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Dual-gender macrochimeric tissue discordance is predicted to be a significant cause of human homosexuality and transgenderism

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Abstract

The existence of human macrochimeras in which large proportions of cells are male and female is predicted to have a correlation with homosexuality and transgender self-identification because in many such cases, the central nervous system, or crucial parts of it, will be of one sex and the gonads and body form will be of the opposite sex. The literature indicates that the sex of nervous system tissue is the primary determinant in higher animals of sexual attraction. Evidence shows that human chimerism may be quite common, occurring in between 5% and 15% of people. Chimerism has been believed to be rare because it usually presents without visible phenotype.
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Hypotheses in the Life Sciences 1 3 pp 63-70
Dual-gender macrochimeric tissue discordance is predicted to be a
significant cause of human homosexuality and transgenderism
Brian P. Hanley
Butterfly Sciences, PO Box 2363, Davis, CA 95617, USA. Email: Brian.Hanley@ieee.org
Abstract
I present literature evidence that suggests that human chimerism may be quite common, occurring in between 5%
and 15% of people. Chimerism has been believed to be rare because it usually presents without visible phenotype. In
addition to the documented occurrence of dual gender macrochimeras with true hermaphrodite phenotype, there are
reports of the occurrence of other natural human macrochimeras. The literature reviewed in this paper suggests that
such macrochimerism is much more common than usually appreciated. Chimerism occurs in a patchy manner, with
male cells outgrowing female in macrochimerism causing the majority to be phenotypically male. The literature also
suggests that the sex of nervous system tissue is the primary determinant in higher animals of sexual attraction.
From this, the existence of human macrochimeras in which large proportions of cells are male and female is
predicted to have a correlation with homosexuality and transgender self-identification because in many such cases,
the central nervous system, or crucial parts of it, will be of one sex and the gonads and body form will be of the
opposite sex. I describe experiments to further clarify this hypothesis, which can also have potential benefit beyond
this specific question.
Keywords: homosexuality; homosexual; transgenderism; transgender; chimerism; chimera; macrochimerism;
macrochimera; tetragametic; dispermic; gender discordance
Introduction
Chimerism
Chimerism is the condition of any single individual
composed of cells derived genetically from more than
one pair of gametes. It is known that chimerism
stemming from dizygotes where at least one is male
and another is female occurs in humans[1, 2]. These
cases were detected due to investigation of the very
rare phenotype of true hermaphroditism. There are very
few instances where macrochimerism could be visible
based on phenotype. The two that are known are first,
true hermaphroditism, and second, apparent mosaicism.
Every other chimera phenotype would present without
any noticeable features.
The term tetragametic chimerism is often used to
describe merging of fraternal twin embryos. However,
the term macrochimerism will be used here since in
theory more than two embryos could merge to become
one chimeric organism and several different kinds of
chimerism have been discovered.
Chimerism presents in quite a few forms, which
derive from different causes. Perhaps the most common
forms of chimerism are fetal microchimerism in
mothers [3, 4] and maternal microchimerism that
occurs in their children [5]. In the former type of
microchimerism, cells from the fetus cross over the
placenta and take up residence in the body of the
mother. In the latter type, maternal cells cross over the
placenta into the fetus and live on in the child. A
somewhat less common form occurs in multiple births
[6, 7] crossing from sibling to sibling. In all these forms
of microchimerism, relatively small numbers of cells
cross over and migrate to organs in the mother, child,
or sibling where they may persist. In mothers, their
offspring’s cells have been shown to persist for decades
after giving birth [3].
Brian P. Hanley
Chimeric tissue sex discordance in homosexuality
64
Transplanting of any organ or tissue, such as a
kidney, bone marrow, and even whole blood
transfusion is also a type of chimerism. Transplanted
tissue can lead to migration of cells from the donor into
the host, and this can be a concern when examining
simple results, such as from blood tests, of possible
chimerism. Chimerism results need to be evaluated for
degree of relatedness as an early method of ruling out
such a possibility. SCID mice can have humanized
immune systems provided for them this way, a method
that has become standardized today [8].
Methods for manipulating mammals to generate
macrochimeras have been known for half a century [9,
10] and experimental examination of in-vitro created
chimeras is well developed [11]. Bringing embryos
together in the morula or early blastocyst stage can
result in aggregation into a chimerical embryo [10, 12].
Experimental chimerism in animals shows a patchy
pattern with most of one organ formed from one
genotype, most of the next from another[13]. Natural
chimerism also occurs with low level infiltration in
organs[14]. As will be discussed below, these results
provide insight into the potential behaviour of
spontaneous chimeras.
Multi-species chimeras can be generated in the lab,
which has generated some controversy. Most
commonly this lab procedure is done by inserting stem
cells from a foreign organism into an animal embryo,
by injection[11]. Prior to registration of markers for
self by the immune system, virtually any tissue will be
accepted.
For the purposes of this discussion, a macrochimera
is a single individual formed from cells originating in
two or more separately fertilized embryos, leading to
large proportions of the resulting organism being
formed by each original participating embryo. It would
not be correct to term the general case tetragametic
because in theory, any number of embryos, each
containing full gametes, could form a single chimera
(e.g. fraternal triplet zygotes merging to a singleton)
although more than two zygotes should be very rare
from natural causes. Consequently, a more accurate
term is dual-gender macrochimerism for the condition
of cells of both sexes being present in large
proportions. Male cells outgrow female cells in mouse
model dual-gender merged embryos [15].
Consequently, it is reasonable to assume that male-
female macrochimeras will be more likely to appear to
be male.
Biological basis of homosexuality
A number of proposed biologically based mechanisms
have been investigated regarding human
homosexuality, all of them with degrees of controversy,
and none have yet been conclusively proven. These
ideas include exposure to prenatal androgens [16],
hypothalamic dimorphism [17-19], birth order [20, 21],
an hypothesized brain differentiation continuum [22],
and antagonistic selection to increase female fecundity
[23, 24]. The mystery of the role of biology in human
homosexuality continues to be an area of strong interest
and it is likely that a variety of biological causes have
impact on human sexuality.
Hypothesis
It is proposed that when the sex of gonadal cells
conflicts with the sex of central nervous system cells in
whole or in part there will be nervous system
development that can be discordant with the apparent
sex as determined by gonads and visible phenotype. It
is further proposed that dual-gender macrochimerism is
one of the causes of homosexuality and transgender
identification. This hypothesis includes transgender
identification, but does not require it, as chimerism can
generate a range of nerve gender proportions in the
brain.
Hypothesis support
The following section provides three lines of evidence
that my hypothesis is a reasonable explanation of some
instances of homosexual or transgender behaviour.
First, the matter of rarity of human chimerism is
discussed centered around Boklage’s work in the field.
There is considerable evidence that the dogma that
chimerism is rare is an artifact resulting from causes
ranging from systematically throwing out evidence to
difficulty of diagnosis and lack of phenotype.
Second, a method is used to derive an absolute
minimum lower bound estimate of the occurrence of
male/female macrochimerism, and to describe other
factors that should justify raising the estimate which are
not readily quantifiable. The purpose of this lower
bound estimate is primarily to prove that the condition
described must occur and what the proportions should
be in the population. Secondarily, it is intended to show
Hypotheses in the Life Sciences ISSN 20428960
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by deduction that the true value should be much higher
due to difficult to quantify factors.
Third, evidence from literature regarding sexual
behavior determination will be discussed that supports
the hypothesis that a male/female macrochimera would
be expected to display nervous system gender
discordance with its gross sexual morphology.
Macrochimerism in humans is not rare
There are a number of major reasons for believing that
macrochimerism in humans is not rare, which Boklage
discusses and which I will summarize here.
Boklage states that spontaneous human chimerism is
not rare [13, 15, 25]. He states, regarding chimerism,
that it is:
“…impossible to differentiate from single-
genotype people by ordinary observation and
seriously difficult to identify even with the best of
the newest biomedical technologies. Cases are
discovered in the population with low frequency
and high technical difficulty, creating the
pervasive false impression that they are
rare.”[13]
It has long been believed that dizygotic (fraternal)
twinning is from dual ovulation. But in examining this
idea over decades Boklage has found that there is no
actual evidence to support this, it is instead a
supposition handed down.
Boklage has assembled a large body of data on
malformations of dizygotic and monozygotic
(identical) twins. What he has shown is that while there
is a variance between singletons and twins, there is not
a significant variance between identical and fraternal
twins. This makes the double ovulation hypothesis that
has been assumed to be true for fraternal twins in his
words “untenable”[25]. He states that all the evidence
points to monozygotic and dizygotic twins sharing the
same (still unknown) twinning mechanism. The
significance of this is that knowing that both types of
twins start from one egg-cell mass points to chimerism
being much more likely.
He also discusses in the same paper that what
appears as mosaicism cannot exclude chimerism and
many cases of apparent mosaicism may well be
chimerism.
Because data showing multiple individuals in a
single sample is routinely thrown out as evidence of
contamination, and the field dogmatically defines as
evidence of poor lab technique any evidence that
monochorionic fetuses are dizygotic, the fraction could
be 5%-15% of the population, perhaps higher, although
the natural mechanism is unknown [11, 13, 15].
Boklage relates the example of a conference
presentation in 1986:
“A young physician from Glasgow tried to tell us
about three monochorionic pairs among 12 in his
sample, in whom he had found (with testing more
extensive and more sensitive than the usual
zygosity genotyping) discordant blood grouping
markers suggesting dizygosity (Mortimer, 1987).
The pillars of the Society came crashing down
about his head. The tenor of the response from the
floor was: ‘... of course, one must know, of course,
that only monozygotic twins can be
monochorionic. Results such as yours suggesting
otherwise must have come from a very unreliable
laboratory …”[13]
There is considerable further discussion regarding
chimeras that are well worth reading in these references
to Boklage and I recommend them. In addition to this,
cases of male-female chimerism have also been
discovered on the basis of hermaphroditic phenotype
[1, 2], so it is proven that the condition does occur. But
generally speaking, chimeras would not be expected to
show any obvious phenotypic signs.
Discussion of rare data for dual-gender
macrochimerism in humans
The overall significance of the numbers worked out
below should not be construed as an upper limit on
occurrence. Instead, the exercise should primarily be
considered a thought process that shows further proof
of occurrence, proportions of occurrence and proceeds
to an open-ended conclusion that provides a minimum.
In recent years two rare cases of women who are
macrochimeras were identified because their children
were identified by genetic testing as not being their
own [15, 26, 27]. One of the tests was ordered by
AFDC/TANF, the other was in preparation for an organ
transplant. There are believed to be other cases, but
since such records are not easily available and
identification is complicated, documenting them has
not been practical. In the case of the AFDC/TANF
Brian P. Hanley
Chimeric tissue sex discordance in homosexuality
66
ordered test, the white mother was threatened with
having her children taken away and possible
prosecution. This strongly motivated her and her
extended family. In the other case, physicians decided
to investigate her case when it was found by tissue
typing for the transplant protocol.
For the purposes of the below estimate, these
mothers are members of a population composed of all
parentage tests conducted. However, there is good
reason to believe that the rare event of diagnosis is the
tip of a figurative iceberg, due to multiple factors: A.
The sample size for the AFDC/TANF segment of
mothers below is overstated due to inability to
determine the exact number of tests ordered to prove
parentage. The true sample size is probably orders of
magnitude smaller than the pool used. B. Social factors
result in poor and minority mothers not having the
resources to prove a parentage genetic test is incorrect.
C. Where parentage tests tell a mother that her child is
not her own and the test is voluntary, there is generally
little or no incentive to pursue an expensive course of
research. D. The geometry of macrochimerism is not
well understood, but evidence shows it is patchy,
leading to the likely probability that the kind of female-
female macrochimerism that has been detected will
most likely have a 50% chance of having a different
test result for the common buccal swab versus gonads
in a female-female chimera.
Unquantifiable social disenfranchisement influencing
reporting of macrochimerism
It should be noted that AFDC/TANF mothers were
virtually destitute as the tests were administered to
prevent welfare fraud. The majority of such recipients
are without access to legal resources required. People
of African ancestry have roughly double the dizygotic
twinning rate of Caucasians, and yet the only
documented macrochimera cases are Caucasian, while
the twinning rates would lead one to believe that twice
the number of macrochimeric mothers of African
ancestry should be expected. This strongly suggests
that where such mothers exist, these mothers were not
properly diagnosed after testing negative for direct
parentage. It is likely that most destitute mothers give
up when confronted with a large government
bureaucracy with the power to take their children and
prosecute them. Thus it is highly unlikely that all
occurrences of macrochimeric mothers have been
properly recorded. The true numbers are unknown but
there is good reason to believe that they are much
higher.
Estimate of fraction of tests showing macrochimeric
mothers
No data are available specifically for maternity testing
or specific to the number of AFDC/TANF tests
conducted. Testing figures are better termed parental
“relatedness testing” [28]. In 2003, approximately
350,000 parental relatedness tests were conducted [29].
In discussion with experts in the field, the ratio of
maternity tests was estimated in a range from 60% to
88% of tests conducted, with the balance paternity
only.
Applying the 60% to 88% yields a range of
maternity tests conducted per year of 210,000 to
308,000. While the number of relatedness tests rose
between 2000 and 2005, for the purposes of this
estimate it will be assumed that the number of
maternity tests remained constant from 2000 to 2005
and that 2003 represents a rough average. Using the
estimated fractions, the maternity test sample size is
1.05 million to 1.54 million over the 5 year period from
2000 to 2005. At least two macrochimeric mothers
have been detected in that total population [26, 27] with
other probable cases. Thus, on this basis alone
female/female macrochimeras are roughly 2 in 1
million births. Applying the 50% detection ratio
because of patchiness discussed above doubles that
value to 4 in 1 million births.
Zygote sex ratio combinations define the ratio of
male/female macrochimerism
Macrochimerism has three possible outcomes, shown
in the style of a classic Punnet square in Table 1. A
fertilized zygote is either XX or XY which denote
genetically female and male zygotes respectively. This
diagram is not actually a Punnet square, since it does
not describe the mixing of genes in diploid cells. The
situation is parallel, however, and the diagram shows
the outcomes correctly. The point of this Punnet square
is to determine the relative frequency of chimera types.
Just as in classical Mendelian genetics, the
occurrence of female/female macrochimeras will be
approximately 25% of the total, male/male
macrochimeras will be 25% of the total, and
male/female macrochimeras will be approximately
50% of the total since they can be formed two different
Hypotheses in the Life Sciences ISSN 20428960
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ways while the others can only be formed one way.
Thus, there should be twice as many male/female
macrochimeras as there are female/female chimeras.
From above, the minimal number of female/female
macrochimeric births is approximately 4 per million.
Doubling that number results in a minimum of 8
male/female macrochimeric births per million as the
next round minimum.
Table 1 – Punnet style square for dizygotic
chimera formation showing the possible
combinations of two fertilized zygotes that form
one normal appearing fetus.
Zygotes XX XY
XX XX/XX XX/XY
XY XY/XX XY/XY
Dizygotic twinning rate differences effect on
male/female macrochimera estimate
Dizygotic twinning rates have significant historical
variance; for instance in Sweden in the 1960s the rate
of dizygotic twinning was half what it was 200 years
before [30] and dizygotic twinning is believed to be
environmentally influenced. Accepted figures for
current dizygotic twinning rates of Caucasians and
those of Sub-Saharan African ancestry are 8 and 16 per
thousand, respectively [30] although these can vary
regionally by a few percentage points. The rates are for
twinning rates prior to major use of in-vitro fertilization
(IVF) procedures because twinning rates are higher
today owing to IVF. Since the rate of macrochimerism
in IVF procedures may be different from that in
naturally conceived births, the higher IVF-influenced
twinning rate will be ignored for purposes of estimation
in this context.
For a macrochimera to appear requires dizygotic [31]
twin embryos to occur. The figures above for dizygotic
twinning rates show that Caucasians should be roughly
1/3 of such twins given an equal population distribution
between the two groups (8/24). Within the
AFDC/TANF federal system that ordered the tests, this
equal population distribution is approximately true
[32]. Other ethnic groups are ignored as they are either
not significantly represented within the AFDC/TANF
population, or else there are no specific dizygotic
twinning data for them. Making the assumption that
there should be equivalent rates of dizygotic twin
merging for all ethnic groups would indicate that for
the 4 Caucasian cases of female/female dizygotic
chimerism developed above there should be at least 8
more, for a total of 12 female/female chimeras in both
ethnic groups. As was previously discussed, Table 1
shows that there should be double that number of
male/female chimeras, or 24 of them per million births,
which is approximately 1 per 50,000 births.
Conclusion regarding rare event
detection of chimeras
This 1 per 50,000 number should be viewed as an
exercise in light of the major factors that lead to
believing that this figure is probably off by orders of
magnitude. Even for those most doubtful of this
hypothesis, applying this rate of occurrence gives us a
population minimum of 30,000 such people in the
developed world. The question then becomes not, “Are
there dual-gender macrochimeras?” but “How many
dual-gender macrochimeras are really out there?” The
true number could be quite large.
Nervous system sex and sexual
orientation in humans and animals
The human brain is a large distributed system of
approximately 100 billion cells divided into two
hemispheres. In a mixed sex chimera, nerve cell sex
ratios in the brain would be expected to be mixed in a
continuum from all male to all female where the
quantum element is a single cell among the
approximately 100 billion cells. Chimerism occurs in a
patchwork fashion and migration paths of cells can be
complex in embryos[13, 33]. Along that continuum of
patchwork composition of the brain the locations of
patches and their interactions could vary a great deal.
The distributed nature of the brain thus provides a
logical basis for a range from transgender
identification, to exclusive homosexuality and
bisexuality.
A wild chimeric zebrafinch with half of its brain
made up of male cells and the other half made up of
female cells showed dimorphic sexual differentiation of
the two sides of the brain but both sides of the brain
had an identical hormonal environment [34]. In an
experiment on quail, chimeric female brains in male
quail bodies did not result in male behavior [35]. A
large amount of work in humans shows sex-based
neural differentiation [36] and the long term evidence
Brian P. Hanley
Chimeric tissue sex discordance in homosexuality
68
from the John’s Hopkins experiment of boys raised as
girls shows discordant sexual identity based on brain
sex that is independent of nurture, parental beliefs, the
child’s formal beliefs or of hormones [37]. This
discordance conflicts with the earlier belief that sex
reassignment was a straightforward matter [38].
The John’s Hopkins sex-reassignment experiment
occurred at a time when it was practiced to raise boys
with ablated or ambiguous genitalia as girls, treating
them with hormones and transgender surgery. The
belief was that hormones in humans determined sexual
orientation entirely, as occurs in most fish and
invertebrates such as shellfish, so all that was necessary
was to bring physical morphology into coincidence
with hormones. The fact that treatment of males with
estrogen results in softening of skin, development of
breasts and other female secondary characteristics
helped create this view. Similarly, the masculinizing
response of females to androgens was also thought
indicative. An early review of the case of Joan provided
support for this experimental treatment modality [38].
However, long term review of the case of Joan/John
showed problems with this approach and it turns out
that most genetically male children treated with female
hormones self-identified as males, sometimes
becoming suicidal owing to gender discordance [37,
39]. Thus, the idea that hormones alone activate the
brain so as to determine sexual orientation is no longer
credible.
Suggested Experiments
Without studies to examine this matter, it is impossible
to determine beyond argument how prevalent dual-
gender macrochimerism is even though it must be
granted that it does occur. Such studies would be
expensive to conduct and require many years. These
would need to be large-scale studies examining
multiple tissues for presence and proportions of cells
using relatedness measures as well as valid population
surveys.
Blood testing conducted through blood banks, or on
subject volunteers, may be usable as an initial
screening system, but validation should be attempted to
ensure that it does not result in a low detection artifact
since there is no guarantee that blood will always detect
macrochimerism. In addition to blood studies, the
determination of relatedness between cells within a
single body by various kinds of biopsy is needed.
Conducting such studies requires the determination of
frequency of macrochimerism in the general population
and determination of frequency in tissues of
homosexual and transgender individuals. To do that
reliably will require a large sample size both of subjects
and of samples per subject.
It would be important to map the relatedness
geometry of tissues in identified human macrochimeras
to better understand the variability of distribution that
naturally occurs since it may well differ significantly
from experimental models. The Visible Human
Project® [40] has done a great deal for anatomy. A
“best case” chimera study would include large numbers
of identified donated chimeras processed similarly,
taking many relatedness samples of each section to map
them. This could tell us if there are patterns to
placement of chimeric cells, and if so, what those
patterns are.
However, such studies could be justified on the basis
of more than just answering this question if it could be
practical to do full sequencing of those hundreds of
thousands of section samples. If it were practical to do
full sequencing, the study would have relevance to
many areas: undiagnosed cancer incidence,
precancerous conditions, persistent viral diseases,
microbiological population distributions, mosaicism
incidence, forensics and probably surprises we could
not possibly predict.
Examination of chimeric brains would be required to
properly examine this question. There are special
problems examining brains, since living biopsies are
out of the question, except where neurosurgery is
already required to take place. Even then, results would
be unlikely to mean a great deal because it wouldn’t be
possible to map enough of a living brain. This means
that studies would need to occur on donated chimera
brains, with many samples taken. Relatedness data
would be available for brains as part of whole body
studies, but it may be impractical to perform as many
as desirable in toto. As a fallback, processing of
donated brains in a similar manner to that proposed for
a whole-body study would be important.
In summary, the set of experiments that should be
done are extensive, expensive and the experiments and
their results could be controversial. These facts should
not prevent researchers from trying to move forward,
but do explain a significant reason for writing up this
hypothesis at this stage in its development. Depending
on how such studies were done, they could provide
benefits far beyond just this question. Such studies
Hypotheses in the Life Sciences ISSN 20428960
69
would be cross-disciplinary, require collaboration
between multiple labs, and would be best performed
with data collection separated from analysis to provide
the optimum utility for data discovered.
Conclusion
The true rate of occurrence for dual-gender
macrochimerism is unknown, but evidence suggests
strongly it may be high. Such chimerism has been
identified, and so have same-sex chimeras. While the
hard numbers indicate rarity, there are multiple reasons
to believe that chimerism is not uncommon. It may in
fact be the case that homosexuality and transgender
identity are a primary indicator. If it is true that a
sizeable percentage of humans are macrochimeras, then
half of those are dual gender chimeras, and the majority
of the dual-gender macrochimeras are male. That
would suggest that such chimerism could be a
significant mechanism in homosexuality and
transgender identification.
Since discordance of sex between nervous system
cells and gonads leads to apparent sexual identity
discordance in many animal species, it follows that in
humans it will express as a similar discordance when
the gonadal cells are in conflict with the sex of the cells
in the central nervous system. This tissue discordance
hypothesis has not yet been considered as a probable
cause of homosexuality or transgender identification in
humans.
Sexual behaviour in humans is doubtless multi-
factorial, with psychological, cultural and biological
explanations all providing some contribution. Proposed
biological causes are multiple, although none has yet
proved conclusive. Dual-gender macrochimerism
provides a compelling biological rationale for these
phenomena.
For any specific individual, macrochimerism is
clearly a biological accident that no one could control
and is impossible to change after the fact. It is the
author’s hope that greater understanding of the biology
of homosexual and transsexual behaviour will have a
positive impact on the lives of homosexual and
transsexual people, through explaining that (some of)
the reasons for the differences between homosexual
and heterosexual people reside in deep biological
causes.
Glossary
AFDC – Aid to Families with Dependent Children
SCID – Severe Combined Immunodeficiency
TANF – Temporary Assistance for Needy Families
Author’s Contributions
All work is that of Brian P. Hanley, PhD
Acknowledgements
The author declares no conflict of interest.
No external funding sources were used for this article.
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l]
... The resulting singleton carried both her own original DNA and that of the non-identical twin, thus creating a chimera. Research in the area of uterine chimerism is still sketchy, but there are many suggestions that the phenomenon might explain intersex conditions, even the phenomenology of transgendered people (Hanley 2011), or at a different level, the observation that some people have eyes of different colours. ...
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... The resulting singleton carried both her own original DNA and that of the non-identical twin, thus creating a chimera. Research in the area of uterine chimerism is still sketchy, but there are many suggestions that the phenomenon might explain intersex conditions, even the phenomenology of transgendered people (Hanley 2011), or at a different level, the observation that some people have eyes of different colours. ...
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