Xq28 is a chromosome band and genetic marker situated at the tip of the X chromosome which has been studied since at least 1980. [1] The band contains three distinct regions, totaling about 8 Mbp of genetic information. [2] 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. [3]
The 1993 study by Hamer et al. 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 for 40 families 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 in that small sample. It was concluded that at least one form of male homosexuality is preferentially transmitted through the maternal side and is genetically linked to the Xq28 region. [3]
A follow-up study, Hu et al. (1995), conducted by the Hamer lab in collaboration with two groups of statistical experts in 1995, 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. [4]
Hamer's findings were highlighted in scientific journals including Science , [5] Nature [6] and the topic of a mini-symposium in Scientific American . [7] [8]
In June 1994, an article in the Chicago Tribune by John Crewdson stated that an anonymous junior researcher in Hamer's laboratory alleged that Hamer selectively presented the data in his 1993 paper in the journal Science . The junior researcher had assisted in the gene mapping in Hamer's 1993 study. Shortly after voicing her questions, she was summarily dismissed from her post-doctoral fellowship in Hamer's lab; who dismissed her could not be determined. Later, she was given another position in a different lab. [9] Hamer stated that Crewdson's article was "seriously in error" and denied the allegations made against him. [10] [11] [12] An official inquiry launched by the Office of Research Integrity (ORI) to investigate the allegations of selective presentation of the data ended in December 1996. It determined that Hamer had not committed any scientific misconduct in his study. [10]
Two further studies in the 1990s gave mixed results. One was an X chromosome linkage analysis of 54 pairs of gay brothers carried out by the independent research group of Sanders et al. in 1998. The results of the study were indistinguishable from the results of the study by Hu et al.: both reported that the chromosomal location of maximum sharing was locus DXS1108 and both reported similar degrees of allele sharing (66% versus 67%). [13] The second study by Rice et al. in 1999 studied 52 pairs of Canadian gay brothers and found no statistically significant [note 1] linkage in alleles and haplotypes. Consequently, they concluded against the possibility of any gene in the Xq28 region having a large genetic influence on male sexual orientation (though they could not rule out the possibility of a gene in this region having a small influence). [14] Rice et al. also asserted that their results do not exclude the possibility of finding male homosexuality genes elsewhere in the genome. [15] Hamer criticized the study for not selecting families for their study population based on maternal transmission as selecting only families that show an excess of maternal gay relatives is necessary to detect the Xq28 linkage. [14] A meta-analysis of all data available at that time (i.e., Hamer et al. (1993), Hu et al. (1995), Rice et al. (1999), and the unpublished 1998 study by Sanders et al. indicated that Xq28 has a significant but not exclusive role in male sexual orientation. [13]
The authors of the meta-analysis (which included three authors of the Rice et al. study, Rice, Risch and Ebers) presented several methodological reasons due to which Rice et al. (1999) may have been unable to detect statistically significant linkage between Xq28 and male sexual orientation: the families genotyped by Rice et al. were non-representative as they had an excess of paternal instead of maternal gay relatives thus obscuring the display of any X-chromosome linkage; the statistical power of their sample was insufficient to adequately detect linkage [note 2] and they lacked definite criteria for what constituted as homosexuality (the researchers depended on their own judgement and sometimes based their judgement on a single question to the subject). [13] They also lacked criteria "to select appropriate families for the study of a putative X-linked locus" [13] — as they did not select families based on the presence of maternal transmission of homosexuality, the Xq28 contribution to male sexual orientation may have been hidden. [14] In addition, the meta-analysis revealed that the family pedigree data of Rice et al. (1999), in contrast to the genotyping data, seemed to support X chromosome linkage for homosexuality. [13] [note 3]
In 2012, a large, comprehensive genome-wide linkage study of male sexual orientation was conducted by several independent groups of researchers. [16] The study population included 409 independent pairs of gay brothers from 384 families, who were analyzed with over 300,000 single-nucleotide polymorphism markers. The study confirmed the Xq28 linkage to homosexuality by two-point and multipoint (MERLIN) LOD score mapping. Significant linkage was also detected in the region near the centromere 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." It was the largest study of the genetic basis of homosexuality to date and was published online in November 2014. [17]
In August 2019, a genome-wide association study of 493,001 individuals concluded that hundreds or thousands of genetic variants underlie homosexual behavior in both sexes, with 5 variants in particular being significantly associated. They stated that in contrast to linkage studies that found substantial association of sexual orientation with variants on the X-chromosome, they found no excess of signal (and no individual genome-wide significant variants) on Xq28 or the rest of the X chromosome. [18]
Xq28 is a large, complex, and gene-dense region. [19] Among its various genes are the 12 genes of the melanoma-associated antigen (MAGE) family, [20] of which MAGEA11 has been identified as a coregulator for the androgen receptor. [21] Mutations involving the production of extra copies of the MECP2 and IRAK1 genes within Xq28 have been associated with phenotypes including anxiety and autism in mice. [22]
Sexual orientation is an enduring pattern of romantic or sexual attraction to persons of the opposite sex or gender, the same sex or gender, or to both sexes or more than one gender. These attractions are generally subsumed under heterosexuality, homosexuality, and bisexuality, while asexuality is sometimes identified as the fourth category.
The relationship between biology and sexual orientation is a subject of research. While scientists do not know the exact cause of sexual orientation, they theorize that it is caused by a complex interplay of genetic, hormonal, and environmental influences. Hypotheses for the impact of the post-natal social environment on sexual orientation, however, are weak, especially for males.
The Y chromosome is one of two sex chromosomes in therian mammals and other organisms. The other sex chromosome is the X chromosome. Y is normally the sex-determining chromosome in many species, since it is the presence or absence of Y that determines the male or female sex of offspring produced in sexual reproduction. In mammals, the Y chromosome contains the gene SRY, which triggers male development. The DNA in the human Y chromosome is composed of about 62 million base pairs, making it similar in size to chromosome 19. The Y chromosome is passed only from father to son. With a 30% difference between humans and chimpanzees, the Y chromosome is one of the fastest-evolving parts of the human genome. The human Y chromosome carries 693 genes, with 107 of these being protein-coding, but some genes are repeated and that makes the number of exclusive protein-coding genes just 42, the numbers are given for telomere-to-telomere CHM13. The Consensus Coding Sequence (CCDS) Project only classified 63 out of 107. All single-copy Y-linked genes are hemizygous except in cases of aneuploidy such as XYY syndrome or XXYY syndrome. Because of fake gaps inserted in GRCh38 it may be not obvious that CHM13 added 30 million base pairs into the Y chromosome, which is almost half of it that was unknown before 2022.
In human genetics, the Y-chromosomal most recent common ancestor is the patrilineal most recent common ancestor (MRCA) from whom all currently living humans are descended. He is the most recent male from whom all living humans are descended through an unbroken line of their male ancestors. The term Y-MRCA reflects the fact that the Y chromosomes of all currently living human males are directly derived from the Y chromosome of this remote ancestor. The analogous concept of the matrilineal most recent common ancestor is known as "Mitochondrial Eve", the most recent woman from whom all living humans are descended matrilineally. As with "Mitochondrial Eve", the title of "Y-chromosomal Adam" is not permanently fixed to a single individual, but can advance over the course of human history as paternal lineages become extinct.
Genetic linkage is the tendency of DNA sequences that are close together on a chromosome to be inherited together during the meiosis phase of sexual reproduction. Two genetic markers that are physically near to each other are unlikely to be separated onto different chromatids during chromosomal crossover, and are therefore said to be more linked than markers that are far apart. In other words, the nearer two genes are on a chromosome, the lower the chance of recombination between them, and the more likely they are to be inherited together. Markers on different chromosomes are perfectly unlinked, although the penetrance of potentially deleterious alleles may be influenced by the presence of other alleles, and these other alleles may be located on other chromosomes than that on which a particular potentially deleterious allele is located.
Yeast artificial chromosomes (YACs) are genetically engineered chromosomes derived from the DNA of the yeast, Saccharomyces cerevisiae, which is then ligated into a bacterial plasmid. By inserting large fragments of DNA, from 100–1000 kb, the inserted sequences can be cloned and physically mapped using a process called chromosome walking. This is the process that was initially used for the Human Genome Project, however due to stability issues, YACs were abandoned for the use of Bacterial artificial chromosome
The year 1993 in science and technology involved many significant events, listed below.
Dean Hamer is an American geneticist, author, and filmmaker He is known for his research on the role of genetics in sexual orientation and for a series of popular books and documentaries that have changed the understanding and perceptions of human sexuality and gender identity.
Fraternal birth order has been correlated with male sexual orientation, with a significant volume of research finding that the more older brothers a male has from the same mother, the greater the probability he will have a homosexual orientation. Ray Blanchard and Anthony Bogaert first identified the association in the 1990s and named it the fraternal birth order effect. Scientists have attributed the effect to a prenatal biological mechanism, since the association is only present in men with older biological brothers, and not present among men with older step-brothers and adoptive brothers. The mechanism is thought to be a maternal immune response to male fetuses, whereby antibodies neutralize male Y-proteins thought to play a role in sexual differentiation during development. This would leave some regions of the brain associated with sexual orientation in the 'female typical' arrangement – or attracted to men. Biochemical evidence for this hypothesis was identified in 2017, finding mothers with a gay son, particularly those with older brothers, had heightened levels of antibodies to the NLGN4Y Y-protein than mothers with heterosexual sons.
The heritability of autism is the proportion of differences in expression of autism that can be explained by genetic variation; if the heritability of a condition is high, then the condition is considered to be primarily genetic. Autism has a strong genetic basis. Although the genetics of autism are complex, autism spectrum disorder (ASD) is explained more by multigene effects than by rare mutations with large effects.
INAH-3 is the short form for the third interstitial nucleus of the anterior hypothalamus, and is the sexually dimorphic nucleus of humans. The INAH-3 is significantly larger in males than in females regardless of age and larger in heterosexual males than in homosexual males and heterosexual females.
Neil Risch is an American human geneticist and professor at the University of California, San Francisco (UCSF). Risch is the Lamond Family Foundation Distinguished Professor in Human Genetics and Director of the Institute for Human Genetics and Professor of Epidemiology and Biostatistics at UCSF.
A relationship between handedness and sexual orientation has been suggested by a number of researchers, who report that heterosexual individuals are somewhat more likely to be right-handed than are homosexual individuals.
The relationship between the environment and sexual orientation is a subject of research. In the study of sexual orientation, some researchers distinguish environmental influences from hormonal influences, while other researchers include biological influences such as prenatal hormones as part of environmental influences.
Sexual orientation is an enduring pattern of romantic or sexual attraction to persons of the opposite sex or gender, the same sex or gender, or to both sexes or more than one gender, or none of the aforementioned at all. The ultimate causes and mechanisms of sexual orientation development in humans remain unclear and many theories are speculative and controversial. However, advances in neuroscience explain and illustrate characteristics linked to sexual orientation. Studies have explored structural neural-correlates, functional and/or cognitive relationships, and developmental theories relating to sexual orientation in humans.
Genopolitics is the study of the genetic basis of political behavior and attitudes. It combines behavior genetics, psychology, and political science and it is closely related to the emerging fields of neuropolitics and political physiology.
The hormonal theory of sexuality holds that, just as exposure to certain hormones plays a role in fetal sex differentiation, such exposure also influences the sexual orientation that emerges later in the individual. Prenatal hormones may be seen as the primary determinant of adult sexual orientation, or a co-factor with genes, biological factors and/or environmental and social conditions.
Epigenetic theories of homosexuality concern the studies of changes in gene expression or cellular phenotype caused by mechanisms other than changes in the underlying DNA sequence, and their role in the development of homosexuality. Epigenetics examines the set of chemical reactions that switch parts of the genome on and off at strategic times and locations in the organism's life cycle. However, epigenetic theories tangle a multiplicity of initiating causes and of resulting final effects and will never lead to a single cause or a single result. Hence, any interpretation of such theories may not focus just one isolated reason of a multiplicity of causes or of effects.
The Science of Desire: The Search for the Gay Gene and the Biology of Behavior is a 1994 book by the geneticist Dean Hamer and the journalist Peter Copeland, in which the authors discuss Hamer's research into the genetics of homosexuality.
Eric Vilain is a physician-scientist and professor in the fields of Disorders/Differences of Sex Development (DSDs) and precision medicine. He has been the director of the Center for Genetic Medicine Research at Children's National Medical Center and the chair of the Department of Genomics and Precision Medicine at the George Washington University School of Medicine & Health Sciences in Washington, D.C. since 2017. Vilain is a fellow of the American College of Medical Genetics, serves on the International Olympic Committee's Medical Commission, and sits on the Board of Scientific Counselors for the National Institute of Child Health and Human Development (NICHD).
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