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Insights & Perspectives
Homosexuality via canalized sexual
development: A testing protocol
for a new epigenetic model
William R. Rice
1)
*, Urban Friberg
2)
and Sergey Gavrilets
3)
We recently synthesized and reinterpreted published studies to advance an
epigenetic model for the development of homosexuality (HS). The model is
based on epigenetic marks laid down in response to the XX vs. XY karyotype in
embryonic stem cells. These marks boost sensitivity to testosterone in XY
fetuses and lower it in XX fetuses, thereby canalizing sexual development. Our
model predicts that a subset of these canalizing epigenetic marks stochastically
carry over across generations and lead to mosaicism for sexual development in
opposite-sex offspring the homosexual phenotype being one such outcome.
Here, we begin by outlining why HS has been under-appreciated as a
commonplace phenomenon in nature, and how this trend is currently being
reversed in the field of neurobiology. We next briefly describe our epigenetic
model of HS, develop a set of predictions, and describe how epigenetic profiles
of human stem cells can provide for a strong test of the model.
Keywords:
.epigenetics; gonad-trait discordance; homosexuality
Introduction
Homosexuality (HS) is commonly as-
sumed to be very rare in nature but this
perception appears to be an artifact
associated with an historical reluctance
to publish socially and religiously
controversial information. For example,
consider the early 20th century natural-
ist George Murray Levick who recorded
the following observation in his field
notes while observing Ade
´
lie’s penguins
in Antarctica “Here on one occasion I
saw what I took to be a cock copulating
with a hen. When he had finished,
however, and got off, the apparent hen
turned out to be a cock, and the act was
again performed with their positions
reversed, the original “hen” climbing
on to the back of the original cock,
whereupon the nature of their proceed-
ing was disclosed.” (reprinted in [1]).
Levick was so taken aback by these
“socially inappropriate” behaviors that
he hid them in his notebook by record-
ing them in code with Greek letters. He
also decided against publishing them
except in the relatively obscure expedi-
tion’s reports where they were rejected
for publication [1]. Circumventing this
type of reporting bias, several books
have been written in the last 15 years in
which the authors searched the pub-
lished literature for observations
usually mentioned as an aside in an
unrelated context describing homo-
sexual behavior in nature. Many hun-
dreds of such examples were found
across a broad spectrum of species
[24]. For instance, homosexual behav-
ior has been recorded in 93 species of
birds [5]. Representative examples in-
clude a 14% incidence of female-female
nesting pairs of Western Gulls in
California [6] and this value is 31% for
Laysan albatrosses on the island of
Oahu [7]. Male-male pairs occur at a rate
of 56% in Australian black swans [8],
and in graylag geese 15% of males only
participated in male-male pair bonds
over their lifetime, while 37% were
bisexual [9]. Even species as familiar
as barnyard sheep have about 8%
strictly homosexual males [10] yet
almost no one except sheep breeders is
DOI 10.1002/bies.201300033
1)
Department of Ecology, Evolution & Marine
Biology, University of California, Santa Barbara,
CA, USA
2)
Department of Evolutionary Biology, Uppsala
University, Uppsala, Sweden
3)
Department of Ecology and Evolutionary
Biology, Department of Mathematics,
National Institute for Mathematical and
Biological Synthesis (NIMBioS), University of
Tennessee, Knoxville, TN, USA
*Corresponding author:
William R. Rice
E-mail: rice@lifesci.ucsb.edu
Abbreviations:
AR, androgen receptor; E, estradiol; hESC, human
embryonic stem cell; HFSC, hair follicle stem cell;
HS, homos exuality; SA, sexually antagonistic; T,
testosterone
764 www.bioessays-journal.com Bioessays 35: 764–770, ß 2013 The Authors. Bioessays published by WILEY Periodicals, Inc. This is an
open access article under the terms of the Creative Commons Attribution Non-Commercial-NoDerivs
License, which permits use and distribution in any medium, provided the original work is properly cited, the
use is non-commercial and no modifications or adaptations are made.
Hypotheses
aware of this fact, presumably because
it has been socially inappropriate to
mention it.
HS appears to be relatively common
in humans. For example, one well
designed study of a large sample of
twins in Australia, that convincingly
guaranteed anonymity, found an inci-
dence of HS of 8% in both sexes when
measured as a Kinsey score of same-sex
partner preference >0 [11]. HS is not a
dichotomous alternative to heterosexu-
ality in that there is an empirically
verified continuum between exclusive
attraction to same-sex and opposite-sex
sexual partners (see [11] for a quantifi-
cation of the homosexual/heterosexual
spectrum in both sexes). This continu-
um is usually measured by a Kinsey
score that varies from 0 (no attraction to
same-sex partners) to 6 (exclusive
attraction to same-sex partners). Here
we use the term homosexual to include
all Kinsey scores >0, i.e. to include even
weak attraction to members of the same
sex.
Neurophysiological studies have
documented physical differences be-
tween homosexuals and heterosexuals
([12], and reviewed in [13]). For example,
females usually have cerebral hemi-
spheres of similar size whereas in males
the right hemisphere is larger. Also,
functional connectivity of the paired
amygdala with other parts of the brain is
markedly sexually dimorphic. PET and
MRI neuroimaging was used to show
that both of these sexual dimorphisms
in neuroanatomy are reversed in homo-
sexual men and women [12]. Similar
reversals in sexual dimorphism were
found in the neural pathways that
homosexual men and women used
when they process two putative sex
pheromones derived from testosterone
(4,16-androstadien-3-one) and proges-
terone [estra-1,3,5(10),16-tetraen-3-ol]
([14, 15], but see [16] for conflicting
evidence on androstadienone). These
studies illustrate how the biological
underpinnings of HS are beginning to
emerge as a new research focus in
neurobiology.
Because of the established high
incidence of male HS in sheep, this
species is currently being used as the
main neurophysiological model system
to determine how sexually dimorphic
nuclei in the brain become sex-reversed
in homosexuals (reviewed in [17]). In the
more tractable rodent model systems,
there is a strong reliance on the
intracellular conversion of testosterone
(T) to estradiol (E) during fetal and
neonatal androgen signaling that is
absent in humans and sheep. As a
consequence, the estrogen receptor
mediates much of the sexual dimor-
phism in the rodent brain, rather than
the androgen receptor (AR) as occurs in
human males, and this major change in
the hormonal signaling pathway makes
rodents less useful in the study of
human HS.
Our hypothesis of an epigenetic
contribution to HS was motivated by
several observations from published
studies that we found to be collectively
more compatible with an epigenetic
compared to a genetic causation of HS:
(i) HS has substantial realized herita-
bility yet it has low concordance
between monozygotic twins in both
sexes (20%, reviewed in [18]) and
genome-wide genetic associations
studies have failed to find any
associated genetic markers with
male HS, even when SNP density
is high [10].
(ii) HS is expected to be selected
against by natural selection and
there is only limited evidence for a
counterbalancing benefit through
kin selection, overdominance, or
sexually antagonistic selection
yet its prevalence is substantially
higher than predicted by feasible
forms of mutation-selection bal-
ance (reviewed in [19]).
(iii) Mutations in humans that reverse
sexually dimorphic fetal androgen
profiles only partially reverse sexu-
al dimorphism in these individuals
(reviewed in [20, 21]).
(iv) Epigenetic marks in mice that
mosaically reverse some but not
other sexually dimorphic behaviors
and gene expression profiles in the
brain can and do carry over across
generations and contribute to heri-
table discordance between the
gonad and behavior [22, 23].
Any hypothesis for a sexual pheno-
type in humans must build on the
overwhelming evidence supporting the
“classical” view of the ontogeny of
sexual dimorphism in mammals (also
known as the Jost paradigm, reviewed
in [24]). In this paradigm, there is a long-
term “organizational” influence of high
vs. low androgen exposure during fetal
and perinatal development that leads to
sexual dimorphism of the brain, genita-
lia, and behavior at birth and early
childhood. These organizational effects
of fetal androgen exposure have a
cellular-level memory that controls the
subsequent “activational” influence of
androgens and estrogens at puberty on
the development of secondary sexual
traits, including sexual behavior
(reviewed in [18]). There is also recent
evidence that the cellular-level memory
of high fetal/neonatal androgen expo-
sure is produced by androgen-depen-
dent epigenetic changes (including both
histone tail modifications and DNA
methylation) that modulate gene ex-
pression independent of the DNA
sequences of genes and their regulatory
elements (reviewed in [25]).
The classical view, however, cannot
account for all sexual dimorphisms. It is
well established that many cellular-
level sexual dimorphisms precede the
fetal developmental time when there is
androgen secretion by the testes of XY
males. For example, preimplantation
mammalian XX and XY embryos have
different metabolic rates, growth rates,
and responses to environmental stres-
sors (reviewed in [26]). These differences
are associated with: (i) different gene
expression profiles including many
hundreds of genes, most of which are
autosomal, and (ii) XX- and XY-specific
DNA methylation levels that have been
reported on the promotors of specific
gene loci (reviewed in [27]). Later in
ontogeny, but prior to the time when T is
first secreted by the testes in males,
there is XX vs. XY differential expression
of at least 51 genes in the developing
mouse brain most of which are
autosomal [28]. These observations
demonstrate that cellular-level sexual
dimorphism is substantial far in ad-
vance of the organizational effect of
fetal androgen signaling.
Hypothesis: An epigenetic
basis for HS
Here we briefly overview our previously
published model [29] in order to con-
struct a foundation for the focus of this
.....Insights & Perspectives W. R. Rice et al.
765
Bioessays 35: 764–770, ß 2013 The Authors. Bioessays published by WILEY Periodicals, Inc.
Hypotheses
report: how to test the model. We will
focus on discordance between the
gonad and sexual orientation (HS) but
our epigenetic model also applies to
many other discordances (structural
and neurological), as we have described
in detail previously [29]. Our model
begins with the observation that the
difference in T concentration between
XX and XY fetuses alone cannot fully
account for the T-associated sexual
dimorphism that develops during fetal
development [29]. For example, XX
human fetuses homozygous for a null
mutation at the CYP21A2 locus have a
block in the cortisol synthesis pathway
that leads via conversion of accumu-
lated cortisol precursors to elevated
levels of T throughout fetal develop-
ment. Despite a male-typical androgen
profile starting at no later than gesta-
tional week-16 [30], these XX individua-
ls usually have only partially mas-
culinized genitalia and childhood
behavior, nearly all have female-gender
identity, and most have sexual partner
preference for males or only weak levels
of HS (i.e. those forms based on erotic
imagery alone, excluding the sex of
actual sexual partners) (reviewed in
[21]). These observations, and many
others described in our original article,
led us to conclude that XY fetuses have
elevated sensitivity to fetal androgens
and XX fetuses have blunted sensitivity.
XX- and XY- induced epigenetic
marks (epi-marks), that are produced
during the major pulse of genome-wide
epigenetic reprogramming that occurs
in embryonic stem cells, are the most
parsimonious mechanism to account for
the differential sensitivity of XX and XY
fetuses to circulating androgens. This
assumption of our model is supported
by the observations that (i) XX- and XY-
specific epi-marks are empirically estab-
lished to be present by the preimplan-
tation blastocyst stage of mice and cattle
(reviewed in [27]), and (ii) epi-marks in
mice can mediate the cellular memory
associated with the fetal-androgen-in-
duced organizational effects on later
gene expression profiles at puberty
(reviewed in [25]). XX- and XY-specific
epi-marks produced in the early embryo
could steer sexually dimorphic devel-
opment in all cell lineages in a direction
that is concordant with the gonad
(canalization). Such epi-marks pro-
duced in embryonic stem cells could
also account for the substantial realized
heritability of HS because they would be
passed on to all stem cell lineages,
including those of the germ line.
However, from an evolutionary genetics
perspective, canalizing XX- and XY-
specific epi-marks would be sexually
antagonistic (SA-epi-marks) if they
sometimes carry over across genera-
tions and steer sexual development in a
gonad-discordant direction in opposite-
sex descendent offspring (like the
stress-induced trans-generational epi-
marks that partially feminize the brains
of male mice [22, 23].
Our mathematical modeling analy-
sis demonstrated that mutations coding
for SA-epi-marks are expected to accu-
mulate to a frequency of 100% (i.e. to
fixation) over a broad spectrum of
parameter space despite the fitness-
reducing HS phenotype they sometimes
produce in descendent offspring: hence
genetic polymorphism associated with
HS would be expected to be absent
except during brief periods in evolu-
tionary time after they originated. Fixa-
tion of these mutations is expected
because they have a net advantage
due to a high ratio of benefit to
realized-cost. The benefit is large be-
cause the SA-epi-marks always help the
fetus that formed them by buffering
development from gonad-discordant
phenotypes produced from intrinsic
variation in fetal androgen levels as
well as environmental androgen mimics
and antagonists. The realized-cost is
low because the SA-epi-marks only
rarely carry over trans-generationally
in a manner that produces HS in
opposite-sex descendants.
Because there is a wide diversity of
AR cofactors which are highly tissue
specific (>200 [31]), SA-epi-marks at
genes controlling this stage of the
androgen signaling pathway would be
able to influence the phenotype in a
highly mosaic fashion, such that most
traits in an opposite-sex descendent
would be gonad-concordant (like the
genitalia and sexual identity) while a
minority would be gonad discordant
(like sexual preference). However, any
model of HS must account for the low
concordance for this trait between
monozygotic twins. High variation in
epi-mark strength between monozygot-
ic twins can account for this attribute.
For example, CpG DNA methylation
levels differed by as much as 54% at
birth in a sample of four gene promoters
in humans [32]. Our model predicts low
concordance for HS between identical
twins because while they inherit the
same trans-generational SA-epi-mark
that steers sexual preference in a
gonad-discordant direction, each twin
will lay down gonad-concordant epi-
marks independently during ontogeny.
HS occurs only when the shared inher-
ited trans-generational SA-epi-mark is
combined with one or more weaker-
than-average gonad-concordant epi-
marks that are produced de novo during
the ontogeny of each twin (Fig. 1).
Testing the epigenetic
canalization model of HS
Testable predictions
A strength of our model is that it makes
unambiguous and testable predictions:
(1) XX- and XY-specific epi-marks are
present in human embryonic stem
cells (hESCs) in embryos that will
differentiate into heterosexual indi-
viduals (¼ candidate HS-inducing
epi-marks).
(2) One or more candidate HS-inducing
epi-marks are XX- or XY-discordant
in the hESCs of embryos that will
differentiate into HS individuals (¼
HS-associated epi-marks).
(3) At least some HS-associated epi-
marks are sometimes trans-genera-
tionally inherited, and therefore will
be shared with high probability
when at least one monozygotic twin
is homosexual irrespective of the
twins’ concordance for HS.
(4) In HS individuals, one or more HS-
associated epi-marks is combined
with one or more weaker-than-aver-
age gonad-concordant epi-marks (¼
HS-facilitating epi-marks, which may
have been produced after the embry-
onic stem cell stage) that regulate
genes participating in the later stages
of the androgen signaling pathway in
the brain (e.g. AR cofactors and/or
theirmatchingmiRNAs),orare
limited in expression to sexually
dimorphic brain nuclei.
(5) Monozygotic twins that are discor-
dant for HS will be discordant for
the presence of one or more HS-
W. R. Rice et al. Insights & Perspectives
.....
766 Bioessays 35: 764–770, ß 2013 The Authors. Bioessays published by WILEY Periodicals, Inc.
Hypotheses
facilitating epi-marks, and vice
versa for twins that are concordant
for HS.
In Fig. 2 we diagram developmental
stages when sex-specific epi-marks are
potentially produced. The best source of
cells to search for the HS-inducing epi-
marks predicted by our model will be
hESCs, as well as more committed stem
cell lineages leading to the brain. We
lack expertise in the production, cul-
ture, and analysis of stem cells, so the
tests that we propose below may lack
sophistication. We nonetheless hope
that they can at least serve to inspire
those with more suitable experience to
test for an epigenetic basis of HS,
including the specific model that we
have proposed.
XX- and XY-specific
epi-marks in hESCs
Prediction 1 can be tested, in principle,
by comparing genome-wide epigenetic
profiles of hESCs (or other early-embryo
stems cell lineages retaining those epi-
marks transmitted from hESCs to the
fetal brain) between heterosexual males
and females. Established, publicly
available hESC cell culture lines could
be used for this purpose whenever their
sex chromosome karyotype is known
with the caveat that a small percentage
(about 510%, depending on the true
incidence of HS in adults) may not be
from embryos that ultimately would
have become heterosexual. Our model
predicts that consistent differences [at
least 100
(1-prevalence of HS)%] will be
found in the genome-wide epigenetic
profiles of hESCs with XX vs. XY
karyotypes, and these sexually dimor-
phic epi-marks would represent candi-
dates for those causing the HS
phenotype when un-erased across gen-
erations. Failure to find such sex-
specific epi-marks would provide strong
evidence against our epigenetic HS
model. To narrow the search, assayed
genes could be restricted to those that
participate in the androgen signaling
pathways in the brain, especially its
later stages (e.g. AR cofactors).
Assuming that at least some XX- and
XY-associated epi-marks are identified,
they would be classified as candidate
HS-inducing epi-marks. Such sex-specific
epi-marks are not unexpected because it
is already established in the mouse
model system that there is (i) reduced
expression of the de novo DNA meth-
yltransferases Dnmt3a and Dnmt3b as
well as global hypomethylation in XX
compared to XY mESCs, (ii) XX vs. XY
differences in the expression of genes
coding for histone modifiers in blasto-
cysts cells, and (iii) markedly different
autosomal gene expression profiles in
XX and XY blastocysts (reviewed
in [33]). Established hESC cell culture
lines, however, may be less than ideal
windows into the epigenome of in vivo
hESCs due to selection and adaptation
in response to the cell culture environ-
ment. For example, established hESC
lines are predominantly XX (75%,
[34]), indicating potential selection to
lose male-specific epi-marks. Some XX
Figure 1. An epigenetic model for homosexuality. Subscripted symbols represent one or more epi-marks that influence sensitivity to
androgens by the developing genitalia (G
e
) or sexually dimorphic brain regions influencing sexual partner preference (S
p
) or sexual identity (S
i
).
Lighter symbols represent weaker than average epi-marks (e.g. shorter CpG methylation tracts) and bolder symbols represent stronger than
average epi-marks. Male homosexuality begins when a stronger than average epi-mark is produced in the ESCs of a female (in response to
the XX karyotype) that later blunts androgen signaling in one or more brain regions influencing sexual preference thereby canalizing this
phenotype. Next, the epi-mark carries over trans-generationally to a son and is paired with one or more de novo, weaker than average, epi-
marks that influence sexual partner preference. This conflicting combination of epi-marks weakens androgen signaling in a mosaic fashion,
sex-reversing partner preference but not the genitalia nor sexual identity. The same process leads to female homosexuality, but with the
sexes reversed and the trans-generational epi-mark boosting rather than blunting androgen signaling.
.....Insights & Perspectives W. R. Rice et al.
767
Bioessays 35: 764–770, ß 2013 The Authors. Bioessays published by WILEY Periodicals, Inc.
Hypotheses
and XY-specific epi-marks might also be
produced in stem cell lineages derived
from the inner cell mass of pre-implan-
tation blastocysts (the source of most
hESC lines) that give rise to both the
brain and gonad, e.g. the post-implan-
tation epiblast cells.
As an alternative to the use of
established hESC lines to test prediction
1, one could assay newly established
hESC lines while still at low passage
number, and hence with minimal adap-
tation to the cell culture environment.
As a second alternative, one could use
more committed fetal stem cell lineages
sampled from older fetuses that are
expected to share the same sex-specific
epi-marks transmitted to stem cell
lineages leading to both the gonad
and the brain. Amniotic stem cells that
are c-Kit positive (AFS-c-Kit
þ
cells that
have not been artificially induced to
increase potency) are a potential source
of such stem cells because they are
capable of differentiating into cell types
of all three embryonic germ layers, and
preliminary evidence indicates that they
can feasibly differentiate into both
neurons and glial cells [35, 36]. These
cells can also be obtained using the
minimally invasive procedure of amnio-
centesis. However, AFS-c-Kit
þ
cells
would ideally be collected from amniot-
ic fluid at a developmental stage prior to
the onset T secretion by the testes in
males, i.e. before week-8 of gestation.
Sampling amniotic fluid at such an early
developmental stage poses serious tech-
nical difficulties and may only be
feasible in the context of aspiration of
amniotic fluid from the intact amniotic
sac after a spontaneous abortion or
during hysterotomy. Despite this tech-
nical difficulty, AFS-c-Kit
þ
cells may be
a better window into the epi-marks
contained in early-embryo stem line-
ages leading to the brain compared to
hESC lineages derived from the pre-
implantation embryo and adapted to
the cell culture environment.
HS-associated epi-marks
To test prediction 2, comparisons of
candidate HS-inducing epi-marks must
be made between homosexual and
heterosexual individuals of the same
sex. Because the adult sexual orienta-
tion phenotype of hESCs (and AFS-c-
Kit
þ
cells) is unknown, a different,
adult-accessible, population of stem
cells must be assayed. Stem cells from
the brains of homosexual and hetero-
sexual individuals are feasible surro-
gates for screening the candidate HS-
inducing epi-marks of their progenitor
hESCs, but this approach would require
postmortem studies on properly pre-
served cadavers. Alternatively, hair
follicle stem cells (HFSCs, that have
not been artificially induced to increase
potency) of adults have the potential to
differentiate into cell types of all three
embryonic germ layers, including nerve
and glial cells (the main components of
the brain, reviewed in [37]). These stem
cells can be harvested from small,
minimally invasive skin samples and
represent a potential surrogate to sam-
pling stem cells from the brain. To be an
acceptable surrogate to hESCs (or brain
stem cells) from individuals of known
sexual orientation, the same candidate
HS-inducing epi-marks identified from
hESCs (or AFS-c-Kit
þ
cells) must also be
present in these adult stem cells (or at
Figure 2. Potential time points when epi-
marks can be produced in response to the
XX vs. XY karyotype and the presence of
high vs. low circulating androgens.
W. R. Rice et al. Insights & Perspectives .....
768 Bioessays 35: 764–770, ß 2013 The Authors. Bioessays published by WILEY Periodicals, Inc.
Hypotheses
least those candidate HS-inducing epi-
marks that are transmitted to brain stem
cells). If they are not, another surrogate
stem cell lineage must be found. If they
are, then profiles of the candidate HS-
inducing epi-marks can be compared
between homosexuals and heterosex-
uals of each sex to determine whether
or not they differ by the presence of
gonad-discordant epi-marks, i.e. those
found to be sex-discordant only or
predominantly in the homosexuals.
Sex-discordant candidate HS-inducing
epi-marks that are statistically signifi-
cantly associated with the HS pheno-
type would be classified as HS-
associated epi-marks and failure to find
such epi-marks would provide strong
evidence against our epigenetic HS
model. This HFSC-based protocol may
also be useful in testing for epigenetic
causes/associations of HS outside the
context of our specific model.
Concordance and discordance
in inherited epi-marks
between twins
Monozygotic twins containing at least
one HS individual could be used to test
prediction 3, assuming that prediction 2
has been previously confirmed. These
monozygotic twins are predicted to
share the same HS-associated epi-
mark(s) identified in an accessible
stem cell population (like HFSCs)
irrespective of the twin’s concordance
for HS.
If prediction 3 is confirmed, then
predictions 4 and 5 could be tested
together by checking to see if monozy-
gotic twins that are discordant for HS,
but share the same HS-associated epi-
mark, also differ substantially in the
strength of gonad-concordant epi-
marks that influence (i) the same gene
bearing the HS-associated epi-mark,
(ii) one of this gene’s regulators, like
an miRNA, or (iii) a gene interacting
with the one bearing the HS-associated
epi-mark that can modulate its influ-
ence on androgen signaling. If such a
discordance for an associated epi-mark
strength were found, with the weaker-
than average epi-mark in the HS twin,
then it would be classified as an HS-
facilitating epi-mark. Twins that are
concordant for HS are predicted to both
carry one or more HS-facilitating epi-
marks, and this concordance of epi-
marks would be absent in twins that are
discordant for HS. Inconveniently, the
predicted HS-facilitating epi-marks in
homosexuals might only be present in
the brain cells of sexually dimorphic
nuclei that influence sexual partner
preference. In this case, samples from
the corresponding brain tissue(s)
would be needed to be screened for
epi-marks requiring postmortem
analysis of brains from suitably pre-
served cadavers of known sexual orien-
tation. Prediction 4 could also be tested
in isolation, outside the context of
monozygotic twins, by screening to
see if HS individuals carrying an HS-
associated epi-mark are also enriched
for one or more weaker-than-average
epi-marks influencing directly or
indirectly the gene bearing the HS-
associated epi-mark(s) that they carry.
As we described in our original
paper, an alternative partial test of
our epigenetic HS model can be based
on epigenetic profiling of sperm from
fathers with and without HS daughters.
Due to the small sample sizes associated
with human families, ideal fathers
would be those who have female HS
relatives and multiple HS daughters vs.
those with no HS relatives nor daugh-
ters. Our model predicts that sperm
from the fathers with one or more HS
daughters will differ from those with
only heterosexual daughters by carrying
unique (or statistically differentiated)
epi-marks that influence the later stages
of the androgen signaling pathway of
the brain, or their expression is restrict-
ed to a subset of brain tissue, including
sexually dimorphic nuclei that influ-
ence sexual orientation. The same logic
could be applied to unfertilized eggs
from mothers with and without homo-
sexual sons, but sampling these eggs
would require considerably more effort.
Conclusions
Historical, social and religious norms
have interfered with a full appreciation
of the scope and diversity of the
homosexual phenotype in nature, as
well as research into its biological
underpinning. Recently, however, our
understanding of the neurobiology of
the homosexual phenotype has rapidly
expanded. Non-molecular pedigree and
twin studies initially led to the conclu-
sion that genetic polymorphisms
accounted for much of the variation in
sexual orientation observed within hu-
man populations. However, more recent
molecular genetic data provide only
limited support for this interpretation.
Epigenetics provides a feasible alterna-
tive to genetic polymorphism(s) as the
biological foundation for HS (and in
general, gonad-trait discordances that
have a familial association) and a
detailed epigenetic model has recently
been proposed. Current advances in
stem cell technology and the ability to
perform genome-wide epigenetic pro-
files on these cells provide a unique
opportunity to test models of epigenet-
ic-based HS.
Acknowledgments
This work was supported by the Nation-
al Institute for Mathematical and Bio-
logical Synthesis, sponsored by the
National Science Foundation, the U.S.
Department of Homeland Security, and
the U.S. Department of Agriculture, with
additional support from the University
of Tennessee, Knoxville and the Swed-
ish Foundation for Strategic Research.
The authors have declared no conflict of
interest.
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