group_5_presentation_3_-_homosexuality

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====== Homosexuality ======

===== Scientific History =====
 
Sexual Orientation is a term used to describe our patterns of emotional, romantic, and sexual attraction—and our sense of personal and social identity based on those attractions. A person's sexual orientation is not a black or white matter; sexual orientation exists along a continuum, with exclusive attraction to the opposite sex on one end of the continuum and exclusive attraction to the same sex on the other. 

=== Definition of Homosexuality ===

Sexual desire or behavior directed toward a person or persons of one's own sex.

=== Current Perceptions of Causes of Homosexuality ===

Currently there is no consensus about why homosexuality occurs. It is widely believed to be due to a combination of nature and nurture, or a combination of genetic, hormonal, and environmental.

Found that 3.8% of American’s identify as LGBT (1.7% gay or lesbian), and in Canada 1% identify as gay

===== Fetal Androgen Signalling =====

==== Classic Model ====
Sexual dimorphism in brain structure and genitalia is a result of exposure to androgens during fetal development
Levels of circulating androgens differ in XX and XY fetuses. (Exposure to androgen antagonist result in female genitalia in XY fetuses. Elevated androgen levels in XX fetuses cause development of male phenotypic traits.)

Even though males possess the SRY on the Y chromosome, which is what accounts for testes development, activating effects from androgens are required to produce full sexual dimorphism.

==== Proposed Model ====
 Fetal androgen exposure is not sufficient to produce full sexual dimorphism.
·         Testosterone is not an ambiguous indicator of gonadal sex because testosterone levels are similar during many times during fetal development (In a large study of rats, significantly higher circulating T in male compared to female fetuses occurred only between days 17–21 of gestation (Weiszand Ward 1980). Despite this window of significantly elevated T in male fetuses, T levels overlapped between the sexes throughout all time points during gestation)
·         Solution: Males have a greater sensivity to testosterone
·         5-Alpha-reductase-2 gene 3 times higher in males than females (allows for conversion of Testosterone into more concentrated DHT which is required for male sexual development.
·         Sex hormone binding globulin is 2 times higher in females (binds to Testosterone and makes it unavailable for uptake by cells)
·         In monkeys: levels of circulating progesterone are much higher (progesterone has an anti-testosterone effect as it has a high affinity for androgen receptors)
·         Certain XX individuals have a defect on gene CYP21 which results in increased T production, but masculinization is small to none
·         Certain XY have defcicency in 17_-HSD-3 gene Results in inability to produce T. Certain male characteristics still appeared although some were feminized
·         Sex chromosome karyotype regulates T sensitivy prior to androgen exposure
·         Epigenetic modification regulates the control of gene expression for differences in androgen sensitivity in autosomal genes
·         Epi-marks buffer XX fetuses from masculinization and XY fetuses toward it
Homo sexuality
·         No major gene or genetic marker found
  homosexuality occurs when stronger-than-average SA-epi-marks (influencing sexual preference) from an opposite-sex parent escape erasure and are then paired with a weaker-than average de novo sex-specific epi-marks produced in opposite-sex offspring
·         Homosexuality may  have a strong epigenetic basis
·         Epi-marks are laid down in embryonic stem cells and are gender specific, which influence gene expression in later development (androgen sensitivity)
·         Epi marks can sometimes carry over to new generations
·         Masculinizing epi-marks are a response to XY type early embryo and produce male development by increasing testosterone sensitivity
·          Feminizing epimarks cause female development by decreasing testosterone sensitivity.
·         Homo sexuality occurs when a stronger than average epimark can results in sexual preference but not genitalia or sexual identity cross into an opposite sex descendant in a new generation
·         This could cause sexual preference to not be in line with gonads

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===== Genome-wide scan demonstrates significant linkage for male sexual orientation =====

=== Fraternal Birth Order Effect ===
  Study by Blanchard and Bogaert in 1996 took a sample of 604 homosexual and heterosexual males
·      Showed that having older biological brothers increased the odds of homosexuality by 33% with each additional older brother. And then this phenomenon was named the Fraternal Birth Order Effect or (FBO effect)

·      Another study by Bogaert took a sample of 944 homo and heterosexual males and this also showed that having biological older brothers increased the chances of male homosexuality, even if those brothers were raised in a different household. It also showed that the presence of older non-biological siblings had no effect on men’s sexual orientation.
·      This demonstrated that the FBO effect occurs during prenatal life and not during childhood or adolescence – ie. Giving support to nature not nurture

·      (MAYBE INCLUDE) another study by Blanchard et al., took a sample of 3146 men and they found that the FBO effect was also contingent on handedness
They found that the FBO effect only occurred in right-handed males, and not those that are left handed or ambidextrous

=== Maternal Immune Response ===
  According to this theory, which was first proposed by Blanchard and Bogaert in 1996, the FBO effect results because some mothers develop an immune response to Y-linked antigens that are important in male fetal development.
·      They believe that this occurs when cells from the male fetus enter the mother’s circulation during pregnancy. Because the cells originate from a male, they would have proteins specific to males, or Y-linked proteins on the cell surfaces, and that would cause the mother to recognize the cells as “foreign substances”, and therefore develop antibodies towards them.
·      These antibodies would then cross the placental barrier and enter the fetus, and then cross the blood brain barrier where it would affect fetal brain development.
·      Specifically, the antibodies would alter the sex-dimorphic brain structures that are relevant to sexual orientation. For example, one such structure in the hypothalamus, called the interstitial nucleus of the anterior hypothalamus (INAH-3). INAH-3 is known to have a direct role in sexual behaviour, and gonadotropin secretion. Normally the INAH-3 is significantly larger in males than females, but in homosexual men, this region is smaller compared heterosexual men, and actually approximately the same size as heterosexual women.
·      This would affect the male fetus in a way that would lead him to be attracted to men instead of women
·      The degree to which this immune effect alters brain development depends on the number of antibodies that reach the affected brain region and the binding strength of the antibodies
·      Going back to how this is an explanation for the FBO effect, is that the number of antibodies and the binding affinity of those antibodies would increase during a memory immune response, and a memory immune response could occur in subsequent pregnancies with a male fetus. With each subsequent male pregnancy, the immune response becomes stronger and the likelihood of it affecting the male fetus becomes higher.
 
Conditions for MIH
·      Clearly, this response doesn’t occur in every woman that has multiple male children. There are a few conditions that must be met in order for the MIH to be a feasible explanation for the FBO effect.
·      1. There must be evidence that fetal material enters the maternal circulation. This doesn’t happen in every pregnancy, but it is a well-established fact that it is possible for fetal cells to enter the maternal circulation in both normal and abnormal pregnancies.
·      2. A male specific antigen must cause an immune response in females. This is also a well-established statement. It has been shown that H-Y antigens cause immune reactions in females that are exposed to them. Eg. it has been shown that mothers who have given birth to sons are more immunologically reactive to a form of H-Y antigen than those who have not given birth to sons. 
·      3. The relevant Y-linked protein must play a role in the sexual differentiation of the brain. There are many such proteins and genes, such as the gene SMCY, PCDH11Y (protocadherin 11-linked; plays a role in cell adhesion and synapse formation and neural pathway development),  NLGN4Y (neuroligin 4 Y-linked; plays a role in cell adhesion and synaptic functioning), and TBL1Y (linked to cognitive functioning)
(why does it affect the brain tissue and not other sex organs? à not entirely sure but may be because sperm are not mature in the fetus and this effect only occurs in utero, or that there are different forms of proteins that influence sexual development, and it’s possible that the forms that target the brain are more expressed than those that target other tissues)
·      4. A maternal immune response to Y-linked proteins must affect fetal development, including sexual differentiation in the brain.
·      5. The maternal immune response to previous male fetuses need to be amplified each time a mother conceives a male child. Evidence for this has also been shown where in a study by Piper et al., states that 37% of women with a male pregnancy had an immune reaction to H-Y peptides, and this amount increased to 50% of women who have had two or more male pregnancies.


===== Xq28 =====

  Male homosexuals usually have more gay brothers than gay sisters
·         Lesbians have more gay sisters than brothers, therefore factors responsible are partially gender related, distinct in males vs females
·         In this study, goal was to determine whether or not male sexual orientation is genetically influenced
·         76 subjects, one or more relatives from their families (n=122)
·         Used pedigree analysis and family DNA linkage studies, thanks to modern advances, this is possible even for complex traits, such as sexual orientation
·         Found statistically significant correlation between inheritance of gene markers on region of chromosome known as Xq28
Assumed sexual orientation was a dimorphic, not a continuously variable trait
·         Results demonstrated increased rates of homosexual orientation not only in brothers of gay men, but in maternal uncles and sons of maternal aunts
o   Since cousins and uncles are raised in different households under in a different environment, this result favors a genetic basis to homosexuality rather than the rearing conditions
o   Also perhaps suggests linkage on X chromosome
·         Using chromosomal mapping of the loci and isolation on the X chromosome, discovered that in families with 2 homosexual brothers, and no transmission through fathers or to females, 33 of 40 sibling pairs coinherited genetic information in the same region on Xq28
·         This has a type 1 error rate of 0.001 percent
·         Linkage was ruled out, since many different Xq28 traits display Mendelian segregation
·         Rather, it appears there is a gene on Xq28 that contributes to homosexual orientation in males
·         Suggested through results that locus related to sexual orientation lies within approximately 4 million base pairs of DNA on tip of long arm of the X chromosome.
·         Very small region but large enough to contain several hundred genes
 
o   The 7 sibling pairs who did not show the coinheritance at Xq28 should provide useful resource for identifying additional genes or environmental, or cultural factors 

===== References =====

References

Bogaert, A. F., & Skorska, M. (2011). Sexual orientation, fraternal birth order, and the maternal immune hypothesis: A review. Frontiers in Neuroendocrinology, 32(2), 247-254.

Dictionary.com - The world's favorite online English dictionary! (2014, January 1). Retrieved November 25, 2014, from http://www.dictionary.com 
Hamer, D. H., Hu, S., Magnuson, V. L., Hu, N., & Pattatucci, A. M. (1993). A linkage between DNA markers on the X chromosome and male sexual orientation. Science, 261(5119), 321-327.

Puts, D. A., Jordan, C. L., & Breedlove, S. M. (2006). O brother, where art thou? The fraternal birth-order effect on male sexual orientation. Proceedings of the National Academy of Sciences, 103(28), 10531-10532.

Rice, G., Anderson, C., Risch, N., & Ebers, G. (1999). Male homosexuality: Absence of linkage to microsatellite markers at Xq28. Science, 284(5414), 665-667.

Rice, W. R., Friberg, U., & Gavrilets, S. (2012). Homosexuality as a Consequence of Epigenetically Canalized Sexual Development. The Quarterly Review of Biology, 87(4), 343–368. doi:10.1086/668167

Sanders, A. R., Martin, E. R., Beecham, G. W., Guo, S., Dawood, K., Rieger, G., ... & Bailey, J. M. (2014). Genome-wide scan demonstrates significant linkage for male sexual orientation. Psychological medicine, 1-10.

Sexual Orientation. (2014, February 1). Retrieved November 13, 2014, from http://www.psychologytoday.com/basics/homosexuality
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