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NeuroPsychological Traits-Diversity & X-Inactivation Mosaicism

Teresa Binstock binstoct at essex.hsc.colorado.edu
Mon Jun 19 14:46:04 EST 1995


NEUROPSYCHOLOGICAL TRAITS-DIVERSITY  &  X-INACTIVATION IN-BRAIN MOSAICISM.

         ***       ***       Copyright 1995       ***       ***
                           Teresa C. Binstock

I. INTRO:  Psychiatric, neuropsychological, and genetics literatures
often consider data suggesting that certain traits have subgroups of
persons in whom a given trait is linked to the X-chromosome. Usually,
even in best case scenarios, such data generate soft correlations.
     Furthermore, even when subgroups are selected by trait-occurrences
which follow X-linked inheritance patterns, the range of trait severity
is often very large, from not-affected to mildly affected to highly
affected.


II. X-LINKED IN-BRAIN MOSAICISM:  A recently published in-brain X-
inactivation study by Tan SS et al 1995 (Development 121.1029-39) may
contain data revealing why studies of X-linked neuropsychological
phenomena often report weak and/or soft and/or not quite statistically
significant correlations. 
     Consider calico cats and chaemeric mice with "calico-esque" fur
patterns -- both conditions are derived from X-activation mosaicisms of
the creatures' maternal and paternal X-chromosomes. Among humans,
similar mosaicisms are seen in various skin disorders (for marvelous
illustrations and good summary, see review by Rudolf Happle, MD; Arch
Dermatol 1993 129.1460-70). 
     Tan et al 1995 reported that in-brain X-inactivation patterns were
mosaical in various ways, including a 'checkerboard-esque' manner akin
to color patterns in calico cats' fur. 


III. SIGNIFICANCES:  Without here going into detail about the            
     complexities of X-inactivation, several points are offered:

A. Tan et al's findings were murine and not human; but if a
checkerboard-esque mosaicisms of X-inactivation patterns exist in the
brains of human females, then (within individual persons) some brain
areas would be directly affected by mutations of a brain-related X-
linked gene (eg FMR-1 and fragile X syndrome); and other areas of the
same person's brain would not be so affected.

     Certainly, interconnections between (i) areas directly
     affected by the person's specific X-located mutation and (ii)
     areas wherein the mutation was on the inactive X chromosome
     would to some extent affect areas wherein the mutation was
     silenced by inactivation of the X carrying the mutation. 

B. Despite the interconnectedness caveat set forth in item III-A above,
two overall principles remain: 
     1. Due to in-brain X-inactivation mosaicism, some brain areas
     would be directly affected by a specific X-located mutation
     and other areas (by virtue of having the other parent's
     chromosome as the active X) would not be directly affected.
     2. In-brain mosaical patterns would probably be different from
     person to person.

C. Consider how different are the color patterns of calico cats; also
consider that X-linked skin patterns in humans manifest a similar
diversity. Therefore, if checkerboard-esque patterns of in-brain X-
inactivation mosaicisms exist in humans (as do occur in the skin of
rats, hampsters, and humans), then within groups of females with
structurally identical (or virtually identical) X-chromosome gene
mutations which influence brain function:
     we would expect widely different cognitive, emotional, and
     behavioral mutation-related traits from person to person. 

D. This kind of "same-mutation but differing symptoms patterns" is known
to occur among females with any of a number of X-linked human disorders
-- generally regarding peripheral (non-CNS), easily measureable traits.


IV. TO BE PONDERED: The 'soft correlations' often found in studies of X-
linked neuropsychological traits may be an accurate representation of X-
inactivation mosaicism manifested as inter-individual traits diversity. 
(eg, fraX females data in Taylor et al 1994 JAMA 271.7.507-14; see also
Mingroni-Netto et al 1994 AJMG 51.443-6).

A. One ramification for analysis of X-linked neuropsychological traits
is that "soft" or "not quite approaching statitistical significance"
correlations do not necessarily justify the often-suggested conclusion
that "other genes and other chromosomes must be involved".  

B. In other words, at least some X-linked neuropsychological traits in
females may be pleiotropic due more to in-brain X-inactivation mosaicism
than to hypothesized "other genes".

C. Certainly, some clinically defined disorders (eg AD/HD) may have
numerous substrates (only some of which are X-linked) sufficient for
inducing a significant trait (eg AD/HD), and these substrates may well
include genes not on the X-chromosome. 

                         ***       ***       ***

CLOSING REMARKS: 

1. Most people are students neither of molecular genetics nor of
molecular aspects of developmental neuroanatomy, therefore the Tan et al
article may be rather difficult to follow. However, looking at the Tan
et al pictures on p1033 of the article will make very clear that brain
areas are quilt-like in their mosaicism with regard to activation of the
paternal and maternal X-chromosomes.

2. Epidermal and brain tissues originate from a similar portion of the
embryo, suggesting that X-inactivation mosaicism patterns may be similar
in skin and brain -- especially since that possibility has now been
shown in the murine brain by Tan et al.

3. Herein I use the word "checkerboard-esque" rather metaphorically so
as to convey a quilt-like patterns meaning. Both "checkerboard-esque"
and "quilt-like" are my metaphoric words, not those of Tan et al 1995.
Readers of this Internet document are advised to consult the Tan et al
article for a thorough delineation of in-brain X-inactivation patterns. 

4. Via the checkerboard comparison: if a brain-related gene is mutated
and "active" in the red squares, those brain-areas will be structurally
and functionally different from black-squares brain-areas wherein a non-
mutated form of that gene is present. Furthermore, in-brain X-
inactivation patterns are more diverse, more calico-esque than is a
checkerboard. 

5. I wrote Tan et al shortly after their article became available and
included the Rudolf Happle article and a preliminary delineation of the
Tan et al findings' significance to neuropsychology and to related
statistical analyses of X-linked traits. 
     Tan replied (via his colleague Leslie Stone, UCHSC Denver CO USA)
that he and his group had not yet thought of neuropsychological traits
variation as a ramification of his group's in-brain X-inactivation
mosaicism findings. 

6. I believe the findings of Tan et al are of major importance to how X-
linked, mutation-related neuropsychological traits are understood and
their data analysed; and thus I have chosen to place this rather hastily
assembled summary onto the Internet. 

7. Additional references will be provided upon request. 

         ***       ***       Copyright 1995       ***       ***
                           Teresa C. Binstock

                    If, in a paper (etc) of your own,
            you use ideas original to this Internet document,
                    please cite:
                         Teresa C. Binstock 1995
                   <this news group or listserv group>
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Teresa C. Binstock, Researcher                    article first posted
Developmental and Behavioral Neuroanatomy            onto Internet: 
B140 Child Development Unit                              6.19.95
The Children's Hospital
1056 E. 19th Avenue
Denver CO 80218 USA




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