Xq28 is a chromosome band and genetic marker situated at the tip of the X chromosome which has been studied since at least 1980. The band contains three distinct regions, totaling about 8 Mb of genetic information. Xq28 contains the 12 genes of the melanoma-associated antigen (MAGE) family, of which MAGEA11 has been identified as a coregulator for the androgen receptor. Duplications of certain genes within Xq28, namely MECP2 and IRAK1, have been associated with phenotypes including anxiety and autism. The marker came to the public eye in 1993 when studies by Dean Hamer and others indicated a link between the Xq28 marker and male sexual orientation.
Hamer's 1993 and 1995 studies
The 1993 study by Hamer examined 114 families of gay men in the United States and found increased rates of homosexuality among maternal uncles and cousins, but not among paternal relatives. This pattern of inheritance suggested that there might be linked genes on the x-chromosome, since males always inherit their copy of the x-chromosome from their mothers. Polymorphisms of genetic markers of the x-chromosome were analyzed to see if a specific marker was shared by a disproportionate amount of brothers who were both gay. The results showed that among gay brothers, the concordance rate for markers from the Xq28 region were significantly greater than expected for random Mendelian segregation, indicating that a link did exist.
A follow-up study, conducted in 1995 by the Hamer lab in collaboration with two groups of statistical experts, corroborated the original results for males with homosexual brothers sharing Xq28 at significantly elevated rates. This study also included heterosexual brothers, who showed significantly less than expected sharing of the Xq28 region, as expected for a genetic locus that in one form is associated with same-sex attraction and in another form is associated with opposite-sex attraction. In this study no link to Xq28 was found among homosexual females, indicating a different genetic pathway as for most sex-specific phenotypes.
Two further studies in the 1990s gave mixed results. One unpublished study showed weak linkage to the Xq28 region, whereas a second in 1999 studying Canadian material consisting of 52 pairs of gay brothers found no statistically significant linkage in alleles and haplotypes and concluded against an X-linked male homosexuality gene. Hamer's meta-analysis of all data available at that time (i.e., two of his own studies, the Canadian study, and the unpublished study) indicated Xq28 has a significant but not exclusive effect.
In 2012, results from the first large, comprehensive multi-center genetic linkage study of male sexual orientation were reported by an independent group of researchers at the American Society of Human Genetics. The study population included 409 independent pairs of gay brothers, who were analyzed with over 300,000 single-nucleotide polymorphism markers. The data strongly replicated Hamerʻs Xq28 findings as determined by both two-point and multipoint (MERLIN) LOD score mapping. Significant linkage was also detected in the pericentromeric region of chromosome 8, overlapping with one of the regions detected in a previous genomewide linkage study by the Hamer lab  The authors concluded that "our findings, taken in context with previous work, suggest that genetic variation in each of these regions contributes to development of the important psychological trait of male sexual orientation."
On November of 2014, an article published by Psychological Medicine supported the existence of genes on chromosome Xq28 and pericentromeric chromosome 8 influencing development of male sexual orientation. Blood was drawn from 409 gay brothers and straight members of their family totaling 908 individuals in 384 families, and was analyzed.
- Pai, GS; Sprenkle, JA; Do, TT; Mareni, CE; Migeon, BR (1980). "Localization of loci for hypoxanthine phosphoribosyltransferase and glucose-6-phosphate dehydrogenase and biochemical evidence of nonrandom X chromosome expression from studies of a human X-autosome translocation". Proceedings of the National Academy of Sciences of the United States of America 77 (5): 2810–3. Bibcode:1980PNAS...77.2810P. doi:10.1073/pnas.77.5.2810. PMC 349494. PMID 6930669.
- De Sario, Albertina; Geigl, Eva-Maria; Palmieri, Giuseppe; d'Urso, Michele; Bernardi, Giorgio (1996). "A Compositional Map of Human Chromosome Band Xq28". Proceedings of the National Academy of Sciences of the United States of America 93 (3): 1298–302. Bibcode:1996PNAS...93.1298D. doi:10.1073/pnas.93.3.1298. JSTOR 38791. PMC 40074. PMID 8577758.
- Rogner, UC; Wilke, K; Steck, E; Korn, B; Poustka, A (1995). "The melanoma antigen gene (MAGE) family is clustered in the chromosomal band Xq28". Genomics 29 (3): 725–31. doi:10.1006/geno.1995.9945. PMID 8575766.
- Wilson, EM (2010). "Androgen receptor molecular biology and potential targets in prostate cancer". Therapeutic advances in urology 2 (3): 105–17. doi:10.1177/1756287210372380. PMC 3126091. PMID 21789088.
- Samaco, RC; Mandel-Brehm, C; McGraw, CM; Shaw, CA; McGill, BE; Zoghbi, HY (2012). "Crh and Oprm1 mediate anxiety-related behavior and social approach in a mouse model of MECP2 duplication syndrome". Nature Genetics 44 (2): 206–11. doi:10.1038/ng.1066. PMID 22231481.
- Hamer, D.; Hu, S; Magnuson, V.; Hu, N; Pattatucci, A. (1993). "A linkage between DNA markers on the X chromosome and male sexual orientation". Science 261 (5119): 321–7. Bibcode:1993Sci...261..321H. doi:10.1126/science.8332896. PMID 8332896.
- Hu, Stella; Pattatucci, Angela M. L.; Patterson, Chavis; Li, Lin; Fulker, David W.; Cherny, Stacey S.; Kruglyak, Leonid; Hamer, Dean H. (1995). "Linkage between sexual orientation and chromosome Xq28 in males but not in females". Nature Genetics 11 (3): 248–56. doi:10.1038/ng1195-248. PMID 7581447.
- Pool R. Evidence for homosexuality gene. Science. 1993 Jul 16;261(5119):291-2. PubMed PMID 8332894.
- King MC. Human genetics. Sexual orientation and the X. Nature. 1993 Jul22;364(6435):288-9. PubMed PMID 8332183.
- Byne, William (May 1994). "The Biological Evidence Challenged". Scientific American.
- Hamer, Dean; Simon LeVay (May 1994). "Evidence for a Biological Influence in Male Homosexuality". Scientific American.
- Rice et al., 1999. Male homosexuality: Absence of linkage to microsatellite markers at Xq28. Science, 284, 665-667.
- "Genetics and Male Sexual Orientation". Sciencemag.org. 1999-08-06. doi:10.1126/science.285.5429.803a. Retrieved 2013-11-02.
- Genome-wide linkage scan of male sexual orientation. A. R. Sanders, K. Dawood, G. Rieger, J. A. Badner, E. S. Gershon, R. S. Krishnappa, A. B. Kolundzija, S. Guo, G. W. Beecham, E. R. Martin, J.M. Bailey8, Abstract 1957T
- name=pmid15645181>Mustanski BS, Dupree MG, Nievergelt CM, Bocklandt S, Schork NJ, Hamer DH (March 2005). "A genomewide scan of male sexual orientation". Hum. Genet. 116 (4): 272–8. doi:10.1007/s00439-004-1241-4. PMID 15645181.
- Sanders,A. R. and Martin,E. R. and Beecham,G. W. and Guo,S. and Dawood,K. and Rieger,G. and Badner,J. A. and Gershon,E. S. and Krishnappa,R. S. and Kolundzija,A. B. and Duan,J. and Gejman,P. V. and Bailey,J. M. (November 2014). "Genome-wide scan demonstrates significant linkage for male sexual orientation". Psychological Medicine. FirstView: 1–10. doi:10.1017/S0033291714002451.
- Mintz, Zoe (14 February 2014). "Does A ‘Gay Gene’ Exist? New Study Says ‘Xq28’ May Influence Male Sexual Orientation". International Business Times. Retrieved 18 February 2014.
- Molecular Genetic Study of Sexual Orientation A genetic study of gay brothers at Northwestern University.