Abstract
BackgroundGender appears to be determined by independent programs controlled by the sex-chromosomes and by androgen-dependent programming during embryonic development. To enable experimental dissection of these components in the human, we performed genome-wide profiling of the transcriptomes of peripheral blood mononuclear cells (PBMC) in patients with rare defined "disorders of sex development" (DSD, e.g., 46, XY-females due to defective androgen biosynthesis) compared to normal 46, XY-males and 46, XX-females.ResultsA discrete set of transcripts was directly correlated with XY or XX genotypes in all individuals independent of male or female phenotype of the external genitalia. However, a significantly larger gene set in the PBMC only reflected the degree of external genital masculinization independent of the sex chromosomes and independent of concurrent post-natal sex steroid hormone levels. Consequently, the architecture of the transcriptional PBMC-"sexes" was either male, female or even "intersex" with a discordant alignment of the DSD individuals' genetic and hormonal sex signatures.ConclusionA significant fraction of gene expression differences between males and females in the human appears to have its roots in early embryogenesis and is not only caused by sex chromosomes but also by long-term sex-specific hormonal programming due to presence or absence of androgen during the time of external genital masculinization. Genetic sex and the androgen milieu during embryonic development might therefore independently modulate functional traits, phenotype and diseases associated with male or female gender as well as with DSD conditions.
Highlights
Gender appears to be determined by independent programs controlled by the sexchromosomes and by androgen-dependent programming during embryonic development
The disorders of sex development (DSD) patients were comprised of ten 46,XY subjects whose genitalia ranged from normal female to Prader 4, three 46,XX subjects with masculinized genitalia from high prenatal androgenic steroid levels due to congenital adrenal hyperplasia (CAH, 21hydroxlase deficiency) and one Prader 4 45,X0/46,XY subject
RT-PCR confirmed that DDX3Y transcript levels were abundant in these same 46,XY individuals, but absent in the 46,XX subjects
Summary
Gender appears to be determined by independent programs controlled by the sexchromosomes and by androgen-dependent programming during embryonic development. Biological sex is the product of genetic and hormonal programs activated during embryonic development, with the most striking gender differences occurring in the internal and external genitalia. Biological sex is a core determinant of sex-specific behavior [1,2,3] and a major modifier of a variety of maladies including cancer [4,5] and autoimmune diseases [6]. Sex-specific gene expression appears to be the product of two distinct pathways: sex chromosome genotype (46,XX versus 46,XY) [8,9] and androgen-dependent programming during embryogenesis [10,11]. In contrast to established concepts of androgen programming in rodents [12,13,14] it has not been possible to tease out the contributions of these two pathways experimentally in normal male and normal female humans since they always work in parallel
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