title: Disorders of sex development expose transcriptional autonomy of genetic sex and androgen-programmed hormonal sex in human blood leukocytes.
abstract: BACKGROUND
  Gender 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.
  
  
  RESULTS
  A 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.
  
  
  CONCLUSIONS
  A 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.
authors: Department of Pediatrics, Christian Albrechts University of Kiel, Germany. holterhus@pediatrics.uni-kiel.de
authors: Paul-Martin
authors: PM
authors: Holterhus
authors: Jan-Hendrik
authors: JH
authors: Bebermeier
authors: Ralf
authors: R
authors: Werner
authors: Janos
authors: J
authors: Demeter
authors: Annette
authors: A
authors: Richter-Unruh
authors: Gunnar
authors: G
authors: Cario
authors: Mahesh
authors: M
authors: Appari
authors: Reiner
authors: R
authors: Siebert
authors: Felix
authors: F
authors: Riepe
authors: James D
authors: JD
authors: Brooks
authors: Olaf
authors: O
authors: Hiort
mesh_terms: D000328:Adult; D000728:Androgens / Q000502:physiology*; D016000:Cluster Analysis; D012734:Disorders of Sex Development / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D015894:Genome, Human; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism*; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D012730:Sex Chromosomes / Q000235:genetics; D046468:Sexual Development / Q000235:genetics*
chemical_list: D000728:Androgens