sex determination

see also:

• genetics

• in all eutherian mammalian species including humans, sex determination is primarily based upon the genetic karyotype of XX for females and XY for males however, we now know there are many autosomal genes which are required to allow the bi-potential gonads to differentiate into either ovary or testes (or if it fails a non-functional or dysfunctional gonad - the “default” is not simply an ovary)
• mammals deactivate one of their extra X chromosomes when “female”

• this is required in either XX or XY embryos and requires a number of genes to be activated such as Sf1

• SRY gene on the Y chromosome produces a protein which bends DNA and triggers up-regulation of the autosomal SOX9 gene in the embryo
• there are a number of SRY regulators and these have their own regulators
• there are at least 4 SOX9 regulators
• SOX9 up-regulation then up-regulates the DMRT1 gene in a dose-dependent manner
• DMRT1 then drives differentiation of the gonad into a testis which then produces androgens which results in male phenotype being expressed
  • SOX9 also works with Sf1 to activate the expression of the Amh gene in the Sertoli cells to produce anti-mullerian hormone which prevents the formation of the female genital tract
  • Sf1 causes the interstitial mesenchyme cells of the testes differentiate into Leydig cells and make testosterone
  • Wnt4 expression then becomes undetectable in the gonad
  • later, the Leydig cells secrete another hormone, insulin-like hormone 3 (Insl3) which is required for the descent of the gonads into the scrotum

• in the absence of SRY, SOX9 is not up-regulated and no testis is formed and thus androgen levels remain low and several weeks later the following ovary-determining pathway is activated:
  • RSPO1 drives WNT4 and FOXL2 to cause the gonad to differentiate into an ovary
  • Wnt4 expression remains high in the gonad and is important in creating the ovary

• see Australian Journal of Zoology, 2016,64, 267–276 How Australian mammals contributed to our understanding of sex determination and sex chromosomes
• some 166-190 million years ago, early mammals and marsupials evolved based upon a new sex determination system - the XY system which has been retained in all eutherian mammals since then (although some rodents have lost the Y chromosome as the Y chromosome tends to degrade over time)
• the SOX9 and most of the other genes required for gonadogenesis are autosomal - the SOX9 gene has been highly conserved in all vertebrates and in some is the sex determining factor
• the gene DMRT1 is used by birds as their sex determination locus
• the immediate ancestors of mammals had a SOX3 gene which eventually evolved 166-190mya to be located on the X chromosome while the Y chromosome was just a degraded copy of this X chromosome and the SOX3 then evolved to become SRY - this created the XY sex chromosomes that created the evolutionary divergence of the therian mammals
• SOX3 is normally expressed in the central nervous system and in germ cells, but not in the somatic cells of the testis, so it has no normal role in sex determination but it is thought that SRY arose by a simple rearrangement that truncated SOX3 on the Y chromosome and substituted a promotor that drove its expression into the genital ridge.
• while marsupials only had the ancient X and Y genes, the next step in evolution which created the eutherian mammals was the addition of a number of autosomal genes onto the X chromosome (and thus also the degraded Y chromosome)
• NB. eutherian mammals are ALL mammals except for metatheurians (eg. marsupials) and monotremes (eg. platypus and echidna) and along with this new chromosomal structure came additional features:
  • a corpus callosum
  • a higher metabolic rate with a body temperature of 37degC (cw 35degC in marsupials and 31degC in monotremes)
  • nipples for lactation (present in marsupials but only as skin ducts in monotremes)
  • no longer egg laying as with monotremes or their predecessors which had reptilian/bird like sex determination genes