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Evolution of Sex Determination

Penniman B. Austin seq4 at sfsuvax1.sfsu.edu
Fri Dec 9 05:10:20 EST 1994

Dear Richard,
   Read your extract with interest. It is reproduced here, followed by my

Regards,  Penniman

Extract from: Gordon, R. (1995). The Hierarchical Genome and 
Differentiation Waves: Novel Unification of Development, Genetics, and 
Evolution (Singapore: World Scientific), in prep.

Proposition 39A: the sex of an individual is determined by triggering of 
an expansion or a contraction differentiation wave, corresponding to 
female and male (or vice versa).

In mammals, the reproductive system starts out as a sexually "neutral" 
tissue, the fetal gonad, a tissue competent to begin sexual 
differentiation into either a female or male. While a male "Y chromosomal 
gonadogenesis gene" ({Platt, 1990}), perhaps the "Y-linked gene Sry" 
({Lovell-Badge, 1993}) may exist (cf. {Eicher, 1988; Mittwoch, 1989}), 
our species occasionally produces an XY female ({Kingsbury, Frost & 
Cookson, 1987; Hipkin, 1993}) or an XX male ({Zakharia & Krauss, 1990}). 
It is possible that all of these will be attributable to Y-chromosomal 
DNA translocations and deletions ({Muller, 1987; Levine & Suzuki, 1993}), 
"It is concluded that the notion of a single testis-determining gene 
being responsible for male sex differentiation lacks biological 
validity.... The genes involved in testis development may function as 
growth regulators in the tissues in which they are active" ({Mittwoch, 
Thus, let us suppose that some "accident" of development, such as a viral 
infection or fever of the mother, occurs after the tissue is competent, 
but before the "appropriate" wave is initiated somehow by zygotic gene 
products. Sexual development would then proceed apace independent of the 
so-called sex determining gene. Cases of "mixed gonadal dysgenesis" 
({Cantrell et al., 1989}) may be due to both waves proceeding through 
complementary portions of the fetal gonad, rather than one wave 
traversing the whole of the tissue. The demonstration of embryonic 
induction by grafts ({Rashedi et al., 1990}; cf. {Lesimple et al., 1989}) 
and experimental chimeras ({Burgoyne, Buehr & McLaren, 1988}), and a 
genitourinary, pleiotropic gene of "mesenchymal - epithelial transitions" 
({Pritchard-Jones et al., 1990}; cf. {Marcantonio et al., 1994}), may 
implicate a differentiation wave.

It is curious that in crocodiles ({Smith & Joss, 1994}), geckos ({Gutzke 
& Crews, 1988}) and turtles ({Wibbels, Bull & Crews, 1991}) temperature, 
rather than the genome, "determines" whether an egg develops as a male or 
female, with an abruptness akin to a phase transition:

"As in many other turtles, the sexual differentiation of gonads in 
embryos of Emys orbicularis  is temperature-sensitive, 100% phenotypic 
males being obtained below 27.5 degrees C and 100% phenotypic females 
above 29.5 degrees C.... Both sexes differentiate at 28.5 degrees C, 
suggesting that at this intermediate (threshold) temperature, sexual 
differentiation of gonads conforms with sexual genotype" ({Zaborski, 
Dorizzi & Pieau, 1988}).

Within a critical temperature range, genetic determination of sex occurs, 
while above or below, males or females may be produced, depending on 
species ({Dournon, Houillon & Pieau, 1990}), and hormone dependent sex 
reversal can only be attained in a critical period ({Desvages, Girondot & 
Pieau, 1993}), with the exception of placental mammals ({Wolf, 1988}). It 
appears that this temperature sensitive process can be biased by 
exogenously applied sex hormones ({Gutzke & Chymiy, 1988; Gahr, Wibbel & 
Crews, 1992}). These observations may give a clue to the unknown 
mechanism by which it is determined whether a new wave proceeds as an 
expansion or as a contraction wave. If so, it will be interesting to know 
if the type of wave initiated is in strict correlation with the resulting 
sex, independent of species and temperature dependence. However, it will 
take some effort to distinguish this initial step of sex determination 
from the multiple subsequent steps of sex differentiation, many hormone 
dependent ({Voutilainen, 1992}), which are perhaps involved in cases of 
sexual ambiguity ({New & Josso, 1988; Crews, Wibbels & Gutzke, 1989; 
de la Chapelle et al., 1990; Wilker et al., 1994}) and "alternative 
pathways for the development of the same final sex" in fish ({Shapiro, 

1. Your premise that the mammalian fetal gonad is neutral prior to
entering either of the sex determining pathways is consistent with a
growing number of observations. Whether female or male differentiation
occurs is an active process, requiring the contributions of several genes
and proteins. Furthermore, sex determination and sex differentiation are
widely separated in developmental time and may be reversed. There are
still however, a number of people who operate on the premise that the
"default mode" of the fetus is female and that the action of the
testis-determining factor TDF is equivalent to overall sex
differentiation. This does not adequately address the complexity of sex
differentiation with regard to its various components: chromosomal sex -
usually, but not always, 46, XX for females, and 46, XY for males; H-Y
antigenic sex, recognized  through a microscope in most cases on the
surface of 46, XY but not 46, XX cells; gonadal sex - usually either
ovarian or testicular or, rarely, as a combination ovotestis; prenatal
hormonal sex - either masculinizing, feminizing, or sometimes failing; sex
of the internal reproductive organs; sex of the external reproductive
organs; neuroanatomical sex (of the brain and central nervous system. 
2. With regard to the XY female, a number of these individuals have been
shown to have deletions1,2,3 or base pair substitutions4 in the conserved
motif of the SRY nucleotide sequence. More recently, two independent teams
studying XY females with intact SRY genes, discovered a gene on the X
chromosome (DSS: Dosage Sensitive Sex reversal/SRVX: Sex Reversal X) that
appears to cause differentiation toward the female when present in a
"double dose".5,6 
3. The occurrence of XX males is even more complex, due to the phenomenon
of X-inactivation and the aspects of sex determination/differentiation
that are hormone-independent and are a matter of gene dosage. In addition,
there is the matter of the mosaicism associated with an XX genotype. What
has been observed with XX males is: nondisjunction of the X pair followed
by fertilization of an XX egg with a Y sperm, and subsequent loss of the Y
in cells of an early XXY embryo 7,8,9; XX/XXY mosaicism 10; Y-autosome
translocation 11,12; Y-X translocation, specifically translocation of TDF
from distal Yp near the PAR (pseudoautosomal region) to distal Xp
13,14,15; mutation of a gene downstream from TDF in the testis-determining
4. It is also important to note that anomalies of sex determination and
differentiation are sometimes accompanied by other phenotypic effects such
as retardation and adrenal hyperplasia.
5. How would your hypothesis apply to cancer in a pregnant woman? 


1. Vilain, E., McElreavey, K., Jaubert, F., Raymond, J.-P., Riuchaud,F.,
and Fellous, M. (1992) Familial case with sequence variant in the
testis-determining region associated with two sex phenotypes. Am J. Hum
Genet. 50:1008-1011
2. Beer-Romano, P., Reindollar, R.H., Fusaris, K., Gray, M.R., and Page,
D.C. (1992)
Mutations identified by rapid screening of the SRY locus in 46, XY gonadal
dysgenesis and true hermaphrodite patients with denaturing gradient gel
electrophoresis (DGGE).
Annu. Meet. Soc. Gynecol. Invest., San Antonio Sci. Program Abstr., Abstr.
No. 146, p.181.
3. Hawkins, J.R., Taylor, A., Berta, P., Levilliers, J., van der Auwera,
B., and Goodfellow, P.N. (1992a) Mutational analysis of SRY: nonsense and
missense mutations in XY sex reversal. Hum. Genet. 88: 471-474. Hawkins,
J.R., Taylor, A., Goodfellow, P.N.,
Migeon, C.J., Smith, K.D., and Berkovitz, G.D. (1992b). Evidence for
increased prevalence of SRY mutations in XY females with complete rather
than partial gonadal dysgenesis. Am. J. Hum. Genet. 51:979-984.
4. Jaeger, R.J., Anvret, M., Hall, K., and Scherer, G. (1990) A human XY
female with a frame shift mutation in the candidate testis-determining
gene SRY. Nature (London) 348:452-454.
5. Arn, P., Chen, H., Tuck-Miller, C.M., Mankinen, C., Wachtel, G., Li,
S., Shen, C.-C., Wachtel, S.S. (1994) SRVX, a sex reversing locus in
Xp21.2->p22.11. Hum. Genet. 93:389-393.
6. Bardoni, B., Zanaria, E., Guioli, S., Floridia, G., Worley, K.C.,
Tonini, G., Ferrante, E., Chiumello, G., McCabe, E.R.B., Fraccaro, M.,
Zuffardi, O., and Camerino, G. (1994) A dosage sensitive locus at
chromosome Xp21 is involved in male to female sex reversal.
7. de la Chapelle, A., Hortling, H., Niemi, M., and Wennstrom, J. (1964)
XX sex chromosomes in a human male. First case. Acta Med. Scand., Suppl.
8. Dosik, H., Wachtel, S.S., Khan, F., Spergel, G., and Koo, G.C., (1976) 
Evidence for the presence of Y-chromosomal genes in a phenotypic male with
a 46,XX karyotype. J. Am. Med. Assoc. 236: 2505-2508.
9. Miro, R., Caballin, M.R., Marsini, S., and Egozcue, J. (1978) Mosaicism
in XX males. Hum. Genet. 45:103-106.
10. de la Chapelle, A.,  Hastbacka, J., Korhonen, T., and Maenpaa, J.
(1990). The etiology of XX sex reversal. Reprod. Nutr. Dev.  (Suppl. 1),
39s-49s. [Same as one of your references.]

11. Koo, G.C., Wachtel, S.S., Krupen-Brown, K., Mittl, L.R., Breg, W.R.,
Genel, M., Rosenthal, I.M., Borgaonkar, D.S., Miller, D.A., Tantravahi,
R., Schreck, R.R., Erlanger, B.R., and Miller, O.J. (1977). Mapping the
locus of the H-Y gene on the human Y chromosome. Science 198:940-942.
12. Verjaal, M., Treffers, P.E., Nagai, Y., and Leschot, N.J., (1978)
Prenatal diagnosis of a de novo Y/22 translocation. J. Med. Genet.
13. Madan, K., and Walker, S. (1974) Possible evidence for Xp+ in an XX
male. Lancet 1:1223.
14. Wachtel, S.S., Koo, G.C., Breg, W.R., Thaler, H.T., Dillard, G.M.,
Rosenthal, I.M.,
Dosik, H., Gerald, P.S., Saenger, P., New, M., Lieber, E., and Miller,
O.J. (1976) Serologic detection of a Y-linked gene in XX males and XX true
hermaphrodites. N. Engl.
J. Med. 295:750-754.
15. Evans, H.J., Buckton, K.E., Spowart, G., and Carothers, A.D. (1979)
Heteromorphic X chromosomes in XX males: Evidence for the involvement of
X-Y interchange. Hum. Genet. 49:11-31.
16. Page, D.C., de la Chapelle, A., and Weissenbach, J. (1985) Chromosome
DNA in related human XX males. Nature (London) 315:224-226.

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