revised posting (6.24.95):
SEX DIFFERENTIATION: MODIFYING THE PARADIGM
Numerous scientific articles describe gonadal and hormonal aspects of sex
differentiation. Many such articles describe gonadal and hormonal effects
upon various regions and components of the brain. Additional factors in
gonadal and hormonal differentiation of the human brain include enzymes
such as 3-beta hydroxysteroid dehydrogenase, 21-hydroxylase, and
Often, information from these articles is utilized by writers (etc) who
argue either for or against "biological bases" of sexual- and/or gender-
However, and for the moment not considering psychogenic aspects
of learned sexual-differentiation:
TO EQUATE sexual differentation (SD)
with SD arising from gonadal/hormonal (g/h-SD) processes
This erroneous presumption is very prevalent and biases research
into the biological (molecular, genetic, etc) basis of male/female brain
differences and also weakens the Nature side of Nature/Nurture arguments.
To equate SD with g/h-SD is erroneous because in recent years
numerous sceintific article have been reporting genomic-DNA sex
differences that are neither gonadal nor hormonal.
Until scientists (including neuroscientists and behavioralists)
acknowledge and research possible ramifications of these sex differences,
many possible genomic-DNA contributors to sexual- and/or gender-
orientation shall be overlooked.
Because the Nature/Nurture arguement still "rages", the following
mini-paper is offered in its ever so crude form:
ABSTRACT, POSTER, AND PAPER in 1994:
The following points are summarized from an abstract and paper entitled
"Sex Differentiation: Modifying the Paradigm" first presented at the 8th
Biennial Retreat of the Developmental Psychobiology Research Group of the
University of Colorado (USA) Health Sciences Center in May of 1994.
The retreat was entitled "Gender Differences in Brain and Behavior", and
Teresa Christine Binstock is author of and retains copyright to the above
named abstract and paper and to this summary thereof.
MAIN POINTS of the abstract:
I. For many decades the concept "Sexual Differentiation" (SD) has been
conceived as the equivalent of gonadal/hormonal SD (i.e., g/h-SD).
A. The presumption that SD is the equivalent g/h-SD is erroneous and
misleading, because there are genomic sex differences (other than lack of
or presence of SRY) that are neither gonadal nor hormonal.
B. Examples of SD that is neither gonadal nor hormonal nor SRY-related
include but are not necessarily limited to:
1. alphoid repeat sequences (satellite DNA) of the X and Y chromosomes.
2. within the X,Y pseudoautosomal regions, an RNA protein that is similar
but different on the X and Y chromosomes.
3. differences in replication timing of the X and Y chromosomes -- i.e.,
among human males, the Y and X chromosomes have replication-timimg patterns
different from the replication-timing patterns of the active X
and the inactive X chromosomes in human females.
4. differences in the levels of HPRT in pre-morula blastomeres of mouse
and human embryos.
5. different male/female lengths of autosomomal chromosomes. Note that in
this useage length may in fact be "length" because chromosomal length is
often defined in terms of recombination rates and a related concept of
centiMorgans (cM), and dependending upon what text a person is reading,
physical length of an autosomal chromosome is not quite the equivalent of
"length" defined in cM units. Regardless, something is causing a
recombination-rate difference between male and female autosomes (thus a cM
sex difference for most autosomes). Furthermore, in some
specific areas of certain chromosomes this sex difference (re: cM) is
reversed. Furthermore, to some extent actual, physical length of
autosomes is "kinda, sorta like" cM recombninational "length" (pardon the
slang, but that's about as accurate as many texts are re: cM-length versus
6. Another interesting category is: Sexual Reversals that appear
to be independent of SRY (and its presence or lack), such as
occurs in campomelic dysplasia.
SOME REFERENCES ARE PROVIDED AT END OF THIS DOCUMENT
C. These male/female sex differences exist from the time of conception
and thus preceed development of the gonadal ridge and are accurately
described as sex differences which are neither gonadal nor hormonal.
D. These sex differences that are neither hormonal nor gonadal may, if
dysregulated, contribute to alterations of sexual- and/or gender-
orientation in some individuals. Such a possibility cannot be a priori
overlooked, and research that does so overlook is erroneously,
misleadingly conceived if based upon a stated or implicit presumption
that all SD = g/h-SD.
INSTEAD: g/h-SD is a subset of overall genomically determined SD.
II. For many decades, the vomeronasal organ (VO) in humans has been
described variously as not existing, so small as to be of little
importance, and as a mere rudiment of pre-human evoluHtionary development.
At least one 1994 neuroanatomy text states "authoritatively" that
significant VO processing does not occur in humans.
A. This well established belittling of the human VO is erroneous and
B. Between 1980 and 1994, various mainstream scientific journals have
published at least 10 studies documenting aspects of the occurrence,
ultrastructure, and function of the human VO.
C. The VO is strongly implicated in mammalian responses to sexual
pheromones emitted by other creatures of the same species.
III. We Repeat: Gonadal/hormonal SD is a subset of SD; some SD is genomic
and is neither gonadal nor hormonal and even preceeds development of the
gonadal ridge and thus also preceeds and is more fundamental than
subsequent hormonally induced SD.
IV. Although erroneous, the presumptive equating of SD with g/h-SD is
A. A misleading SD-paradigm misdirects and biases research.
B. Mistakenly equating SD with g/h-SD leads to misconstructed
observations, rationales, experiments, and discussions (i) about
male/female brain differences, and (ii) about possible causes of gender-
and/or sexual orientation.
C. Mistakenly equating SD with g/h-SD also biases aspects of the Nature
versus Nurture debate.
V. Similarly, outmoded notions about the human VO wrongfully bias
research concerning (i) male and female brain function, and (ii) possible
mechanisms and/or pathogeneses of sexual and/or gender orientation.
VI. Circa 1995 and beyond, ideas about human SD and about
biological components of gender orientation and sexual orientation are on
less than solid footing if they fail to consider either the human
vomeronasal organ or genomic SD which is neither gonadal nor hormonal.
Copyright 1994 1995
Teresa C. Binstoct
A miscellany of topically arranged references is included herewith; and,
when completed, a newly re-written paper on this topic can be obtained from:
Teresa C. Binstock via Binstoct at essex.hsc.colorado.edu
TWO POSTSCRIPTIONAL COMMENTATIONS:
1. The Nature side of the Nature/Nurture argument won't be complete until
scientists quit ignoring genomic-DNA sex differences which are neither
hormonal nor gonadal.
2. The "complex interplay" truce between the Nature-as-cause adherents and
the Nurture-as-cause adherents has diluted, weakened validity until
scientists and Nature/Nurture debatesters quit ignoring the possible
contributions of genomic-DNA sex differences which are neither hormonal
This list of references is not intended as inclusive, and I would
appreciate learning of other genomic-level sex differences that are
independent of SRY-related gonadal/hormonal differentiation, but the
following are as a "starting kit"...
I. HPRT LEVELS IN PRE-MORULA BLASTOMERES
Comment: HPRT is an enzyme related to methylation, a process very important
to the expression and/or silencing of gene expression.
Epstein, C.J., Travis, B., Tucker, G. and Smith, S.
The direct demonstration of an X-chromosome dosage effect prior to
Basic.Life Sci 12:261-267, 1978.
Kratzer, P.G. and Gartler, S.M.
Hypoxanthine guanine phosphoribosyl transferase expression in early mouse
Basic.Life Sci 12:247-260, 1978.
Monk, M. and Harper, M.
X-chromosome activity in preimplantation mouse embryos from XX and XO
J Embryol.Exp Morphol. 46:53-64, 1978.
Biochemical studies on X-chromosome activity in preimplantation mouse
Basic.Life Sci 12:239-246, 1978.
Expression of maternally and embryonically derived hypoxanthine
phosphoribosyl transferase (HPRT) activity in mouse eggs and early embryos.
Genetics 104:685-698, 1983.
Braude, P.R., Monk, M., Pickering, S.J., Cant, A. and Johnson, M.H.
Measurement of HPRT activity in the human unfertilized oocyte and pre-
Prenat.Diagn. 9:839-850, 1989.
Reid, L.H., Gregg, R.G., Smithies, O. and Koller, B.H.
Regulatory elements in the introns of the human HPRT gene are necessary for
its expression in embryonic stem cells.
Proc Natl Acad Sci U.S.A. 87:4299-4303, 1990.
II. ALPHOID REPEAT SEQUENCES
Comment: Satellite DNA and alphoid repeat sequences are often centromeric
and may contribute to nuclear matrix structure and overall cell function.
Schmeckpeper, B.J., Scott, A.F. and Smith, K.D.
Transcripts homologous to a long repeated DNA element in the human genome.
J Biol Chem 259:1218-1225, 1984.
Longmire, J.L., Ambrose, R.E., Brown, N.C., Cade, T.J., Maechtle, T.L.,
Seegar, W.S., Ward, F.P. and White, C.M.
Use of sex-linked minisatellite fragments to investigate genetic
differentiation and migration of North American populations of the
peregrine falcon (Falco peregrinus).
Experientia Suppl 58:217-229, 1991.
Levinson, G., Fields, R.A., Harton, G.L., Palmer, F.T., Maddalena, A.,
Fugger, E.F. and Schulman, J.D.
Reliable gender screening for human preimplantation embryos, using multiple
Hum Reprod. 7:1304-1313, 1992.
Panicker, S.G. and Singh, L.
Banded krait minor satellite (Bkm) contains sex and species-specific
Chromosoma 103:40-45, 1994.
Steuerwald, N., Lambert, H., Steinleitner, A.J. and Herrera, R.J.
Gender determination by multiplex PCR amplification of alphoid repeat
sequences from single cells.
Biotechniques 16:82-84, 1994.
III. CHROMO RECOMBINATION, LENGTH, CM DIFFERENCES
Comment: The following references are just the tip of the iceberg re sex
differences between autosomal chromosomes.
Blanche, H., Zoghbi, H.Y., Jabs, E.W., de Gouyon, B., Zunec, R., Dausset,
J. and Cann, H.M.
A centromere-based genetic map of the short arm of human chromosome 6.
Genomics 9:420-428, 1991.
Carson, N.L. and Simpson, N.E.
A physical map of human chromosome 10 and a comparison with an existing
Genomics 11:379-388, 1991.
Beckmann, J.S., Tomfohrde, J., Barnes, R.I., Williams, M., Broux, O.,
Richard, I., Weissenbach, J. and Bowcock, A.M.
A linkage map of human chromosome 15 with an average resolution of 2 cM and
containing 55 polymorphic microsatellites.
Hum Mol Genet 2:2019-2030, 1993.
Dawson, E., Shaikh, S., Weber, J.L., Wang, Z., Weissenbach, J., Powell,
J.F. and Gill, M.
A continuous linkage map of 22 short tandem repeat polymorphisms on human
Genomics 17:245-248, 1993.
Petrukhin, K.E., Speer, M.C., Cayanis, E., Bonaldo, M.F., Tantravahi, U.,
Soares, M.B., Fischer,
S.G., Warburton, D., Gilliam, T.C. and Ott, J.
A microsatellite genetic linkage map of human chromosome 13.
Genomics 15:76-85, 1993.
Straub, R.E., Speer, M.C., Luo, Y., Rojas, K., Overhauser, J., Ott, J. and
A microsatellite genetic linkage map of human chromosome 18.
Genomics 15:48-56, 1993.
IV. CHROMO 9 SEX REVERSALS AND SOX 9
Bennett CP et al.
Deletion 9p and sex reversal.
J Med Genet 30.518-20, 1993.
Ebensperger C et al.
No evidence of mutations in four candidate genes for male sex
determination/differentiation in sex-reversed XY females with compomelic
Ann Genet 34.233-8, 1991.
Wagner T et al.
Autosomal sex reversal and compomelic dysplasia are caused by mutations in
and around the SRY-related gene SOX9.
Cell 79.1111-20, 1994.
V. X,Y RIBOSOMAL PROTEINS DIFFERENCES
Fisher EMC et al
Homologous ribosomal protein genes on the human X and Y chromosomes: escape
from X inactivation and possible implications for Turner syndrome.
Cell 63.1205-18, 1990.
VI. DIFFERING REPLICATION-TIMING SEQUENCES
Teresa comment: I'm amidst re-finding these references within boxed, moved,
and gradually unboxed piles of articles, and will forward them soon after
they are re-located.
Singer-Sam, J., Chapman, V., LeBon, J.M. and Riggs, A.D.
Parental imprinting studied by allele-specific primer extension after PCR:
paternal X chromosome-linked genes are transcribed prior to preferential
paternal X chromosome inactivation.
Proc Natl Acad Sci U.S.A. 89:10469-10473, 1992.
Lavedan, C., Hofmann-Radvanyi, H., Rabes, J.P., Roume, J. and Junien, C.
Different sex-dependent constraints in CTG length variation as explanation
for congenital myotonic dystrophy [letter] [see comments].
Lancet 341:237, 1993.
McPhaul, M.J., Herbst, M.A., Matsumine, H., Young, M. and Lephart, E.D.
Diverse mechanisms of control of aromatase gene expression.
J Steroid Biochem Mol Biol 44:341-346, 1993.
Olaisen, B., Bekkemoen, M., Hoff-Olsen, P. and Gill, P.
Human VNTR mutation and sex.
Experiential Suppl 67:63-69, 1993.
Fisher EM et al.
Human sex-chromosome-specific repeats within a region of pseudoautosomal/Yq
Genomics 7.625-8 1990.
Ellis NA et al.
Cloning of PBDX, an MIC2-related gene that spans the pseudoautosomal
boundary on chromosome Xp. [see 2nd new paragraph, p398]
Nature Genetics 6.394-400.
*** *** Very Important *** ***
Cremer, T., Kurz, A., Zirbel, R., Dietzel, S., Rinke, B., Schrock, E.,
Speicher, M.R., Mathieu, U., Jauch, A., Emmerich, P. and et al,
Role of chromosome territories in the functional compartmentalization of
the cell nucleus.
Cold Spring Harb.Symp.Quant.Biol 58:777-792, 1993.
VII. VOMERONASAL REFERENCES:
1. Fernandez-Fewell, G.D. and Meredith, M. c-fos expression in vomeronasal
pathways of mated or pheromone-stimulated male golden hamsters:
contributions from vomeronasal sensory input and expression related to
mating performance. J Neurosci. 14:3643-3654, 1994.
2. Johnson, E.W., Eller, P.M. and Jafek, B.W. Calbindin-like
immunoreactivity in epithelial cells of the newborn and adult human
vomeronasal organ. Brain Res. 638:329-333, 1994.
3. Pfeiffer, C.A. and Johnston, R.E. Hormonal and behavioral responses of
male hamsters to females and female odors: roles of olfaction, the
vomeronasal system, and sexual experience. Physiol Behav 55:129-138, 1994.
4. Wang, R., Jiang, S. and Gu, R. [Immunohistochemical study of the
olfactory mucosa and vomeronasal organ in rat, guinea pig and human fetus].
Chung.Hua.Erh.Pi.Yen.Hou.Ko.Tsa.Chih. 29:23-26, 1994.
5. Boehm, N. and Gasser, B. Sensory receptor-like cells in the human
foetal vomeronasal organ. Neuroreport. 4:867-870, 1993.
6. Takami, S., Getchell, M.L., Chen, Y., Monti-Bloch, L., Berliner, D.L.,
Stensaas, L.J. and Getchell, T.V. Vomeronasal epithelial cells of the adult
human express neuron-specific molecules. Neuroreport. 4:375-378, 1993.
7. Johnston, R.E. Vomeronasal and/or olfactory mediation of ultrasonic
calling and scent marking by female golden hamsters. Physiol Behav
8. Mitchell, J.B. and Gratton, A. Mesolimbic dopamine release elicited by
activation of the accessory olfactory system: a high speed
chronoamperometric study. Neurosci.Lett. 140:81-84, 1992.
9. Garcia-Velasco, J. and Mondragon, M. The incidence of the vomeronasal
organ in 1000 human subjects and its possible clinical significance. J
Steroid Biochem.Mol.Biol. 39:561-563, 1991.
10. Monti-Bloch, L. and Grosser, B.I. Effect of putative pheromones on the
electrical activity of the human vomeronasal organ and olfactory
epithelium. J Steroid Biochem.Mol.Biol. 39:573-582, 1991.
11. Moran, D.T., Jafek, B.W. and Rowley, J.C. The vomeronasal (Jacobson's)
organ in man: ultrastructure and frequency of occurrence. J Steroid
Biochem.Mol.Biol. 39:545-552, 1991.
12. Stensaas, L.J., Lavker, R.M., Monti-Bloch, L., Grosser, B.I. and
Berliner, D.L. Ultrastructure of the human vomeronasal organ. J Steroid
Biochem.Mol.Biol. 39:553-560, 1991.
13. Ortmann, R. [The sensory cells of the fetal vomeronasal organ in the
human. A contribution to the variability of their differentiation and
rudimentary development]. HNO. 37:191-197, 1989.
14. Harrison, D. Preliminary thoughts on the incidence, structure and
function of the mammalian vomeronasal organ. Acta Otolaryngol.(Stockh)
15. Singer, A.G., Agosta, W.C., Clancy, A.N. and Macrides, F. The chemistry
of vomeronasally detected pheromones: characterization of an aphrodisiac
protein. Ann.N.Y.Acad.Sci. 519:287-298, 1987.
16. Johns, M.A. The role of the vomeronasal organ in behavioral control of
reproduction. Ann.N.Y.Acad.Sci. 474:148-157, 1986.
17. Johnson, A., Josephson, R. and Hawke, M. Clinical and histological
evidence for the presence of the vomeronasal (Jacobson's) organ in adult
humans. J Otolaryngol. 14:71-79, 1985.
18. Nakashima, T., Kimmelman, C.P. and Snow, J.B. Vomeronasal organs and
nerves of Jacobson in the human fetus. Acta Otolaryngol.(Stockh)
19. Lehman, M.N. and Winans, S.S. Vomeronasal and olfactory pathways to the
amygdala controlling male hamster sexual behavior: autoradiographic and
behavioral analyses. Brain Res. 240:27-41, 1982.
20. Porter, R.H. and Moore, J.D. Human kin recognition by olfactory cues.
Physiol Behav 27:493-495, 1981.
21. Kreutzer, E.W. and Jafek, B.W. The vomeronasal organ of Jacobson in the
human embryo and fetus. Otolaryngol.Head.Neck Surg. 88:119-123, 1980.
22. Wysocki, C.J. Neurobehavioral evidence for the involvement of the
vomeronasal system in mammalian reproduction. Neurosci.Biobehav.Rev.
23. Keith, L., Draunieks, A. and Krotoszynski, B.K. Olfactory study: human
pheromones. Arch.Gynakol. 218:203-204, 1975.
24. Winans, S.S. and Scalia, F. Amygdaloid nucleus: new afferent input from
the vomeronasal organ. Science 170:330-332, 1970.