Sex Diff Paradigm: Question, Answer, Experiments

Teresa Binstock binstoct at essex.hsc.colorado.edu
Mon Jul 31 12:59:13 EST 1995



In response to my mini-papers (i) Sex Differentiation: Modifying the
Paradigm, and (ii) SD-Philosopy, a Net participant asked me the following
question:

>  Have any of the non-gonadal genomic level sex differences
>  definitely been shown to affect in a way that is not explained
>  by hormone production / metabolism / reception 
>  (a) the differentiation of the internal or external genitalia, and or 
>  (b) the sexual differentiation of the nervous system -- 
>  in either humans or other vertebrates?

RESPONSES to the question:

I.   Methylation of CpG islands and, relatedly, X-chromosome inactivation
are very related to the transcription of many genes. Early in embryonic
development (prior to the first hint of the gonadal ridge and thus of
gonadal hormones), levels of a methylation-related enzyme HPRT are twice as
high in females as in males. 
     This is due to the fact that very early in embryonic development in
the female, both X chromosomes are active; ie one is not yet inactivated.
That HPRT is expressed (in early embryonic development) at twice the 
level in females as in males suggests that some methylation-related 
encoding of at least some genes may be sexually dimorphic independently 
of SRY or lack of SRY.
     Interestingly, in the subgroup of male-HS subgroups studied by Hamer,
if I remember correctly, the X chromosomal difference noted among 33 of 40
male HS was regarding methylation of a specific locus.


II.  Alphoid repeat sequences (a phrase usually applied to DNA-satellite
sequences in/near the centromere) are profoundly different on the X and Y
chromosomes and are so dependably different as to be a way used for the sex
determination of human conceptuses and human tissue damaged beyond external
recognition.
    Given the role of telomeres and centromeres in shaping the cell nucleus
and in positioning its components with regard to the nuclear matrix, a
major sex difference in a major structural element (eg alphoid repeats
in/near centromeres) may well contribute to sexually dimorphic cellular 
function.


III. Chromosomal length is described in two confusingly interrelated ways,
(i) actual physical length (APL) and (ii) centi-Morgans (cM). APL is easily
understood; in contrast, cM is based upon rates of recombination and only
to some extent does cM correspond to APL. 
     What is clear is that human chromosomes including the autosomes (ie
chromosomes other than X and Y) are sexually dimorphic. Usually, this
dimorphism is described in terms of cM, which means (i) the precise
significance is difficult to determine, especially as regards nucleus/cell
function, and (ii) something is causing the different rates of
recombination. 
     Several projects would shed light upon this issue. Among humans, XX
males and XY females could be tested with regard to chromosomal cM length.
Does an XX male have chromosomes lengths of typical female length or of
typical male length? Does an XY female have chromosomes lengths of typical
male length or of typical female length? 
     Gonadectomy and cross-hormonal manipulations of species such as mice,
hamsters, etc., could be examined with regard to their chromosomal cM
length, so as to establish answers to questions such as: (i) Is the cM sex
difference caused by hormones? (ii) Does the cM sex difference reverse
itself if the creature's hormonal milieu is reversed? (iii) Is the cM sex
difference in chromosomes present in the zygote, and if not, by what
embryonic stage is the cM sex difference apparent? (iv) Are the cM sex
differences for the various chromosomes present in neurons? In other
tissues? Not in some tissues?
                    NOTE that these are just some of
                    the issues to be addressed.

IV.  My hunch is that the gonadal/hormonal paradigm {ie sex differentiation
(SD) is the equivalent of gonadal/hormonal SD} became a conceptual mind-set
because so many aspects of SD are gonadal and hormonal. This is especially
true regarding easily observable "primary" and secondary sexual
characteristics -- eg genitalia. Note that the word "primary" is placed in
quotes -- this so as to emphasize that there are genomic-level sex
differences that are even more primary than external genitalia.

V.   Until researchers address the possible ramifications of genomic level
sex differences which are neither gonadal nor hormonal, we ought not a
priori mandate (i) that such non-g/h sex differences may 
contribute to sexual and/or gender orientation, or (ii) that dysregulation 
of such non-g/h sex differences may contribute to varieties of sexual 
and/or gender orientation. 

VI.  The Nature side of the "Nature/Nurture debate and its complex
interplay compromise" is inherently weakened until genomic non-g/h sex
differences are researched. 
     A first step is to begin acknowledging the existence of genomic
     non-g/h sex differences and that they have yet to be researched
     with regards to possible behavioral effects.

                              ************

Because I have accepted the challenge of scouring the scientific literature
to discover and to develop these notions, I'm going to add a copyright
notice, which already appears in the two mini-papers and the abstract and
poster that preceeded the mini-papers. 

References in support of the above notions are in my mini-papers, which
will be provided upon request to my e-mail address.

                              ************
                           Copyright 1994/1995
                              ************

                                                            7.31.95

Teresa Binstock, Researcher
Developmental and Behavioral Neuroanatomy
Denver





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