors and sex as a biological variable (Clayton, 2018;Stachenfeld & Mazure, 2022) will increase in complexity as genomic epidemiology studies incorporate more diverse populations. Sex and gender disparities in health are not due solely to universal biological differences between males and females, nor is variation in these disparities solely a product of cultural and behavioral diversity; instead, the impact of sex on health and disease depends on complex interactions between population-level genetic adaptation to ancestral environments and physiological responses to contemporary socio-ecologies.…”

Section: Discussionmentioning

confidence: 57%

Sex-biased gene regulation varies across human populations as a result of adaptive evolution

Reynolds

Niedbalski

2023

Preprint

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Human males and females exhibit a wide range of diversity in biology and behavior. However, studies of sexual dimorphism and gender disparities in health generally emphasize ostensibly universal molecular sex differences, such as sex chromosomes and circulating hormone levels, while ignoring the extraordinary diversity in biology, behavior, and culture acquired by different human populations over their unique evolutionary histories. Using RNA-Seq data and whole genome sequences from 11 human populations, we investigate variation in sex-biased gene expression across human populations and test whether population-level variation in sex-biased expression may have resulted from adaptive evolution in sex-specific regulatory regions. In tests for differential expression, we find that sex-biased gene expression in humans is highly variable, mostly population-specific, and demonstrates between-population reversals. Expression quantitative trait locus (eQTL) mapping reveals sex-specific regulatory regions with evidence of recent positive natural selection, suggesting that variation in sex-biased expression may have evolved as an adaptive response to ancestral environments experienced by human populations. These results indicate that sex-biased gene expression is more flexible than previously thought and is not generally shared among human populations. Instead, molecular phenotypes associated with sex depend on complex interactions between population-specific molecular evolution and physiological responses to contemporary socioecologies.

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Section: Discussionmentioning

confidence: 57%

Sex-biased gene regulation varies across human populations as a result of adaptive evolution

Reynolds

Niedbalski

2023

Preprint

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show abstract

“…However, a growing body of evidence from traditionally underrepresented populations suggests that in fact sex and gender disparities in many diseases are more variable than previously believed (Abarca‐Gómez et al, 2017; Mills et al, 2020; Reynolds et al, 2020; Zhou et al, 2017). The results of the present study imply that our understanding of sex‐linked risk factors and sex as a biological variable (Clayton, 2018; Stachenfeld & Mazure, 2022) will increase in complexity as genomic epidemiology studies incorporate more diverse populations. Sex and gender disparities in health are not due solely to universal biological differences between males and females, nor is variation in these disparities solely a product of cultural and behavioral diversity; instead, the impact of sex on health and disease depends on complex interactions between population‐level genetic adaptation to ancestral environments and physiological responses to contemporary socio‐ecologies.…”

Section: Discussionmentioning

confidence: 80%

Sex‐biased gene regulation varies across human populations as a result of adaptive evolution

Reynolds,

Niedbalski

2023

American Journal of Biological Anthropology

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ObjectivesStudies of human sexual dimorphism and gender disparities in health focus on ostensibly universal molecular sex differences, such as sex chromosomes and circulating hormone levels, while ignoring the extraordinary diversity in biology, behavior, and culture acquired by different human populations over their unique evolutionary histories.Materials and MethodsUsing RNA‐Seq data and whole genome sequences from 1000G and HGDP, we investigate variation in sex‐biased gene expression across 11 human populations and test whether population‐level variation in sex‐biased expression may have resulted from adaptive evolution in regions containing sex‐specific regulatory variants.ResultsWe find that sex‐biased gene expression in humans is highly variable, mostly population‐specific, and demonstrates between population reversals. Expression quantitative trait locus mapping reveals sex‐specific regulatory regions with evidence of recent positive natural selection, suggesting that variation in sex‐biased expression may have evolved as an adaptive response to ancestral environments experienced by human populations.DiscussionThese results indicate that sex‐biased gene expression is more flexible than previously thought and is not generally shared among human populations. Instead, molecular phenotypes associated with sex depend on complex interactions between population‐specific molecular evolution and physiological responses to contemporary socioecologies.

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“…Ideally, an increased understanding of sex specific mechanisms underlying sex differences in pulmonary immunity would lead to improved treatment and precision medicine options for respiratory infection ( Stachenfeld and Mazure, 2022 ). In the COVID-19 pandemic, observations of a male bias in mortality led to clinical trials involving estrogen or selective ER modulator administration or androgen blockade.…”

Section: Discussionmentioning

confidence: 99%

Sex chromosome complement and sex steroid signaling underlie sex differences in immunity to respiratory virus infection

2023

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Epidemiological studies have revealed sex differences in the incidence and morbidity of respiratory virus infection in the human population, and often these observations are correlated with sex differences in the quality or magnitude of the immune response. Sex differences in immunity and morbidity also are observed in animal models of respiratory virus infection, suggesting differential dominance of specific immune mechanisms. Emerging research shows intrinsic sex differences in immune cell transcriptomes, epigenomes, and proteomes that may regulate human immunity when challenged by viral infection. Here, we highlight recent research into the role(s) of sex steroids and X chromosome complement in immune cells and describe how these findings provide insight into immunity during respiratory virus infection. We focus on the regulation of innate and adaptive immune cells by receptors for androgen and estrogens, as well as genes with a propensity to escape X chromosome inactivation. A deeper mechanistic knowledge of these pathways will help us to understand the often significant sex differences in immunity to endemic or pandemic respiratory pathogens such as influenza viruses, respiratory syncytial viruses and pathogenic coronaviruses.

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Precision medicine requires understanding how both sex and gender influence health

Cited by 17 publications

References 14 publications

Sex-biased gene regulation varies across human populations as a result of adaptive evolution

Sex-biased gene regulation varies across human populations as a result of adaptive evolution

Sex‐biased gene regulation varies across human populations as a result of adaptive evolution

Sex chromosome complement and sex steroid signaling underlie sex differences in immunity to respiratory virus infection

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