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Sex-specific genetic architecture of human disease

Key Points

  • Nearly all human diseases are sexually dimorphic with respect to prevalence, age of onset, severity or disease course. Sex-specific differences in physiology, behaviour or anatomy might contribute to some of the differences in disease risk, but genetics also plays a part.

  • Gene expression patterns differ between males and females of all species examined, not only for genes on the sex chromosomes, but also for genes on the autosomes.

  • Genes with sex-biased gene expression evolve rapidly at the protein-coding level, whereas differences in gene regulation are often highly conserved.

  • Differences in gene expression between the sexes probably contribute to sexual dimorphism in disease risk and course.

  • Studies of disease-associated quantitative traits in humans suggest that many have a sex-specific genetic architecture, with estimates of heritability differing between males and females.

  • Genotype-by-sex interactions are common in model organisms, indicating that genotype-specific effects differ between males and females. Recent examples of genotype-by-sex interactions on disease risk suggest that such effects might be common in humans as well.

  • Genetic linkage and association studies that do not consider sex-specific genotype effects could miss a significant proportion of genes contributing to risk for complex diseases.

Abstract

Sexual dimorphism in anatomical, physiological and behavioural traits are characteristics of many vertebrate species. In humans, sexual dimorphism is also observed in the prevalence, course and severity of many common diseases, including cardiovascular diseases, autoimmune diseases and asthma. Although sex differences in the endocrine and immune systems probably contribute to these observations, recent studies suggest that sex-specific genetic architecture also influences human phenotypes, including reproductive, physiological and disease traits. It is likely that an underlying mechanism is differential gene regulation in males and females, particularly in sex steroid-responsive genes. Genetic studies that ignore sex-specific effects in their design and interpretation could fail to identify a significant proportion of the genes that contribute to risk for complex diseases.

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Figure 1: Approximate mean sex-steroid levels in plasma in males and females.
Figure 2: Models of genotype–sex interactions reflecting genotype effects that differ between males and females.
Figure 3: Sex-specific prevalence rates, age of onset and sex ratios for common sex-skewed diseases.
Figure 4: Sex-specific heritabilities in males and females.
Figure 5: Strategy for discovering sex-specific eQTLs contributing to sexual dimorphism in disease risk.

References

  1. 1

    Alonso, L. C. & Rosenfield, R. L. Oestrogens and puberty. Best Pract. Res. Clin. Endocrinol. Metab. 16, 13–30 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. 2

    Carrel, L. & Willard, H. F. X-inactivation profile reveals extensive variability in X-linked gene expression in females. Nature 434, 400–404 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. 3

    Korstanje, R. et al. Influence of sex and diet on quantitative trait loci for HDL cholesterol levels in an SM/J by NZB/BlNJ intercross population. J. Lipid Res. 45, 881–888 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. 4

    Mackay, T. F. The genetic architecture of quantitative traits: lessons from Drosophila. Curr. Opin. Genet. Dev. 14, 253–257 (2004). A classic review of gene–environment (including genotype–sex) interactions in Drosophila.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. 5

    Ueno, T. et al. Rat model of familial combined hyperlipidemia as a result of comparative mapping. Physiol. Genomics 17, 38–47 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6

    Choi, B. G. & McLaughlin, M. A. Why men's hearts break: cardiovascular effects of sex steroids. Endocrinol. Metab. Clin. North Am. 36, 365–377 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 7

    Postma, D. S. Gender differences in asthma development and progression. Gend. Med. 4 (Suppl. B), S133–S146 (2007).

    PubMed  PubMed Central  Google Scholar 

  8. 8

    Lockshin, M. D. Sex differences in autoimmune disease. Lupus 15, 753–756 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9

    Harper, P. S. Practical Genetic Counseling 5th edn (Reed Educational and Professional Publishing, Oxford, 1998).

    Google Scholar 

  10. 10

    Gater, R. et al. Sex differences in the prevalence and detection of depressive and anxiety disorders in general health care settings: report from the World Health Organization Collaborative Study on Psychological Problems in General Health Care. Arch. Gen. Psychiatry 55, 405–413 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 11

    Andersen, K. et al. Gender differences in the incidence of AD and vascular dementia: The EURODEM Studies. EURODEM Incidence Research Group. Neurology 53, 1992–1997 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12

    Aleman, A., Kahn, R. S. & Selten, J. P. Sex differences in the risk of schizophrenia: evidence from meta-analysis. Arch. Gen. Psychiatry 60, 565–571 (2003).

    PubMed  PubMed Central  Google Scholar 

  13. 13

    Wooten, G. F., Currie, L. J., Bovbjerg, V. E., Lee, J. K. & Patrie, J. Are men at greater risk for Parkinson's disease than women? J. Neurol. Neurosurg. Psychiatry 75, 637–639 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14

    Matanoski, G., Tao, X. G., Almon, L., Adade, A. A. & Davies-Cole, J. O. Demographics and tumor characteristics of colorectal cancers in the United States, 1998–2001. Cancer 107, 1112–1120 (2006).

    PubMed  PubMed Central  Google Scholar 

  15. 15

    Patsopoulos, N. A., Tatsioni, A. & Ioannidis, J. P. Claims of sex differences: an empirical assessment in genetic associations. JAMA 298, 880–893 (2007). A comprehensive review and critique of the evidence for sex-specific genetic effects on risk for common diseases.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. 16

    Barrett-Connor, E. Commentary: masculinity, femininity and heart disease. Int. J. Epidemiol. 36, 621–622 (2007).

    PubMed  PubMed Central  Google Scholar 

  17. 17

    Uekert, S. J. et al. Sex-related differences in immune development and the expression of atopy in early childhood. J. Allergy Clin. Immunol. 118, 1375–1381 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18

    Whitacre, C. C., Reingold, S. C. & O'Looney, P. A. A gender gap in autoimmunity. Science 283, 1277–1278 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19

    Straub, R. H. The complex role of estrogens in inflammation. Endocr. Rev. 28, 521–574 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20

    Dobyns, W. B. et al. Inheritance of most X-linked traits is not dominant or recessive, just X-linked. Am. J. Med. Genet. A 129A, 136–143 (2004).

    PubMed  PubMed Central  Google Scholar 

  21. 21

    Lahn, B. T. & Page, D. C. Functional coherence of the human Y chromosome. Science 278, 675–680 (1997).

    CAS  PubMed  Google Scholar 

  22. 22

    Lange, J., Skaletsky, H., Bell, G. W. & Page, D. C. MSY Breakpoint Mapper, a database of sequence-tagged sites useful in defining naturally occurring deletions in the human Y chromosome. Nucleic Acids Res. 36, D809–814 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23

    Reinius, B. et al. An evolutionarily conserved sexual signature in the primate brain. PLoS Genet. 4, e1000100 (2008). An elegant demonstration of the conserved evolution of sexual dimorphism in gene expression patterns in the brain of primates.

    PubMed  PubMed Central  Google Scholar 

  24. 24

    Rinn, J. L. & Snyder, M. Sexual dimorphism in mammalian gene expression. Trends Genet. 21, 298–305 (2005). A modern overview of the evolution of sexual dimorphism in gene expression.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 25

    Yang, X. et al. Tissue-specific expression and regulation of sexually dimorphic genes in mice. Genome Res. 16, 995–1004 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26

    Ellegren, H. & Parsch, J. The evolution of sex-biased genes and sex-biased gene expression. Nature Rev. Genet. 8, 689–698 (2007). A comprehensive review of sexual dimorphism in the regulatory genome.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. 27

    Reinke, V., Gil, I. S., Ward, S. & Kazmer, K. Genome-wide germline-enriched and sex-biased expression profiles in Caenorhabditis elegans. Development 131, 311–323 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28

    Ranz, J. M., Castillo-Davis, C. I., Meiklejohn, C. D. & Hartl, D. L. Sex-dependent gene expression and evolution of the Drosophila transcriptome. Science 300, 1742–1745 (2003). One of the first genome-wide characterizations of sex-biased gene expression patterns in more than one species of Drosophila.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 29

    Baker, D. A., Meadows, L. A., Wang, J., Dow, J. A. & Russell, S. Variable sexually dimorphic gene expression in laboratory strains of Drosophila melanogaster. BMC Genomics 8, 454 (2007).

    PubMed  PubMed Central  Google Scholar 

  30. 30

    Santos, E. M., Kille, P., Workman, V. L., Paull, G. C. & Tyler, C. R. Sexually dimorphic gene expression in the brains of mature zebrafish. Comp. Biochem. Physiol. A Mol. Integr. Physiol. 149, 314–324 (2008).

    PubMed  PubMed Central  Google Scholar 

  31. 31

    Nishida, Y., Yoshioka, M. & St-Amand, J. Sexually dimorphic gene expression in the hypothalamus, pituitary gland, and cortex. Genomics 85, 679–687 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32

    Zhang, Y., Sturgill, D., Parisi, M., Kumar, S. & Oliver, B. Constraint and turnover in sex-biased gene expression in the genus Drosophila. Nature 450, 233–237 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33

    Sartori-Valinotti, J. C., Iliescu, R., Fortepiani, L. A., Yanes, L. L. & Reckelhoff, J. F. Sex differences in oxidative stress and the impact on blood pressure control and cardiovascular disease. Clin. Exp. Pharmacol. Physiol. 34, 938–945 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34

    Zammaretti, F., Panzica, G. & Eva, C. Sex-dependent regulation of hypothalamic neuropeptide Y-Y1 receptor gene expression in moderate/high fat, high-energy diet-fed mice. J. Physiol. 583, 445–454 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35

    Bhasin, J. M. et al. Sex specific gene regulation and expression QTLs in mouse macrophages from a strain intercross. PLoS ONE 3, e1435 (2008). The first explicit study of genetic variation that affects sex-specific variation in gene expression and of sex-specific eQTLs in a mammalian species.

    PubMed  PubMed Central  Google Scholar 

  36. 36

    Angelopoulou, R., Lavranos, G. & Manolakou, P. Establishing sexual dimorphism in humans. Coll. Antropol. 30, 653–658 (2006).

    PubMed  PubMed Central  Google Scholar 

  37. 37

    Visscher, P. M., Hill, W. G. & Wray, N. R. Heritability in the genomics era — concepts and misconceptions. Nature Rev. Genet. 9, 255–266 (2008). An excellent review of the use and misuse of the concept of heritability and its role in modern genetic studies.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38

    Shea, M. K. et al. Genetic and non-genetic correlates of vitamins K and D. Eur. J. Clin. Nutr. 21 Nov 2007 (doi: 10.1038/sj.ejcn.1602959).

    PubMed  PubMed Central  Google Scholar 

  39. 39

    Santamaria, A. et al. Quantitative trait locus on chromosome 12q14.1 influences variation in plasma plasminogen levels in the San Antonio Family Heart Study. Hum. Biol. 79, 515–523 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 40

    de Simone, G. et al. Assessment of the interaction of heritability of volume load and left ventricular mass: the HyperGEN offspring study. J. Hypertens. 25, 1397–1402 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41

    Pan, L., Ober, C. & Abney, M. Heritability estimation of sex-specific effects on human quantitative traits. Genet. Epidemiol. 31, 338–347 (2007).

    PubMed  PubMed Central  Google Scholar 

  42. 42

    Weiss, L. A., Pan, L., Abney, M. & Ober, C. The sex-specific genetic architecture of quantitative traits in humans. Nature Genet. 38, 218–222 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43

    Ober, C., Abney, M. & McPeek, M. S. The genetic dissection of complex traits in a founder population. Am. J. Hum. Genet. 69, 1068–1079 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44

    Abney, M., McPeek, M. S. & Ober, C. Heritabilities of quantitative traits in a founder population. Am. J. Hum. Genet. 68, 1302–1307 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. 45

    Seda, O. et al. Systematic, genome-wide, sex-specific linkage of cardiovascular traits in French Canadians. Hypertension 51, 1156–1162 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46

    Karasik, D. & Ferrari, S. L. Contribution of gender-specific genetic factors to osteoporosis risk. Ann. Hum. Genet. 72, 696–714 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47

    Wang, C. et al. A computational model for sex-specific genetic architecture of complex traits in humans: implications for mapping pain sensitivity. Mol. Pain 4, 13 (2008).

    PubMed  PubMed Central  Google Scholar 

  48. 48

    Brookes, S. T. et al. Subgroup analyses in randomized trials: risks of subgroup-specific analyses; power and sample size for the interaction test. J. Clin. Epidemiol. 57, 229–236 (2004).

    PubMed  PubMed Central  Google Scholar 

  49. 49

    Higaki, J. et al. Deletion allele of angiotensin-converting enzyme gene increases risk of essential hypertension in Japanese men: the Suita Study. Circulation 101, 2060–2065 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50

    O'Donnell, C. J. et al. Evidence for association and genetic linkage of the angiotensin-converting enzyme locus with hypertension and blood pressure in men but not women in the Framingham Heart Study. Circulation 97, 1766–1772 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51

    Stankovic, A., Zivkovic, M. & Alavantic, D. Angiotensin I-converting enzyme gene polymorphism in a Serbian population: a gender-specific association with hypertension. Scand. J. Clin. Lab. Invest. 62, 469–475 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52

    Fornage, M. et al. Variation in the region of the angiotensin-converting enzyme gene influences interindividual differences in blood pressure levels in young white males. Circulation 97, 1773–1779 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. 53

    Weiss, L. A., Abney, M., Cook, E. H., Jr & Ober, C. Sex-specific genetic architecture of whole blood serotonin levels. Am. J. Hum. Genet. 76, 33–41 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. 54

    Anholt, R. R. & Mackay, T. F. Quantitative genetic analyses of complex behaviours in Drosophila. Nature Rev. Genet. 5, 838–849 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55

    Mackay, T. F. & Anholt, R. R. Of flies and man: Drosophila as a model for human complex traits. Annu. Rev. Genomics Hum. Genet. 7, 339–367 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. 56

    Melo, J. A., Shendure, J., Pociask, K. & Silver, L. M. Identification of sex-specific quantitative trait loci controlling alcohol preference in C57BL/6 mice. Nature Genet. 13, 147–153 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57

    Peirce, J. L., Derr, R., Shendure, J., Kolata, T. & Silver, L. M. A major influence of sex-specific loci on alcohol preference in C57Bl/6 and DBA/2 inbred mice. Mamm. Genome 9, 942–948 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. 58

    Athirakul, K. et al. Increased blood pressure in mice lacking cytochrome P450 2J5. FASEB J. 20 Aug 2008 (doi: fj.08-114413v1).

  59. 59

    Ponder, C. A., Munoz, M., Gilliam, T. C. & Palmer, A. A. Genetic architecture of fear conditioning in chromosome substitution strains: relationship to measures of innate (unlearned) anxiety-like behavior. Mamm. Genome 18, 221–228 (2007).

    PubMed  PubMed Central  Google Scholar 

  60. 60

    Mattson, D. L. et al. Chromosomal mapping of the genetic basis of hypertension and renal disease in FHH rats. Am. J. Physiol. Renal Physiol. 293, F1905–F1914 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. 61

    Tu, K., Chen, Z. & Lipscombe, L. L. Prevalence and incidence of hypertension from 1995 to 2005: a population-based study. CMAJ 178, 1429–1435 (2008).

    PubMed  PubMed Central  Google Scholar 

  62. 62

    Kearney, P. M. et al. Global burden of hypertension: analysis of worldwide data. Lancet 365, 217–223 (2005).

    PubMed  PubMed Central  Google Scholar 

  63. 63

    Burt, V. L. et al. Prevalence of hypertension in the US adult population. Results from the Third National Health and Nutrition Examination Survey, 1988–1991. Hypertension 25, 305–313 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. 64

    Martins, D., Nelson, K., Pan, D., Tareen, N. & Norris, K. The effect of gender on age-related blood pressure changes and the prevalence of isolated systolic hypertension among older adults: data from NHANES III. J. Gend. Specif. Med. 4, 10–13, 20 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. 65

    Kato, N. et al. Comprehensive analysis of the renin-angiotensin gene polymorphisms with relation to hypertension in the Japanese. J. Hypertens. 18, 1025–1032 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. 66

    Rigat, B. et al. An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels. J. Clin. Invest. 86, 1343–1346 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. 67

    Krege, J. H. et al. Male–female differences in fertility and blood pressure in ACE-deficient mice. Nature 375, 146–148 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. 68

    Leung, A. & Chue, P. Sex differences in schizophrenia, a review of the literature. Acta Psychiatr. Scand. Suppl. 401, 3–38 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. 69

    McGrath, J. et al. A systematic review of the incidence of schizophrenia: the distribution of rates and the influence of sex, urbanicity, migrant status and methodology. BMC Med. 2, 13 (2004).

    PubMed  PubMed Central  Google Scholar 

  70. 70

    Cardno, A. G. & Gottesman, II. Twin studies of schizophrenia: from bow-and-arrow concordances to star wars Mx and functional genomics. Am. J. Med. Genet. 97, 12–17 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. 71

    Shifman, S. et al. Genome-wide association identifies a common variant in the reelin gene that increases the risk of schizophrenia only in women. PLoS Genet. 4, e28 (2008).

    PubMed  PubMed Central  Google Scholar 

  72. 72

    Wedenoja, J. et al. Replication of linkage on chromosome 7q22 and association of the regional Reelin gene with working memory in schizophrenia families. Mol. Psychiatry 13, 673–684 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. 73

    Hong, S. E. et al. Autosomal recessive lissencephaly with cerebellar hypoplasia is associated with human RELN mutations. Nature Genet. 26, 93–96 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. 74

    Eastwood, S. L. & Harrison, P. J. Interstitial white matter neurons express less reelin and are abnormally distributed in schizophrenia: towards an integration of molecular and morphologic aspects of the neurodevelopmental hypothesis. Mol. Psychiatry 8, 769, 821–731 (2003).

    CAS  Google Scholar 

  75. 75

    Hassold, T. & Hunt, P. To err (meiotically) is human: the genesis of human aneuploidy. Nature Rev. Genet. 2, 280–291 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. 76

    Baker, B. S., Carpenter, A. T., Esposito, M. S., Esposito, R. E. & Sandler, L. The genetic control of meiosis. Annu. Rev. Genet. 10, 53–134 (1976).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. 77

    Coop, G. & Przeworski, M. An evolutionary view of human recombination. Nature Rev. Genet. 8, 23–34 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. 78

    Kong, A. et al. Sequence variants in the RNF212 gene associate with genome-wide recombination rate. Science 319, 1398–1401 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. 79

    Coop, G., Wen, X., Ober, C., Pritchard, J. K. & Przeworski, M. High-resolution mapping of crossovers reveals extensive variation in fine-scale recombination patterns among humans. Science 319, 1395–1398 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. 80

    Broman, K. W., Murray, J. C., Sheffield, V. C., White, R. L. & Weber, J. L. Comprehensive human genetic maps: individual and sex-specific variation in recombination. Am. J. Hum. Genet. 63, 861–869 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. 81

    Cheung, V. G., Burdick, J. T., Hirschmann, D. & Morley, M. Polymorphic variation in human meiotic recombination. Am. J. Hum. Genet. 80, 526–530 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. 82

    Martinez, F. D. CD14, endotoxin, and asthma risk: actions and interactions. Proc. Am. Thorac. Soc. 4, 221–225 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. 83

    Zambelli-Weiner, A. et al. Evaluation of the CD14/-260 polymorphism and house dust endotoxin exposure in the Barbados Asthma Genetics Study. J. Allergy Clin. Immunol. 115, 1203–1209 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. 84

    Simpson, A. et al. Endotoxin exposure, CD14, and allergic disease: an interaction between genes and the environment. Am. J. Respir. Crit. Care Med. 174, 386–392 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. 85

    Berchtold, N. C. et al. Gene expression changes in the course of normal brain aging are sexually dimorphic. Proc. Natl Acad. Sci. USA 105, 15605–15610 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. 86

    Gupta, V. & Singh, S. M. Sex dimorphism in antitumor response of chemotherapeutic drug cisplatin in a murine host-bearing a T-cell lymphoma. Anticancer Drugs 19, 583–592 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. 87

    Jackson, A., Stephens, D. & Duka, T. Gender differences in response to lorazepam in a human drug discrimination study. J. Psychopharmacol. 19, 614–619 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. 88

    Klein, W. Gender differences in clinical trials in coronary heart disease: response to drug therapy. Eur. Heart J. 17, 1786–1790 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. 89

    Dixon, A. L. et al. A genome-wide association study of global gene expression. Nature Genet. 39, 1202–1207 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. 90

    Stranger, B. E. et al. Relative impact of nucleotide and copy number variation on gene expression phenotypes. Science 315, 848–853 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. 91

    Zhang, W. et al. Evaluation of genetic variation contributing to differences in gene expression between populations. Am. J. Hum. Genet. 82, 631–640 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. 92

    Morley, M. et al. Genetic analysis of genome-wide variation in human gene expression. Nature 430, 743–747 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. 93

    Storey, J. D. A direct approach to false discovery rates. J. Royal Stat. Soc. B 64, 479–198 (2002).

    Google Scholar 

  94. 94

    Gilad, Y., Rifkin, S. A. & Pritchard, J. K. Revealing the architecture of gene regulation: the promise of eQTL studies. Trends Genet. 24, 408–415 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. 95

    Darwin, C. On the Origins of Species by Means of Natural Selection (John Murray, London, 1859).

    Google Scholar 

  96. 96

    Cunningham, J. T. Sexual Dimorphism in the Animal Kingdom (Adam and Charles Black, London, 1900).

    Google Scholar 

  97. 97

    Kimura, K. I., Ote, M., Tazawa, T. & Yamamoto, D. Fruitless specifies sexually dimorphic neural circuitry in the Drosophila brain. Nature 438, 229–233 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. 98

    Stockinger, P., Kvitsiani, D., Rotkopf, S., Tirian, L. & Dickson, B. J. Neural circuitry that governs Drosophila male courtship behavior. Cell 121, 795–807 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. 99

    Kimchi, T., Xu, J. & Dulac, C. A functional circuit underlying male sexual behaviour in the female mouse brain. Nature 448, 1009–1014 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. 100

    Plavcan, J. M. Sexual dimorphism in primate evolution. Yearb. Phys. Anthropol. 44, 25–53 (2001).

    Google Scholar 

  101. 101

    Andersson, M. Sexual Selection (Princeton Univ. Press, New Jersey, 1994). Comprehensive review and synthesis of essential topics in sexual selection, providing insight into the evolution of sex differences in nature and the role of selection and constraint in the development of secondary sexual traits.

    Google Scholar 

  102. 102

    Geary, D. C. Male, Female: The Evolution of Human Sex Differences (American Psychological Association, Washington DC, 1998).

    Google Scholar 

  103. 103

    Wizeman, T. M. & Pardue, M.-L. (eds) Exploring the Biological Contributions to Human Health: Does Sex Matter? (National Academy Press, Washington DC, 2001).

    Google Scholar 

  104. 104

    Badyaev, A. V. & Hill, G. E. Avian sexual dichromatism in relation to phylogeny and ecology. Ann. Rev. Ecol. Evol. Syst. 34, 27–49 (2003).

    Google Scholar 

  105. 105

    Lande, R. Sexual dimorphism, sexual selection, and adaptation in polygenic characters. Evolution 34, 292–305 (1980). A classic study that uses quantitative population genetic models to show that genetic correlations influence the expression and evolution of sexually dimorphic traits.

    PubMed  PubMed Central  Google Scholar 

  106. 106

    Rice, W. R. & Chippindale, A. K. Intersexual ontogenetic conflict. J. Evol. Biol. 14, 685–693 (2001).

    Google Scholar 

  107. 107

    Nelson, J. L. Microchimerism in human health and disease. Autoimmunity 36, 5–9 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. 108

    Lambert, N. C. et al. Quantification of maternal microchimerism by HLA-specific real-time polymerase chain reaction: studies of healthy women and women with scleroderma. Arthritis Rheum. 50, 906–914 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. 109

    Maloney, S. et al. Microchimerism of maternal origin persists into adult life. J. Clin. Invest. 104, 41–47 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. 110

    Reed, A. M., Picornell, Y. J., Harwood, A. & Kredich, D. W. Chimerism in children with juvenile dermatomyositis. Lancet 356, 2156–2157 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. 111

    Reed, A. M., McNallan, K., Wettstein, P., Vehe, R. & Ober, C. Does HLA-dependent chimerism underlie the pathogenesis of juvenile dermatomyositis? J. Immunol. 172, 5041–5046 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. 112

    Yan, Z. et al. Male microchimerism in women without sons: quantitative assessment and correlation with pregnancy history. Am. J. Med. 118, 899–906 (2005).

    PubMed  PubMed Central  Google Scholar 

  113. 113

    Loubiere, L. S. et al. Maternal microchimerism in healthy adults in lymphocytes, monocyte/macrophages and NK cells. Lab. Invest. 86, 1185–1192 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. 114

    Stevens, A. M., Hermes, H. M., Rutledge, J. C., Buyon, J. P. & Nelson, J. L. Myocardial-tissue-specific phenotype of maternal microchimerism in neonatal lupus congenital heart block. Lancet 362, 1617–1623 (2003).

    PubMed  PubMed Central  Google Scholar 

  115. 115

    Stevens, A. M. et al. Liver biopsies from human females contain male hepatocytes in the absence of transplantation. Lab. Invest. 84, 1603–1609 (2004).

    PubMed  PubMed Central  Google Scholar 

  116. 116

    Khosrotehrani, K., Johnson, K. L., Cha, D. H., Salomon, R. N. & Bianchi, D. W. Transfer of fetal cells with multilineage potential to maternal tissue. JAMA 292, 75–80 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. 117

    Nelson, J. L. et al. Microchimerism and HLA-compatible relationships of pregnancy in scleroderma. Lancet 351, 559–562 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. 118

    Johnson, K. L. et al. Fetal cell microchimerism in tissue from multiple sites in women with systemic sclerosis. Arthritis Rheum. 44, 1848–1854 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. 119

    Ando, T., Imaizumi, M., Graves, P. N., Unger, P. & Davies, T. F. Intrathyroidal fetal microchimerism in Graves' disease. J. Clin. Endocrinol. Metab. 87, 3315–3320 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. 120

    Nelson, J. L. et al. Maternal microchimerism in peripheral blood in type 1 diabetes and pancreatic islet beta cell microchimerism. Proc. Natl Acad. Sci. USA 104, 1637–1642 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. 121

    Klintschar, M., Schwaiger, P., Mannweiler, S., Regauer, S. & Kleiber, M. Evidence of fetal microchimerism in Hashimoto's thyroiditis. J. Clin. Endocrinol. Metab. 86, 2494–2498 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. 122

    Artlett, C. M. et al. Chimeric cells of maternal origin in juvenile idiopathic inflammatory myopathies. Childhood Myositis Heterogeneity Collaborative Group. Lancet 356, 2155–2156 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. 123

    Miyashita, Y., Ono, M., Ono, M., Ueki, H. & Kurasawa, K. Y chromosome microchimerism in rheumatic autoimmune disease. Ann. Rheum. Dis. 59, 655–656 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. 124

    Badenhoop, K. Intrathyroidal microchimerism in Graves' disease or Hashimoto's thyroiditis: regulation of tolerance or alloimmunity by fetal-maternal immune interactions? Eur. J. Endocrinol. 150, 421–423 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. 125

    Nelson, J. L. Maternal–fetal immunology and autoimmune disease: is some autoimmune disease auto-alloimmune or allo-autoimmune? Arthritis Rheum. 39, 191–194 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. 126

    Gammill, H. S. & Nelson, J. L. Naturally acquired microchimerism. Int. J. Dev. Biol. (in the press).

  127. 127

    Reik, W. & Walter, J. Genomic imprinting: parental influence on the genome. Nature Rev. Genet. 2, 21–32 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. 128

    Falls, J. G., Pulford, D. J., Wylie, A. A. & Jirtle, R. L. Genomic imprinting: implications for human disease. Am. J. Pathol. 154, 635–647 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. 129

    Wilkins, J. F. & Haig, D. What good is genomic imprinting: the function of parent-specific gene expression. Nature Rev. Genet. 4, 359–368 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. 130

    Morison, I. M., Ramsay, J. P. & Spencer, H. G. A census of mammalian imprinting. Trends Genet. 21, 457–465 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. 131

    Bunzel, R. et al. Polymorphic imprinting of the serotonin-2A (5-HT2A) receptor gene in human adult brain. Brain Res. Mol. Brain Res. 59, 90–92 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. 132

    Giannoukakis, N., Deal, C., Paquette, J., Kukuvitis, A. & Polychronakos, C. Polymorphic functional imprinting of the human IGF2 gene among individuals, in blood cells, is associated with H19 expression. Biochem. Biophys. Res. Commun. 220, 1014–1019 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. 133

    Wolf, J. B., Cheverud, J. M., Roseman, C. & Hager, R. Genome-wide analysis reveals a complex pattern of genomic imprinting in mice. PLoS Genet. 4, e1000091 (2008).

    PubMed  PubMed Central  Google Scholar 

  134. 134

    Kaufman, J. M. & Vermeulen, A. The decline of androgen levels in elderly men and its clinical and therapeutic implications. Endocr. Rev. 26, 833–876 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. 135

    Khosla, S. et al. Relationship of serum sex steroid levels and bone turnover markers with bone mineral density in men and women: a key role for bioavailable estrogen. J. Clin. Endocrinol. Metab. 83, 2266–2274 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. 136

    Winters, S. J., Talbott, E., Guzick, D. S., Zborowski, J. & McHugh, K. P. Serum testosterone levels decrease in middle age in women with the polycystic ovary syndrome. Fertil. Steril. 73, 724–729 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. 137

    Cooper, G. S. & Stroehla, B. C. The epidemiology of autoimmune diseases. Autoimmun. Rev. 2, 119–125 (2003).

    PubMed  PubMed Central  Google Scholar 

  138. 138

    Mendez, E. P. et al. US incidence of juvenile dermatomyositis, 1995–1998: results from the National Institute of Arthritis and Musculoskeletal and Skin Diseases Registry. Arthritis Rheum. 49, 300–305 (2003).

    PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors are grateful to R. Rosenfield and J. L. Nelson for discussions, and to S. Khosla and E. Atkinson for providing primary data on sex-steroid levels in adults. The authors are supported in part by National Institutes of Health (NIH) grants HD021244, HL070831 and HL085197 (C.O.), GM077959 (Y.G.) and T32 HL07605 (D.A.L.). Y.G. is also supported by the Sloan foundation.

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Glossary

Heterogametic

Refers to the sex that produces gametes that have two different sex chromosomes. In mammals, males are the heterogametic sex (XY) and females are homogametic (XX), whereas in birds females are heterogametic (ZW).

Genetic architecture

Refers to the underlying genetic basis for a trait.

Pyloric stenosis

A common birth defect that results from the narrowing of the pylorus (lower part of the stomach), which prevents food and other stomach contents from passing into the intestine. This condition causes severe vomiting in infancy. Also called infantile hypertrophic pyloric stenosis.

Regulatory genome

The total set of different DNA molecules of an organelle, cell or organism that are involved in the regulation of gene expression.

Sexual selection

Differential reproductive success resulting from the competition for fertilization, which can occur through competition among the same sex (mate competition) or through attraction to the opposite sex (mate choice).

Ontogenetic conflict

Occurs when the same allele has different fitness consequences in juveniles and adults or in males and females.

Expression QTL

(eQTL). Loci at which genetic allelic variation is associated with variation in gene expression.

Alloimmune

An immune reaction against cells from another individual of the same species. Alloimmunity can occur during transfusion or transplantation, or during pregnancy.

Heritability

The proportion of the total phenotypic variance for a given trait that can be attributed to genetic variation among individuals.

Forced expiratory volume at 1 second

(FEV1). The volume exhaled in the first second of a forced expiratory manoeuvre. This index is used to assess airway obstruction, bronchoconstriction or bronchodilation.

Type I error

The probability of rejecting the null hypothesis when it is true, also referred to as a false positive.

Multiple testing

An analysis in which multiple independent hypotheses are tested. Multiple testing must be taken into account during statistical analysis, as the combined probability of type I error increases in an unadjusted analysis.

Consomic strain

Inbred strain in which a chromosome has been replaced by a homologous chromosome from another inbred strain.

Penetrance

The probability of observing a specific phenotype in individuals carrying a particular genotype.

Linkage disequilibrium

(LD). The nonrandom association of alleles at two or more loci. The pattern of linkage disequilibrium in a given genomic region reflects the history of natural selection, mutation, recombination, genetic drift, and other demographic and evolutionary forces.

Nondisjunction

The failure of chromosomes to separate at anaphase.

Aneuploidy

The presence of an abnormal number of chromosomes, either more or less than the diploid number.

Ectopic exchange

Homologous recombination between non-allelic chromosomal regions.

Odds ratio

(OR). Compares the likelihood of an outcome (for example, a disease) between two groups (for example, cases and controls). It is measured as the ratio of the odds in one group to the odds in the second group and can be calculated by the following formula: OR = p(1 − q)/q(1 − p), where p is the probability of the event occurring for the first group and q the probability for the second group.

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Ober, C., Loisel, D. & Gilad, Y. Sex-specific genetic architecture of human disease. Nat Rev Genet 9, 911–922 (2008). https://doi.org/10.1038/nrg2415

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