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 personal pattern of romantic attraction 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. Patterns are generally categorized 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 on-going 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. However, evidence is weak for hypotheses that the post-natal social environment impacts sexual orientation, especially for males.
The Y chromosome is one of two sex chromosomes in therian mammals and other organisms. Along with the X chromosome, it is part of the XY sex-determination system, in which the Y is the sex-determining because it is the presence or absence of Y chromosome that determines the male or female sex of offspring produced in sexual reproduction. In mammals, the Y chromosome contains the SRY gene, which triggers development of male gonads. The Y chromosome is passed only from male parents to male offspring.
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.
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 films that have changed scientific and public understandings and perceptions of human sexuality and gender.
Y linkage, also known as holandric inheritance, describes traits that are produced by genes located on the Y chromosome. It is a form of sex linkage.
Gene mapping or genome mapping describes the methods used to identify the location of a gene on a chromosome and the distances between genes. Gene mapping can also describe the distances between different sites within a gene.
Fraternal birth order, also known as the older brother effect, 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.
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, Founding Director of the Institute for Human Genetics, and Professor of Epidemiology and Biostatistics at UCSF. He specializes in statistical genetics, genetic epidemiology and population genetics.
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.
Marker assisted selection or marker aided selection (MAS) is an indirect selection process where a trait of interest is selected based on a marker linked to a trait of interest, rather than on the trait itself. This process has been extensively researched and proposed for plant- and animal- breeding.
In genetics, a centimorgan or map unit (m.u.) is a unit for measuring genetic linkage. It is defined as the distance between chromosome positions for which the expected average number of intervening chromosomal crossovers in a single generation is 0.01. It is often used to infer distance along a chromosome. However, it is not a true physical distance.
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.
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.
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.
James Francis Gusella is a Canadian molecular biologist and geneticist known for his work on Huntington's disease and other neurodegenerative diseases in humans. He is the Bullard Professor of Neurogenetics in the Department of Genetics at Harvard Medical School and an investigator at the Center for Genomic Medicine at the Mass General Research Institute.
Eric Vilain is a physician-scientist and professor in the fields of Differences of Sex Development (DSDs) and precision medicine. He is the Associate Vice Chancellor for Scientific Affairs at the University of California, Irvine Health Affairs and also the director of the UCI Institute for Clinical and Translational Science. He previously was 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. 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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