Blanchard and Klassen (1997) reported that each additional older brother increases the odds of a man being gay by 33%. [ 54 ] [ 55 ]  This is now "one of the most reliable epidemiological variables ever identified in the study of sexual orientation". [ 56 ]  To explain this finding, it has been proposed that male fetuses provoke a maternal immune reaction that becomes stronger with each successive male fetus. This maternal immunization hypothesis (MIH) begins when cells from a male fetus enter the mother's circulation during pregnancy or while giving birth. [ 57 ]  Male fetuses produce H-Y antigens which are "almost certainly involved in the sexual differentiation of vertebrates". These Y-linked proteins would not be recognized in the mother's immune system because she is female, causing her to develop antibodies which would travel through the placental barrier into the fetal compartment. From here, the anti-male bodies would then cross the blood/brain barrier (BBB) of the developing fetal brain, altering sex-dimorphic brain structures relative to sexual orientation, increasing the likelihood that the exposed son will be more attracted to men than women. [ 57 ]  It is this antigen which maternal H-Y antibodies are proposed to both react to and 'remember'. Successive male fetuses are then attacked by H-Y antibodies which somehow decrease the ability of H-Y antigens to perform their usual function in brain masculinization. [ 54 ]


In 2017, researchers discovered a biological mechanism of gay people who tend to have older brothers. They believed the  Neuroligin 4 Y-linked  protein was responsible for a later son being gay. They found that women had significantly higher anti-NLGN4Y levels than men. In addition, mothers of gay sons, particularly those with older brothers, had significantly higher anti-NLGN4Y levels than did the control samples of women, including mothers of heterosexual sons. The results suggest an association between a maternal immune response to NLGN4Y and subsequent sexual orientation in male offspring. [ 10 ]


The fraternal birth order effect, however, does not apply to instances where a firstborn is homosexual. [ 58 ] [ 59 ] [ 60 ] [ 61 ]


Research conducted in Sweden [ 62 ]  has suggested that gay and straight men respond differently to two odors that are believed to be involved in  sexual arousal . The research showed that when both heterosexual women and gay men are exposed to a testosterone derivative found in men's sweat, a region in the hypothalamus is activated. Heterosexual men, on the other hand, have a similar response to an estrogen-like compound found in women's urine. [ 63 ]  The conclusion is that sexual attraction, whether same-sex or opposite-sex oriented, operates similarly on a biological level. Researchers have suggested that this possibility could be further explored by studying young subjects to see if similar responses in the hypothalamus are found and then correlating these data with adult sexual orientation. [ citation needed ]


A number of sections of the  brain  have been reported to be sexually dimorphic; that is, they vary between men and women. There have also been reports of variations in brain structure corresponding to sexual orientation. In 1990,  Dick Swaab  and Michel A. Hofman reported a difference in the size of the  suprachiasmatic nucleus  between homosexual and heterosexual men. [ 64 ]  In 1992, Allen and Gorski reported a difference related to sexual orientation in the size of the  anterior commissure , [ 65 ]  but this research was refuted by numerous studies, one of which found that the entirety of the variation was caused by a single outlier. [ 66 ] [ 67 ] [ 68 ]


Research on the physiologic differences between male and female brains are based on the idea that people have male or a female brain, and this mirrors the behavioral differences between the two sexes. Some researchers state that solid scientific support for this is lacking. Although consistent differences have been identified, including the size of the brain and of specific brain regions, male and female brains are very similar. [ 69 ] [ 70 ] [ 71 ] [ 72 ] [ 73 ] [ 74 ]


LeVay also conducted some of these early researches. He studied four groups of  neurons  in the  hypothalamus  called INAH1, INAH2, INAH3 and INAH4. This was a relevant area of the brain to study, because of evidence that it played a role in the regulation of  sexual behaviour in animals , and because INAH2 and INAH3 had previously been reported to differ in size between men and women. [ 47 ]


He obtained brains from 41 deceased hospital patients. The subjects were classified into three groups. The first group comprised 19 gay men who had died of  AIDS -related illnesses. The second group comprised 16 men whose sexual orientation was unknown, but whom the researchers presumed to be heterosexual. Six of these men had died of AIDS-related illnesses. The third group was of six women whom the researchers presumed to be heterosexual. One of the women had died of an AIDS-related illness. [ 47 ]


The  HIV-positive people  in the presumably heterosexual patient groups were all identified from medical records as either  intravenous drug abusers  or recipients of  blood transfusions . Two of the men who identified as heterosexual specifically denied ever engaging in a homosexual sex act. The records of the remaining heterosexual subjects contained no information about their sexual orientation; they were assumed to have been primarily or exclusively heterosexual "on the basis of the numerical preponderance of heterosexual men in the population". [ 47 ]


LeVay found no evidence for a difference between the groups in the size of INAH1, INAH2 or INAH4. However, the INAH3 group appeared to be twice as big in the heterosexual male group as in the gay male group; the difference was highly significant, and remained significant when only the six AIDS patients were included in the heterosexual group. The size of INAH3 in the homosexual men's brains was comparable to the size of INAH3 in the heterosexual women's brains. [ citation needed ]


William Byne and colleagues attempted to identify the size differences reported in INAH 1–4 by replicating the experiment using brain sample from other subjects: 14 HIV-positive homosexual males, 34 presumed heterosexual males (10 HIV-positive), and 34 presumed heterosexual females (9 HIV-positive). The researchers found a significant difference in INAH3 size between heterosexual men and heterosexual women. The INAH3 size of the homosexual men was apparently smaller than that of the heterosexual men, and larger than that of the heterosexual women, though neither difference quite reached statistical significance. [ 67 ]


Byne and colleagues also weighed and counted numbers of neurons in INAH3 tests not carried out by LeVay. The results for INAH3 weight were similar to those for INAH3 size; that is, the INAH3 weight for the heterosexual male brains was significantly larger than for the heterosexual female brains, while the results for the gay male group were between those of the other two groups but not quite significantly different from either. The neuron count also found a male-female difference in INAH3, but found no trend related to sexual orientation. [ 67 ]


LeVay has said that Byne replicated his work, but that he employed a two-tailed statistical analysis, which is typically reserved for when no previous findings had employed the difference. LeVay has said that "given that my study had already reported a INAH3 to be smaller in gay men, a one tailed approach would have been more appropriate, and it would have yielded a significant difference [between heterosexual and homosexual men]". [ 12 ] : 110


J. Michael Bailey  has criticized LeVay's critics—describing the claim that the INAH-3 difference could be attributable to AIDS as "aggravating", since the "INAH-3 did not differ between the brains of straight men who died of AIDS and those who did not have the disease". [ 75 ] : 120   Bailey has further criticized the second objection that was raised, that being gay might have somehow caused the difference in INAH-3, and not vice-versa, saying "the problem with this idea is that the hypothalamus appears to develop early. Not a single expert I have ever asked about LeVay's study thought it was plausible that sexual behavior caused the INAH-3 differences." [ 75 ] : 120


The SCN of homosexual males has been demonstrated to be larger (both the volume and the number of neurons are twice as many as in heterosexual males). These areas of the hypothalamus have not yet been explored in homosexual females nor bisexual males nor females. Although the functional implications of such findings still have not been examined in detail, they cast serious doubt over the widely accepted Dörner hypothesis that homosexual males have a "female hypothalamus" and that the key mechanism of differentiating the "male brain from originally female brain" is the epigenetic influence of testosterone during prenatal development. [ 76 ]


A 2010 study by Garcia-Falgueras and Swaab stated that "the fetal brain develops during the intrauterine period in the male direction through a direct action of testosterone on the developing nerve cells, or in the female direction through the absence of this hormone surge. In this way, our gender identity (the conviction of belonging to the male or female gender) and sexual orientation are programmed or organized into our brain structures when we are still in the womb. There is no indication that social environment after birth has an effect on gender identity or sexual orientation." [ 77 ]


The  domestic ram  is used as an experimental model to study early programming of the neural mechanisms which underlie homosexuality, developing from the observation that approximately 8% of domestic rams are sexually attracted to other rams (male-oriented) when compared to the majority of rams which are female-oriented. In many species, a prominent feature of sexual differentiation is the presence of a sexually dimorphic nucleus (SDN) in the preoptic hypothalamus, which is larger in males than in females.


Roselli et al. discovered an ovine SDN (oSDN) in the preoptic hypothalamus that is smaller in male-oriented rams than in female-oriented rams, but similar in size to the oSDN of females. Neurons of the oSDN show  aromatase  expression which is also smaller in male-oriented rams versus female-oriented rams, suggesting that sexual orientation is neurologically hard-wired and may be influenced by hormones. However, results failed to associate the role of neural aromatase in the sexual differentiation of brain and behavior in the sheep, due to the lack of defeminization of adult sexual partner preference or oSDN volume as a result of aromatase activity in the brain of the fetuses during the critical period. Having said this, it is more likely that oSDN morphology and homosexuality may be programmed through an androgen receptor that does not involve  aromatisation . Most of the data suggests that homosexual rams, like female-oriented rams, are masculinized and defeminized with respect to mounting, receptivity, and gonadotrophin secretion, but are not defeminized for sexual partner preferences, also suggesting that such behaviors may be programmed differently. Although the exact function of the oSDN is not fully known, its volume, length, and cell number seem to correlate with sexual orientation, and a dimorphism in its volume and of cells could bias the processing cues involved in partner selection. More research is needed in order to understand the requirements and timing of the development of the oSDN and how prenatal programming effects the expression of mate choice in adulthood. [ 78 ]


Childhood gender nonconformity  is a strong predictor of adult sexual orientation that has been consistently replicated in research, and is thought to be strong evidence of a biological difference between heterosexual and non-heterosexuals. A review authored by  J. Michael Bailey  states: "childhood gender nonconformity comprises the following phenomena among boys: cross-dressing, desiring to have long hair, playing with dolls, disliking competitive sports and rough play, preferring girls as playmates, exhibiting elevated separation anxiety, and desiring to be—or believing that one is—a girl. In girls, gender nonconformity comprises dressing like and playing with boys, showing interest in competitive sports and rough play, lacking interest in conventionally female toys such as dolls and makeup, and desiring to be a boy". This gender nonconformist behavior typically emerges at preschool age, although is often evident as early as age 2. Children are only considered gender nonconforming if they persistently engage in a variety of these behaviors, as opposed to engaging in a behavior on a few times or on occasion. It is also not a one-dimensional trait, but rather has varying degrees. [ 3 ]


Children who grow up to be non-heterosexual were, on average, substantially more gender nonconforming in childhood. This is confirmed in both retrospective studies where homosexuals, bisexuals and heterosexuals are asked about their gender typical behavior in childhood, and in prospective studies, where highly gender nonconforming children are followed from childhood into adulthood to find out their sexual orientation. A review of retrospective studies that measured gender nonconforming traits estimated that 89% of homosexual men exceeded heterosexual males level of gender nonconformity, whereas just 2% of heterosexual men exceeded the homosexual median. For female sexual orientation, the figures were 81% and 12% respectively. A variety of other assessments such as childhood home videos, photos and reports of parents also confirm this finding. [ 3 ]  Critics of this research see this as confirming stereotypes; however, no study has ever demonstrated that this research has exaggerated childhood gender nonconformity. J. Michael Bailey argues that gay men often deny that they were gender nonconforming in childhood because they may have been bullied or maltreated by peers and parents for it, and because they often do not find femininity attractive in other gay males and thus would not want to acknowledge it in themselves. [ 75 ] : 80   Additional research in Western cultures and non-Western cultures including Latin America, Asia, Polynesia, and the Middle East supports the validity of childhood gender nonconformity as a predictor of adult non-heterosexuality. [ 3 ]


This research does not mean that all non-heterosexuals were gender nonconforming, but rather indicates that long before sexual attraction is known, non-heterosexuals, on average, are noticeably different from other children. There is little evidence that gender nonconforming children have been encouraged or taught to behave that way; rather, childhood gender nonconformity typically emerges despite conventional socialization. [ 3 ]  Medical experiments in which infant boys were sex reassigned and reared as girls did not make them feminine nor attracted to males. [ 3 ]


Between the 1960s and 2000, many newborn and infant boys were surgically reassigned as females if they were born with malformed penises, or if they lost their penises in accidents. [ 3 ] : 72–73   Many surgeons believed such males would be happier being socially and surgically reassigned female. In all seven published cases that have provided sexual orientation information, the subjects grew up to be attracted to females. Six cases were exclusively attracted to females, with one case 'predominantly' attracted to females. In a review article in the journal  Psychological Science in the Public Interest ,  six researchers including  J. Michael Bailey  state this establishes a strong case that male sexual orientation is partly established before birth:


This is the result we would expect if male sexual orientation were entirely due to nature, and it is opposite of the result expected if it were due to nurture, in which case we would expect that none of these individuals would be predominantly attracted to women. They show how difficult it is to derail the development of male sexual orientation by psychosocial means.


They further argue that this raises questions about the significance of the social environment on sexual orientation, stating, "If one cannot reliably make a male human become attracted to other males by cutting off his penis in infancy and rearing him as a girl, then what other psychosocial intervention could plausibly have that effect?" It is further stated that neither  cloacal exstrophy  (resulting in a malformed penis), nor surgical accidents, are associated with abnormalities of prenatal androgens, thus, the brains of these individuals were male-organized at birth. Six of the seven identified as heterosexual males at follow up, despite being surgically altered and reared as females, with researchers adding: "available evidence indicates that in such instances, parents are deeply committed to raising these children as girls and in as gender-typical a manner as possible." Bailey et al. describe these sex reassignments as 'the near-perfect quasi-experiment' in measuring the impact of 'nature' versus 'nurture' with regards to male homosexuality. [ 3 ]


Sexual practices that significantly reduce the frequency of heterosexual intercourse also significantly decrease the chances of  successful reproduction , and for this reason, they would appear to be  maladaptive  in an  evolutionary  context following a simple Darwinian model (competition amongst individuals) of natural selection—on the assumption that homosexuality would reduce this frequency. Several theories have been advanced to explain this contradiction, and new experimental evidence has demonstrated their feasibility. [ 79 ] [ 4 ]


The "gay uncle hypothesis" posits that people who themselves do not have children may nonetheless increase the prevalence of their family's genes in future generations by providing resources (e.g., food, supervision, defense, shelter) to the offspring of their closest relatives. [ 80 ]


This hypothesis is an extension of the theory of kin selection, which was originally developed to explain apparent altruistic acts which seemed to be maladaptive. The initial concept was suggested by  J. B. S. Haldane  in 1932 and later elaborated by many others including  John Maynard Smith ,  W. D. Hamilton ,  Mary Jane West-Eberhard , and  E. O. Wilson . [ 81 ] [ 82 ]  This concept was also used to explain the patterns of certain social insects where most of the members are non-reproductive. Conversely, social psychologist  David Buss  has argued that there is no empirical evidence that supports the hypothesis. [ 83 ]


In 2001,  Evolution and Human Behavior  published a questionnaire survey of 57 heterosexual and 66 homosexual male subjects in the  United States  that found that homosexual subjects were no more likely to provide financial resources towards family members, heterosexual subjects were more likely give more financial resources to siblings than homosexual subjects, and homosexual subjects tended to be more estranged from family members. [ 84 ]  In 2005,  Archives of Sexual Behavior  published a replication study with 60 heterosexual and 60 homosexual male subjects in  England  that likewise found no significant differences between heterosexual and homosexual subjects in familial affinity or generosity towards family members. [ 85 ]  Vasey, Pocock, and VanderLaan (2007) and Vasey and VanderLaan (2010) tested the theory on the Pacific island of  Samoa , where they studied women, straight men, and the  fa'afafine , men who prefer other men as sexual partners and are accepted within the culture as a distinct third gender category. Vasey and VanderLaan found that the  fa'afafine  said they were significantly more willing to help kin, yet much less interested in helping children who are not family, providing the first evidence to support the kin selection hypothesis. The hypothesis is consistent with other studies on homosexuality, which show that it is more prevalent amongst both siblings and twins. [ 86 ] [ 87 ] [ 88 ]


Anthropologist Raymond Hames notes that Vasey and VanderLaan's research on the  fa'afafine  identifies them as "transgendered androphilic males" as opposed to "sex-gender congruent androphiles" or "egalitarian homosexuals" in Western societies. [ 89 ]  Based on research conducted in  Japan  that found no evidence that homosexual Japanese men exhibited elevated avuncular tendencies compared to heterosexual counterparts, Vasey and VanderLaan (2011) provides evidence that if an adaptively designed avuncular male androphilic phenotype exists and its development is contingent on a particular social environment, then a collectivistic cultural context is insufficient, in and of itself, for the expression of such a phenotype. [ 90 ]  In 2011 and 2014, the  Journal of Cognition and Culture  published two studies that found that  Canadian  homosexual men exhibited significantly greater altruistic tendencies toward kin versus non-kin children relative to heterosexual men and women, but did not find that Canadian homosexual males exhibited significantly higher altruistic behavior towards nieces and nephews over geographic disconnect. [ 91 ] [ 92 ]


In 2016, the  Journal of Sex Research  published a study comprising 278 homosexual (or  kathoey ) and heterosexual male subjects in  Italy  and  Spain  and from the  Urak Lawoi  of  Thailand  that found no greater kin altruism or avuncularity among homosexual subjects in any of the three cultures and that kin altruism and avuncularity was associated with societal differences in cultural norms about general altruism toward non-kin children. [ 93 ]  In 2017,  Evolutionary Psychological Science  published a  logistic regression  analysis of the results of 17,295 female subjects across 58 countries on  World Values Survey  questionnaires about attitudes toward homosexuality that found that subjects that were potentially most in need of  alloparental  support exhibited significantly more positive attitudes towards homosexuals, which the researchers suggested was circumstantial evidence in support of the hypothesis on a global scale. [ 94 ]  In 2018,  Archives of Sexual Behavior  published a study comparing avuncular tendencies between heterosexual and homosexual men on  Java  in  Indonesia  that found that homosexual men reported an increased willingness to transfer resources and money toward nephews and nieces but only reduced the direct reproductive cost to homosexual men by 20%, with the researchers concluding that kin selection alone was an insufficient explanation of male homosexuality. [ 95 ]


Some scholars [ 79 ]  have suggested that homosexuality is indirectly adaptive, by conferring a reproductive advantage on heterosexual siblings or their children. By way of analogy, the  allele  (a particular version of a gene) which causes  sickle cell disease  when two copies are present, also confers an  adaptive advantage  when one copy is present by providing resistance to  malaria  with non-symptomatic  sickle cell trait —which is known as "heterozygote advantage". [ 96 ]


Brendan Zietsch of the Queensland Institute of Medical Research proposes the alternative theory that men exhibiting female traits become more attractive to females and are thus more likely to mate, provided the genes involved do not drive them to complete rejection of heterosexuality. [ 97 ]


In a 2008 study, its authors stated that "There is considerable evidence that human sexual orientation is genetically influenced, so it is not known how homosexuality, which tends to lower reproductive success, is maintained in the population at a relatively high frequency." They hypothesized that "while genes predisposing to homosexuality reduce homosexuals' reproductive success, they may confer some advantage in heterosexuals who carry them". Their results suggested that "genes predisposing to homosexuality may confer a mating advantage in heterosexuals, which could help explain the evolution and maintenance of homosexuality in the population". [ 98 ]  However, in the same study, the authors noted that "nongenetic alternative explanations cannot be ruled out" as a reason for the heterosexual in the homosexual-heterosexual twin pair having more partners, specifically citing "social pressure on the other twin to act in a more heterosexual way" (and thus seek out a greater number of sexual partners) as an example of one alternative explanation. The study acknowledges that a large number of sexual partners may not lead to greater reproductive success, specifically noting there is an "absence of evidence relating the number of sexual partners and actual reproductive success, either in the present or in our evolutionary past". [ 98 ]


The heterosexual advantage hypothesis was given strong support by the 2004 Italian study demonstrating increased  fecundity  in the female matrilineal relatives of gay men. [ 99 ] [ 100 ]  As originally pointed out by Dean Hamer, [ 101 ]  even a modest increase in reproductive capacity in females carrying a "gay gene" could easily account for its maintenance at high levels in the population. [ 100 ]


In 2004, Italian researchers conducted a study of about 4,600 people who were the relatives of 98 homosexual and 100 heterosexual men. Female relatives of the homosexual men tended to have more offspring than those of the heterosexual men. Female relatives of the homosexual men on their mother's side tended to have more offspring than those on the father's side. The researchers concluded that there was genetic material being passed down on the X chromosome which both promote  fertility  in the mother and homosexuality in her male offspring. The connections discovered would explain about 20% of the cases studied, indicating that it being a highly significant factor to account for, but not the sole genetic factor determining sexual orientation. [ 99 ] [ 100 ]  A 2008 follow-up study using a comparative survey design found that 147 white and non-white homosexual men had a significantly more relatives in their maternal lines than 155 heterosexual men but not in the paternal line, and while the maternal aunts of white homosexual men had significantly elevated fecundity as compared to white heterosexual men, every class of relative for non-white heterosexual men showed elevated fecundities as compared to non-white homosexual men. [ 102 ]


Noting subsequent research by the original researchers that found that female relatives in the maternal line of homosexual men have higher fertility, [ 103 ]  anthropologist  Ruth Mace  suggests that homosexuality is maintained by antagonistic pleiotropy and cites a cross-cultural study spanning 48 societies that found that male homosexuality was more prevalent in  stratified societies , did not appear to be a  cultural universal , and is possibly maintained by  hypergyny . [ 104 ] [ 105 ]  While the original cross-cultural study's empirical findings, conceptual basis, and methodology has been disputed by other researchers, [ 106 ] [ 107 ]  a subsequent cross-cultural study of 107 societies across 6 continents replicated the previous study's findings. [ 108 ]


In 2005,  Archives of Sexual Behavior  published a study comparing family size and fecundity among family relatives between 301 homosexual men and 404 heterosexual men and found that the mean family size for homosexual men was significantly larger than heterosexual men as well as increased fecundity among the relatives of homosexual men. [ 109 ]  In 2007, the  Proceedings of the Royal Society: Series B  published a study comparing the number of siblings of a sample of Samoan heterosexual males to  fa'afafine  counterparts that found that the  fa'afafine  tend to have more siblings, and specifically, a greater number of older brothers, older sisters, and younger brothers, [ 110 ]  and  Archives of Sexual Behavior  published a replication study in 2011 that found that likewise showed that the  fa'afafine  had a greater number of siblings than heterosexual males, which the researchers suggested indicates that a maternal fecundity effect exists in Samoa. [ 111 ]  In 2009,  Archives of Sexual Behavior  published a study that examined the  probands  of 152 homosexual men and 98 heterosexual men that found a significant fecundity increase in mothers (including  primiparous  mothers) but no evidence of increased paternal fecundity, which the researchers concluded suggested the existence of a sexually antagonistic inheritance partly linked to the X-chromosome promoting fecundity in females and homosexual sexual orientation in males. [ 112 ]


In 2009, the  Journal of Sexual Medicine  published a study of 151 homosexual or bisexual men and 88 exclusively heterosexual men that found that significantly higher fecundity of female relatives of the maternal line (including mothers, maternal grandparents, and maternal aunts) for both bisexuals and homosexuals compared to the corresponding relatives of heterosexual subjects, which the researchers argued provided evidence for an association between X-chromosomal genetic factors with bisexuality in men and fecundity promotion in female carriers. [ 113 ]  In 2010,  Archives of Sexual Behavior  published a study comparing the pedigree sizes of 694 homosexual men and 894 heterosexual men sampled at  pride parades  that found that homosexual men had more relatives, especially paternal relatives, but no evidence that male sexual orientation is transmitted predominantly through the maternal line—which the researchers noted was contrary to previous research. [ 114 ]  In 2012,  Archives of Sexual Behavior  published a study that compared the probands of 4,784 firstborn homosexual men and 40,197 first-born heterosexual men across 6 datasets that found that the homosexual probands had significantly fewer siblings or a statistically insignificant difference in the number of siblings—which the researcher concluded was a direct contradiction of an antagonistic pleiotropy explanation of homosexuality, but also that such an explanation could not be tested solely by comparing the number of siblings of heterosexual and homosexual subjects because of the  confounding  impact of the fraternal birth order effect. [ 115 ] [ 116 ]


In 2012,  PLOS One  published a study that compared the fecundity of the paternal and maternal line grandmothers, aunts, and uncles of 86 Samoan heterosexual males and 86  fa'afafine  that found elevated fecundity in the paternal and maternal line grandmothers of  fa'afafine  but not their aunts or uncles. [ 117 ]  In 2012, the  Journal of Sexual Medicine  published a study examining the  phenotypic expression  of the genetic factors that influence increased fecundity in female relative carriers that found that as compared with corresponding female relatives of heterosexual men, mothers and maternal aunts of homosexual men had fewer  gynecological disorders  and  complicated pregnancies , had  reduced family stability  and a  higher divorce and spousal separation rate , and self-reported less interest in having children, less emphasis on romantic love within couples, and less importance on their social life, but scored higher on the  extraversion  scale of a  Big Five personality traits  questionnaire. [ 118 ]


In 2017,  Archives of Sexual Behavior  published a study investigating differences in fertility rates of the paternal and maternal biological relatives of 191  fa'afafine  and 191 homosexual Samoan male subjects that found that the mothers and maternal grandmothers of  fa'afafine  showed elevated fertility as compared with homosexual men but not for paternal grandmothers or aunts, which led the researchers to conclude that their findings in Samoa for an antagonistic pleiotropy explanation of homosexuality provided only equivocal support. [ 119 ]  In 2018,  Human Nature  published a study investigating the fecundity among 30,203 relatives of 650 homosexual or bisexual women as compared with 808 heterosexual women that found that the direct fitness of homosexual females was four times lower than that of heterosexual females, but that the  pedigree size  and relative average fecundity in both the paternal and maternal sides of the families of the homosexual women were significantly higher than the families of the heterosexual women—which the researchers suggested appeared to offset the loss in fitness. [ 120 ]


In 2020,  Archives of Sexual Behavior  published a study that investigated fecundity among the relatives of 115 transgendered men and 112 homosexual men in the  Isthmus Zapotec  culture of  Mexico  (whom the Isthmus Zapotec refer to as  muxe gunaa  and the  muxe nguiiu  respectively) as compared with 171 heterosexual men and found that the mothers and paternal aunts of the transgendered men had higher fecundity than those of homosexual and heterosexual men, but found no such differences between the families of the heterosexual men and the homosexual men. [ 121 ]  In 2020, the  Proceedings of the Royal Society: Series B  published a meta-analysis of 10 studies comprising 5,390 homosexual and heterosexual subjects across 14 samples that found evidence for a fraternal birth order effect but no evidence for a female fecundity effect (i.e. an association between higher maternal fertility and homosexual orientation among male offspring) using a mathematical model proposed by mathematician  Tanya Khovanova , [ 122 ]  but the reviewers noted that Khovanova's methodology restricted samples to one-son and two-son families which resulted in lost data and possibly  biased results , and also made the  assumption  that female offspring could be ignored for simplicity and clarity while the female fecundity effect is specified in terms of total offspring rather than male offspring exclusively. [ 123 ]


In 2022, the  Journal of Sex Research  published a study of 26,542 men and 33,534 women that had entered  same-sex unions in the Netherlands  as compared with 4,607,785 men and 4,405,635 women that found robust evidence of a fraternal birth order effect on both male and female homosexuality and no support for a female fecundity effect, but the researchers qualified that their findings could be a result of sampling through a same-sex unions registry and only considered maternal siblings rather than other female relatives (e.g. sisters, maternal aunts, maternal grandmothers), and as such, that the existence of a female fecundity effect could not be discounted. [ 124 ]  In 2024,  Archives of Sexual Behavior  published a study comparing the fertility of the parents and grandparents of 459 homosexual men and 79 homosexual women to 7,312 heterosexual men and 3,352 heterosexual women in the  Czech Republic  that found higher fertility for only the paternal grandmothers of homosexual men and with a small effect size, leading the researchers to conclude that their findings did not support an antagonistic pleiotropy explanation of homosexuality. [ 125 ]


Some studies have found correlations between physiology of people and their sexuality; these studies provide evidence which suggests that:


J. Michael Bailey  has argued that the early  childhood gender nonconforming behavior  of homosexuals, as opposed to biological markers, are better evidence of homosexuality being an inborn trait. He argues that gay men are "punished much more than rewarded" for their childhood gender nonconformity, and that such behavior "emerges with no encouragement, and despite opposition", making it "the  sine qua non  of innateness". [ 75 ] : 123


Whether genetic or other physiological or psychological determinants form the basis of sexual orientation is a highly politicized issue.  The Advocate , a U.S. gay and lesbian newsmagazine, reported in 1996 that 61% of its readers believed that "it would mostly help gay and lesbian rights if homosexuality were found to be biologically determined". [ 152 ]  A cross-national study in the  United States , the  Philippines , and  Sweden  found that those who believed that "homosexuals are born that way" held significantly more positive attitudes toward homosexuality than those who believed that "homosexuals choose to be that way" or "learn to be that way". [ 153 ] [ 154 ]


The  Equal Protection Clause  of the  14th Amendment  to the  United States Constitution  and the  Due Process Clause  of the  5th Amendment  by  reverse incorporation  requires that when the  federal  or  state governments  create a  classification for a group suspected of being discriminated against , eligibility for heightened  scrutiny  is based on several factors including  immutability . [ 155 ] [ 156 ] [ 157 ]  Evidence that sexual orientation is biologically determined (and therefore perhaps immutable in the legal sense) would strengthen the legal case for heightened scrutiny of laws discriminating on that basis. [ 158 ] [ 159 ] [ 160 ]  In  Obergefell v. Hodges  (2015), the  Supreme Court of the United States  held that the Equal Protection Clause requires state governments to license  same-sex marriages  and recognize same-sex marriages performed by other state governments citing an  amicus curiae  brief that argued that sexual orientation is immutable which was jointly filed by the  American Psychological Association , the  American Psychiatric Association , the  American Academy of Pediatrics , the  American Association for Marriage and Family Therapy , the  National Association of Social Workers , the  American Psychoanalytic Association , the  American Academy of Family Physicians , and the  American Medical Association . [ 161 ] [ 162 ]


The perceived causes of sexual orientation have a significant bearing on the status of sexual minorities in the eyes of social conservatives. The  Family Research Council , a  conservative Christian   think tank  in Washington, D.C., argues in the book  Getting It Straight  that finding people are born gay "would advance the idea that sexual orientation is an innate characteristic, like race; that homosexuals, like African-Americans, should be legally protected against 'discrimination;' and that disapproval of homosexuality should be as socially stigmatized as racism. However, it is not true." On the other hand, some  social conservatives  such as Reverend Robert Schenck have argued that people can accept any scientific evidence while still morally opposing homosexuality. [ 163 ]   National Organization for Marriage  board member and fiction writer  Orson Scott Card  has supported biological research on homosexuality, writing that "our scientific efforts in regard to homosexuality should be to identify genetic and uterine causes... so that the incidence of this dysfunction can be minimized.... [However, this should not be seen] as an attack on homosexuals, a desire to 'commit genocide' against the homosexual community... There is no 'cure' for homosexuality because it is not a disease. There are, however, different ways of living with homosexual desires." [ 164 ]


Some advocates for the rights of sexual minorities resist what they perceive as attempts to pathologise or medicalise 'deviant' sexuality, and choose to fight for acceptance in a moral or social realm. [ 163 ]  The journalist  Chandler Burr  has stated that "[s]ome, recalling earlier psychiatric "treatments" for homosexuality, discern in the biological quest the seeds of genocide. They conjure up the specter of the surgical or chemical "rewiring" of gay people, or of abortions of fetal homosexuals who have been hunted down in the womb." [ 165 ]  LeVay has said in response to letters from gays and lesbians making such criticisms that the research "has contributed to the status of gay people in society". [ 163 ]


Blueprint: How DNA Makes Us Who We Are  is a book by  behavioral geneticist   Robert Plomin , first published in 2018 by  the MIT Press  and  Allen Lane . The book argues that  genetic  factors, and specifically variations in individuals'  DNA , have a large effect on human  psychological traits , accounting for approximately half of all variation in such traits. The book also claims that genes play a more important role in people's personalities  than does the environment . [ 1 ]  In  Blueprint , Plomin argues that environmental effects on human psychological differences, although they exist, are "...mostly random – unsystematic and unstable – which means that we cannot do much about them." [ 2 ]


Science journalist  Matt Ridley  praised  Blueprint  as "a hugely important book." [ 3 ]  Behavior geneticist  Kathryn Paige Harden  criticized the book for overstating the importance of genes for the development of human traits, writing, "Insisting that DNA matters is scientifically accurate; insisting that it is the only thing that matters is scientifically outlandish." [ 4 ]   Steven Mithen  gave the book a mixed review in  the Guardian , in which he wrote, "I am happy to bow to Plomin as a psychologist and a geneticist, but I found his sociology rather lacking, in fact quite baffling." [ 5 ]   Nathaniel Comfort  criticized the book for promoting  genetic determinism  and "play[ing] fast and loose with the concept of heritability". He concluded that "Ultimately, if unintentionally,  Blueprint  is a road map for regressive social policy." [ 6 ]  Journalist  David Goodhart  reviewed the book more positively, calling it "an important and challenging book that reveals to the general reader what has quietly become a new scientific consensus: psychological traits, including intelligence, are significantly influenced by our genes." [ 7 ]  Geneticist Barbara Jennings reviewed the book positively, suggesting that those who have criticized it for being "a manifesto for genetic determinism" are "misreading [...] the book". [ 8 ]


This article about a  psychology  book is a  stub . You can help Wikipedia by  expanding it .


Gender incongruence  is the state of having a  gender identity  that does not correspond to one's  sex assigned at birth . This is experienced by people who identify as  transgender  or  transsexual , and often results in  gender dysphoria . [ 1 ]  The  causes of gender incongruence  have been studied for decades.


Transgender brain studies, especially those on  trans women  attracted to women ( gynephilic ), and those on  trans men  attracted to men ( androphilic ), are limited, as they include only a small number of tested individuals. [ 2 ]   Twin studies  indicate that genes play a role in gender incongruence, although the precise genes involved are not known or well understood. [ 3 ] [ 4 ] [ 5 ]


Environmental factors, such as prenatal hormone exposure, have also been investigated but are difficult to test. [ 5 ]


Gender identity is genetically heritable, but no convincing  candidate genes  are known. [ 6 ] [ 7 ]  Gender incongruence has been associated with certain  alleles  relevant to  steroidogenesis . [ 8 ]


In 2013, a  twin study  combined a survey of pairs of twins where one or both had undergone, or had plans and medical approval to undergo, gender transition, with a literature review of published reports of transgender twins. The study found that one third of identical twin pairs in the sample were both transgender: 13 of 39 (33%) monozygotic or identical pairs of  assigned males  and 8 of 35 (22.8%) pairs of assigned females. Among dizygotic or genetically non-identical twin pairs, there was only 1 of 38 (2.6%) pairs where both twins were trans. [ 9 ]  The significant percentage of identical twin pairs in which both twins are trans and the virtual absence of dizygotic twins (raised in the same family at the same time) in which both were trans would provide evidence that transgender identity is significantly influenced by genetics if both sets were raised in different families. [ 9 ]


In 2018 a review of family and twin studies found that there was "significant and consistent evidence" for gender identity being genetically heritable. [ 7 ]


Sex hormones in the prenatal environment differentiate the male and female brain. One hypothesis proposes that transgender individuals may have been exposed to atypical levels of sex hormones during later stages of fetal development, leading to brain structures atypical of their sex assigned at birth. [ 5 ] [ 10 ]


In people with XX chromosomes,  congenital adrenal hyperplasia  (CAH) results in heightened exposure to prenatal androgens, resulting in masculinization of the genitalia. Individuals with CAH are typically subjected to  medical interventions  including prenatal hormone treatment [ 11 ]  and postnatal genital reconstructive surgeries. [ 12 ]  Such treatments are sometimes criticized by  intersex rights  organizations as non-consensual, invasive, and unnecessary interventions. Individuals with CAH are usually  assigned female  and tend to develop similar cognitive abilities to the typical females, including  spatial ability , verbal ability,  language lateralization ,  handedness  and  aggression . Research has shown that people with CAH and XX chromosomes will be more likely to experience same-sex attraction, [ 11 ]  and at least 5.2% of these individuals develop serious gender dysphoria. [ 13 ]


In males with  5-alpha-reductase deficiency , conversion of  testosterone  to  dihydrotestosterone  is disrupted, decreasing the masculinization of genitalia. Individuals with this condition are typically assigned female and raised as girls due to their feminine appearance at a young age. However, more than half of males with this condition raised as females come to identify as male later in life. Scientists speculate that the definition of masculine characteristics during puberty and the increased social status afforded to men are two possible motivations for a female-to-male transition. [ 13 ]


Transgender brain studies, especially those on  trans women  attracted to women ( gynephilic ), and those on  trans men  attracted to men ( androphilic ), are limited, as they include only a small number of tested individuals. [ 2 ]


Several studies have found a correlation between gender identity and brain structure. [ 14 ] [ 15 ]  A first-of-its-kind study by Zhou  et al.  (1995) found that in the bed nucleus of the  stria terminalis  (BSTc), a region of the brain known for sex and  anxiety responses  (and which is affected by prenatal androgens), [ 16 ]  cadavers of six trans women had female-normal BSTc size, similar to the study's cadavers of cisgender women. While the trans women had undergone hormone therapy, and all but one had undergone sex reassignment surgery, this was accounted for by including cadavers of cisgender men and cisgender women as controls who, for a variety of medical reasons, had experienced hormone reversal. The controls still had sizes typical for their sex, and thus no relationship to post-natal hormone levels (nor to sexual orientation) was found. [ 17 ] [ 18 ]  Other post-mortem studies also found brain differences between cisgender and transgender individuals. [ 19 ]


In 2002, a follow-up study by Chung  et al.  found that significant  sexual dimorphism  in BSTc did not establish until adulthood. Chung  et al.  theorized that changes in fetal hormone levels produce changes in BSTc synaptic density, neuronal activity, or neurochemical content which later lead to size and neuron count changes in BSTc, or alternatively, that the size of BSTc is affected by the generation of a gender identity inconsistent with one's assigned sex. [ 20 ] [ 18 ]


In the textbook Adult Psychopathology and Diagnosis, 7th edition, Lawrence and Zucker suggested that the BSTc may not be a valid biomarker for gender incongruence, as differences in size could be caused by gender-affirming hormone therapy or paraphilias, and might not occur in  homosexual transsexuals . [ 2 ] [ 21 ]


In a review of the evidence in 2006, Gooren considered the earlier research as supporting the concept of gender incongruence as a "sexual differentiation disorder" of the sexually dimorphic brain. [ 22 ]   Dick Swaab  (2004) concurred. [ 23 ]


In 2008, Garcia-Falgueras & Swaab discovered that the interstitial nucleus of the  anterior hypothalamus  ( INAH-3 ), part of the hypothalamic uncinate nucleus, had properties similar to the BSTc with respect to sexual dimorphism and gender incongruence, likewise in line with the trans individuals’ declared genders and likewise regardless of if hormonal transition had occurred or not. [ 18 ] [ 24 ]


A 2009  MRI  study by Luders et al. found that among 24 trans women not treated with hormone therapy, regional  gray matter  concentrations were more similar to those of cisgender men than of cisgender women, but there was a significantly greater volume of gray matter in the right  putamen  compared to cisgender men. Like earlier studies, researchers concluded that transgender identity was associated with a distinct cerebral pattern. [ 25 ] [ non-primary source needed ]  MRI scanning allows easier study of larger brain structures, but independent nuclei are not visible due to lack of contrast between different neurological tissue types, hence other studies on e.g. BSTc were done by dissecting brains post-mortem. [ scientific citation needed ]


Rametti et al. (2011) studied 18 trans men who had not undergone hormone therapy using  diffusion tensor imaging  (DTI), an MRI technique which allows visualizing  white matter , the structure of which is sexually dimorphic. Rametti  et al.  discovered that the trans men's white matter, compared to 19 cisgender gynephilic females, showed higher  fractional anisotropy  values in posterior part of the right SLF, the  forceps minor  and  corticospinal tract ". Compared to 24 cisgender males, they showed only lower FA values in the corticospinal tract. The white matter patterns in trans men were found to be shifted in the direction of cis men. [ 26 ] [ non-primary source needed ]


A 2011 review published in  Frontiers in Neuroendocrinology  found that "Female INAH3 and BSTc have been found in MtF transsexual persons. The only female-to-male (FtM) transsexual person available to us for study so far had a BSTc and INAH3 with clear male characteristics. (...) These sex reversals were found not to be influenced by circulating hormone levels in adulthood, and seem thus to have arisen during development" and that "All observations that support the neurobiological theory about the origin of transsexuality, i.e. that it is the sizes, the neuron numbers, and the functions and connectivity of brain structures, not the sex of their sexual organs, birth certificates or passports, that match their gender identities". [ 27 ]


In 2012 and 2016 studies by Taziaux et al. reported that MtF subjects had  infundibular nuclei  similar to those of cis women. [ 2 ] [ 28 ] [ 29 ]


A 2015 review reported that two studies found a pattern of white matter microstructure differences away from a transgender person's birth sex, and toward their desired sex. In one of these studies, sexual orientation had no effect on the diffusivity measured. [ 30 ]


A 2016 review reported that, for androphilic trans women and gynephilic trans men, hormone treatment may have large effects on the brain, and that  cortical thickness , which is generally thicker in cisgender women's brains than in cisgender men's brains, may also be thicker in trans women's brains, but is present in a different location to cisgender women's brains. [ 2 ]  It also stated that for both trans women and trans men, "cross-sex hormone treatment affects the gross morphology as well as the white matter microstructure of the brain. Changes are to be expected when hormones reach the brain in pharmacological doses. Consequently, one cannot take hormone-treated transsexual brain patterns as evidence of the transsexual brain phenotype because the treatment alters brain morphology and obscures the pre-treatment brain pattern." [ 2 ]


A 2019 review in  Neuropsychopharmacology  found that among transgender individuals meeting diagnostic criteria for gender dysphoria, "cortical thickness, gray matter volume, white matter microstructure, structural connectivity, and corpus callosum shape have been found to be more similar to cisgender control subjects of the same preferred gender compared with those of the same natal sex." [ 31 ]


A 2021 review of brain studies published in the  Archives of Sexual Behavior  found that "although the majority of neuroanatomical, neurophysiological, and neurometabolic features" in transgender people "resemble those of their natal sex rather than those of their experienced gender", for trans women they found feminine and demasculinized traits, and vice versa for trans men. They stated that due to limitations and conflicting results in the studies that had been done, they could not draw general conclusions or identify-specific features that consistently differed between cisgender and transgender people. The review also found differences when comparing cisgender  homosexual  and  heterosexual  people, with the same limitations applying. [ 32 ]


A 2016 review reported that early-onset androphilic transgender women have a brain structure similar to cisgender women's and unlike cisgender men's, but that they have their own brain phenotype. [ 2 ]  It also reported that gynephilic trans women differ from both cisgender female and male controls in non-dimorphic brain areas. [ 2 ]


The available research indicates that the brain structure of androphilic trans women with early-onset gender dysphoria is closer to that of  cisgender  women than that of cisgender men. [ 2 ]  It also reports that gynephilic trans women differ from both cisgender female and male controls in non-dimorphic brain areas. [ 2 ]   Cortical thickness , which is generally thicker in cisgender women's brains than in cisgender men's brains, may also be thicker in trans women's brains, but is present in a different location to cisgender women's brains. [ 2 ]  For trans men, research indicates that those with early-onset gender dysphoria and who are gynephilic have brains that generally correspond to their assigned sex, but that they have their own phenotype with respect to cortical thickness, subcortical structures, and white matter microstructure, especially in the right hemisphere. [ 2 ]   Hormone therapy  can also affect transgender people's brain structure;  estrogen  can cause transgender women's brains to become closer to those of cisgender women, and morphological changes observed in the brains of trans men might be due to the anabolic effects of  testosterone . [ 2 ]


MRI taken on gynephilic trans women have likewise shown differences in the brain from non-trans people, though in ways not directly related to sexual dimorphism. [ 2 ]


Fewer brain structure studies have been performed on transgender men than on transgender women. [ 2 ]  A 2016 review reported that the brain structure of early-onset gynephilic trans men generally corresponds to their assigned sex, but that they have their own phenotype with respect to cortical thickness, subcortical structures, and white matter microstructure, especially in the right hemisphere. [ 2 ]  Morphological increments observed in the brains of trans men might be due to the anabolic effects of testosterone. [ 2 ]


According to the  DSM-5 , gender dysphoria in those  assigned male at birth  tends to follow one of two broad trajectories: early-onset or late-onset. Early-onset gender dysphoria is behaviorally visible in childhood. Sometimes, gender dysphoria may stop for a while in this group, and they may identify as gay or homosexual for a period of time, followed by recurrence of gender dysphoria. This group is usually androphilic in adulthood. Late-onset gender dysphoria does not include visible signs in early childhood, but some report having had wishes to be the opposite sex in childhood that they did not report to others. Trans women who experience late-onset gender dysphoria are more likely be attracted to women and may identify as lesbians or bisexual. It is common for people assigned male at birth who have late-onset gender dysphoria to experience  sexual excitement from cross-dressing . In those  assigned female at birth , early-onset gender dysphoria is the most common course. This group is usually sexually attracted to women. Trans men who experience late-onset gender dysphoria will usually be sexually attracted to men and may identify as gay. [ 33 ]


In the 1980s and 1990s, sexologist  Ray Blanchard  developed  a taxonomy  of male-to-female transsexualism [ 34 ] [ non-primary source needed ]  built upon the work of his colleague  Kurt Freund , [ 35 ] [ non-primary source needed ]  which argues that trans women have one of two primary causes of gender dysphoria. [ 36 ] [ 37 ] [ 38 ]  Blanchard theorized that " homosexual transsexuals " (a taxonomic category referring to trans women attracted to men) are attracted to men and develop gender dysphoria typically during childhood, and characterizes them as displaying overt and obvious femininity since childhood; he characterizes "non-homosexual transsexuals" (trans women who are sexually attracted to women) as developing gender dysphoria primarily due to  autogynephilia  (sexual arousal by the thought or image of themselves as a woman [ 34 ] [ non-primary source needed ] ), and as attracted to women, attracted to both women and men (Blanchard calls this "pseudo-bisexuality", believing attraction to males to be not genuine, but part of the performance of an autogynephilic sexual fantasy), or  asexual . [ citation needed ]


Blanchard's theory has received support from  J. Michael Bailey ,  Anne Lawrence , and  James Cantor . [ 39 ]  Blanchard argued that there are significant differences between the two groups, including sexuality, age of transition, ethnicity,  IQ ,  fetishism , and quality of adjustment. [ 40 ] [ 41 ] [ non-primary source needed ] [ 34 ] [ non-primary source needed ] [ 42 ] [ non-primary source needed ]


Blanchard's typology has been criticized in papers from Veale, Nuttbrock, Moser, and others who argue that it is poorly representative of trans women and non-instructive, and that the experiments behind it are poorly controlled and/or contradicted by other data. [ 43 ] [ 44 ] [ 45 ] [ 39 ] : 27–28   Charles Moser conducted a survey of 29 cisgender women in the healthcare field based on Blanchard's methods for identifying autogynephilia, found that 93% of respondents qualified as autogynephiles based on their own responses. Anne Lawrence criticized the methodology of Mosers survey. [ 39 ] : 27


Blanchard proposed that "homosexual transsexuals", but not "autogynephilic transsexuals", would have feminized brain structure, stating: "if there is any neuroanatomic intersexuality, it is in the homosexual group". [ 2 ]  James Cantor has argued that MRI studies of transgender women offer support for Blanchard's prediction. [ 2 ] [ 46 ]  A 2016 review of transgender brain structure states: "Cantor seems to be right. Nonhomosexual MtFs present differences with heterosexual males in structures that are not sexually dimorphic (Savic & Arver, 2011), while homosexual MtFs (as well as homosexual FtMs) show differences with respect to male and female controls in a series of brain fascicles". [ 2 ] : 1634   The review notes that only one study has compared gynephilic and androphilic transgender women, and that "more independent studies on nonhomosexual MtFs are needed". [ 2 ] : 1634


In  behavioural genetics ,  DeFries–Fulker (DF) regression , also sometimes called  DeFries–Fulker extremes analysis , is a type of  multiple regression analysis  designed for estimating the magnitude of genetic and environmental effects in  twin studies . [ 1 ]  It is named after  John C. DeFries  and  David Fulker , who first proposed it in 1985. [ 2 ]  It was originally developed to assess  heritability  of  reading disability  in twin studies, but it has since been used to assess the heritability of other cognitive traits, and has also been applied to non-twin methodologies. [ 3 ] [ 4 ]


DeFries–Fulker regression analysis is based on the differences in the magnitude of  regression to the mean  in a genetic trait between  monozygotic  (MZ) and  dizygotic  (DZ) twins. In DF regression, the first step is to select  probands  in a twin study selected with extreme scores on the trait being studied, and to regression to the mean among their co-twins depending on whether the probands are part of a MZ or DZ twin pair. DF regression is thus based on the assumption that, to the extent that genetic factors play a role in causing the extreme variation in the studied trait, the magnitude of regression to the mean should be greater in DZ co-twins of probands than in their MZ counterparts. [ 5 ]  This should result in MZ co-twins being more similar to their probands on the trait under study than DZ twins are to theirs. [ 3 ]


Since the DF regression approach was first proposed in 1985, other researchers have proposed modified versions of the DF model that take additional factors into account, including observed covariates [ 6 ]  and opposite-sex DZ twins. [ 7 ]


The probands are chosen with scores that fall below a "cutoff" for what is considered "extreme", and regression is then used to predict the co-twin scores based on those of the probands and a term reflecting whether the twin pair is MZ (1.0) or DZ (0.5). [ 8 ]  The formula used for DF regression is:


where  C  = expected co-twin score,  P  = proband score,  R  = coefficient of relationship (0.5 for DZ twins, 1.0 for MZ twins), and  K  = regression constant.  B 1  represents a measure of co-twin relatedness separate from that of zygosity, while  B 2  can be converted into an estimate of the  heritability  of extreme scores on the trait. [ 5 ]  By comparing MZ and DZ co-twins in this manner, an estimate of "group heritability" is generated. [ 3 ]


Dual inheritance theory  ( DIT ), also known as  gene–culture coevolution  or  biocultural evolution , [ 1 ]  was developed in the 1960s through early 1980s to explain how  human behavior  is a product of two different and interacting  evolutionary  processes:  genetic evolution  and  cultural evolution . Genes and culture continually interact in a feedback loop: [ 2 ]  changes in genes can lead to changes in culture which can then influence genetic selection, and vice versa. One of the theory's central claims is that culture evolves partly through a Darwinian selection process, which dual inheritance theorists often describe by analogy to genetic evolution. [ 3 ]


'Culture', in this context, is defined as 'socially learned behavior', and 'social learning' is defined as copying behaviors observed in others or acquiring behaviors through being taught by others. Most of the modelling done in the field relies on the first dynamic (copying), though it can be extended to teaching.  Social learning , at its simplest, involves blind copying of behaviors from a model (someone observed behaving), though it is also understood to have many potential  biases , including success bias (copying from those who are perceived to be better off), status bias (copying from those with higher status), homophily (copying from those most like ourselves), conformist bias (disproportionately picking up behaviors that more people are performing), etc.  Understanding social learning is a system of pattern replication, and understanding that there are different rates of survival for different socially learned cultural variants, this sets up, by definition, an evolutionary structure: cultural evolution. [ 4 ]


Because genetic evolution is relatively well understood, most of DIT examines cultural evolution and the interactions between cultural evolution and genetic evolution.


DIT holds that genetic and cultural evolution interacted in the evolution of  Homo sapiens .  DIT recognizes that the natural selection of genotypes is an important component of the evolution of human behavior and that cultural traits can be constrained by genetic imperatives. However, DIT also recognizes that genetic evolution has endowed the human species with a parallel evolutionary process of cultural evolution. DIT makes three main claims: [ 5 ]


The human capacity to store and transmit culture arose from genetically evolved psychological mechanisms.  This implies that at some point during the evolution of the human species a type of  social learning  leading to cumulative cultural evolution was evolutionarily advantageous.


Social learning processes give rise to cultural evolution.  Cultural traits are transmitted differently from genetic traits and, therefore, result in different population-level effects on behavioral variation.


Cultural traits alter the social and physical environments under which genetic selection operates.  For example, the cultural adoptions of agriculture and dairying have, in humans, caused genetic selection for the traits to digest starch and  lactose , respectively. [ 6 ] [ 7 ] [ 8 ] [ 9 ] [ 10 ] [ 11 ]  As another example, it is likely that once culture became adaptive, genetic selection caused a refinement of the cognitive architecture that stores and transmits cultural information.  This refinement may have further influenced the way culture is stored and the biases that govern its transmission.


DIT also predicts that, under certain situations, cultural evolution may select for traits that are genetically maladaptive.  An example of this is the  demographic transition , which describes the fall of birth rates within industrialized societies.  Dual inheritance theorists hypothesize that the demographic transition may be a result of a prestige bias, where individuals that forgo reproduction to gain more influence in industrial societies are more likely to be chosen as cultural models. [ 12 ] [ 13 ]


People have defined the word "culture" to describe a large set of different phenomena. [ 14 ] [ 15 ]   A definition that sums up what is meant by "culture" in DIT is:


Culture is socially learned information stored in individuals' brains that is capable of affecting behavior. [ 16 ] [ 17 ]


This view of culture emphasizes population thinking by focusing on the process by which culture is generated and maintained.  It also views culture as a dynamic property of individuals, as opposed to a view of culture as a superorganic entity to which individuals must conform. [ 18 ]  This view's main advantage is that it connects individual-level processes to population-level outcomes. [ 19 ]


Genes affect cultural evolution via psychological predispositions on cultural learning. [ 20 ]   Genes encode much of the information needed to form the human brain.  Genes constrain the brain's structure and, hence, the ability of the brain to acquire and store culture.  Genes may also endow individuals with certain types of transmission bias (described below).


Culture can profoundly influence gene frequencies in a population.


Lactase persistence


One of the best known examples is the prevalence of the genotype for adult lactose absorption in human populations, such as Northern Europeans and some African societies, with a long history of raising cattle for milk. Until around 7,500 years ago, [ 21 ]   lactase production stopped shortly after weaning, [ 22 ]  and in societies which did not develop dairying, such as East Asians and Amerindians, this is still true today. [ 23 ] [ 24 ]  In areas with lactase persistence, it is believed that by domesticating animals, a source of milk became available while an adult and thus strong selection for lactase persistence could occur; [ 21 ] [ 25 ]  in a Scandinavian population, the estimated  selection coefficient  was 0.09-0.19. [ 25 ]  This implies that the cultural practice of raising cattle first for meat and later for milk led to  selection for genetic traits for lactose digestion . [ 26 ]  Recently, analysis of natural selection on the human genome suggests that civilization has accelerated genetic change in humans over the past 10,000 years. [ 27 ]


Food processing


Culture has driven changes to the human digestive systems making many digestive organs, such as teeth or stomach, smaller than expected for primates of a similar size, [ 28 ]  and has been attributed to one of the reasons why humans have such large brains compared to other great apes. [ 29 ] [ 30 ]  This is due to food processing. Early examples of food processing include pounding, marinating and most notably cooking. Pounding meat breaks down the muscle fibres, hence taking away some of the job from the mouth, teeth and jaw. [ 31 ] [ 32 ]  Marinating emulates the action of the stomach with high acid levels. Cooking partially breaks down food making it more easily digestible. Food enters the body effectively partly digested, and as such food processing reduces the work that the digestive system has to do. This means that there is selection for smaller digestive organs as the tissue is energetically expensive, [ 28 ]  those with smaller digestive organs can process their food but at a lower energetic cost than those with larger organs. [ 33 ]  Cooking is notable because the energy available from food increases when cooked and this also means less time is spent looking for food. [ 29 ] [ 34 ] [ 35 ]


Humans living on cooked diets spend only a fraction of their day chewing compared to other extant primates living on raw diets. American girls and boys spent on average 7 to 8 percent of their day chewing respectively (1.68 to 1.92 hours per day), compared to chimpanzees, who spend more than 6 hours a day chewing. [ 36 ]  This frees up time which can be used for hunting. A raw diet means hunting is constrained since time spent hunting is time not spent eating and chewing plant material, but cooking reduces the time required to get the day's energy requirements, allowing for more subsistence activities. [ 37 ]  Digestibility of cooked carbohydrates is approximately on average 30% higher than digestibility of non-cooked carbohydrates. [ 34 ] [ 38 ]  This increased energy intake, more free time and savings made on tissue used in the digestive system allowed for the selection of genes for larger brain size.


Despite its benefits, brain tissue requires a large amount of calories, hence a main constraint in selection for larger brains is calorie intake. A greater calorie intake can support greater quantities of brain tissue. This is argued to explain why human brains can be much larger than other apes, since humans are the only ape to engage in food processing. [ 29 ]  The cooking of food has influenced genes to the extent that, research suggests, humans cannot live without cooking. [ 39 ] [ 29 ]  A study on 513 individuals consuming long-term raw diets found that as the percentage of their diet which was made up of raw food and/or the length they had been on a diet of raw food increased, their BMI decreased. [ 39 ]  This is despite access to many non-thermal processing, like grinding, pounding or heating to 48 °C. (118 °F). [ 39 ]  With approximately 86 billion neurons in the human brain and 60–70 kg body mass, an exclusively raw diet close to that of what extant primates have would be not viable as, when modelled, it is argued that it would require an infeasible level of more than nine hours of feeding every day. [ 29 ]  However, this is contested, with alternative modelling showing enough calories could be obtained within 5–6 hours per day. [ 40 ]  Some scientists and anthropologists point to evidence that brain size in the Homo lineage started to increase well before the advent of cooking due to increased consumption of meat [ 28 ] [ 40 ] [ 41 ]  and that basic food processing (slicing) accounts for the size reduction in organs related to chewing. [ 42 ]  Cornélio et al. argues that improving cooperative abilities and a varying of diet to more meat and seeds improved foraging and hunting efficiency. It is this that allowed for the brain expansion, independent of cooking which they argue came much later, a consequence from the complex cognition that developed. [ 40 ]  Yet this is still an example of a cultural shift in diet and the resulting genetic evolution. Further criticism comes from the controversy of the archaeological evidence available. Some claim there is a lack of evidence of fire control when brain sizes first started expanding. [ 40 ] [ 43 ]  Wrangham argues that anatomical evidence around the time of the origin of  Homo erectus  (1.8 million years ago), indicates that the control of fire and hence cooking occurred. [ 34 ]  At this time, the largest reductions in tooth size in the entirety of human evolution occurred, indicating that softer foods became prevalent in the diet. Also at this time was a narrowing of the pelvis indicating a smaller gut and also there is evidence that there was a loss of the ability to climb which Wrangham argues indicates the control of fire, since sleeping on the ground needs fire to ward off predators. [ 44 ]  The proposed increases in brain size from food processing will have led to a greater mental capacity for further cultural innovation in food processing which will have increased digestive efficiency further providing more energy for further gains in brain size. [ 45 ]  This positive feedback loop is argued to have led to the rapid brain size increases seen in the  Homo  lineage. [ 45 ] [ 40 ]


In DIT, the evolution and maintenance of cultures is described by five major mechanisms: natural selection of cultural variants, random variation, cultural drift, guided variation and transmission bias.


Differences between cultural phenomena result in differential rates of their spread; similarly, cultural differences among individuals can lead to differential survival and reproduction rates of individuals. The patterns of this selective process depend on transmission biases and can result in behavior that is more adaptive to a given environment.


Random variation arises from errors in the learning, display or recall of cultural information, and is roughly analogous to the process of  mutation  in genetic evolution.


Cultural drift  is a process roughly analogous to  genetic drift  in evolutionary biology. [ 46 ] [ 47 ] [ 48 ]   In cultural drift, the frequency of cultural traits in a population may be subject to random fluctuations due to chance variations in which traits are observed and transmitted (sometimes called "sampling error"). [ 49 ]  These fluctuations might cause cultural variants to disappear from a population. This effect should be especially strong in small populations. [ 50 ]  A model by Hahn and Bentley shows that cultural drift gives a reasonably good approximation to changes in the popularity of American baby names. [ 49 ]  Drift processes have also been suggested to explain changes in archaeological pottery and technology patent applications. [ 48 ]   Changes in the songs of song birds are also thought to arise from drift processes, where distinct dialects in different groups occur due to errors in songbird singing and acquisition by successive generations. [ 51 ]   Cultural drift is also observed in an early computer model of cultural evolution. [ 52 ]


Cultural traits may be gained in a population through the process of individual learning.  Once an individual learns a novel trait, it can be transmitted to other members of the population.  The process of guided variation depends on an adaptive standard that determines what cultural variants are learned.


Understanding the different ways that culture traits can be transmitted between individuals has been an important part of DIT research since the 1970s. [ 53 ] [ 54 ]   Transmission biases occur when some cultural variants are favored over others during the process of cultural transmission. [ 55 ]  Boyd and Richerson (1985) [ 55 ]  defined and analytically modeled a number of possible transmission biases.  The list of biases has been refined over the years, especially by Henrich and McElreath. [ 56 ]


Content biases result from situations where some aspect of a cultural variant's content makes them more likely to be adopted. [ 57 ]   Content biases can result from genetic preferences, preferences determined by existing cultural traits, or a combination of the two.  For example, food preferences can result from genetic preferences for sugary or fatty foods and socially-learned eating practices and taboos. [ 57 ]   Content biases are sometimes called "direct biases." [ 55 ]


Context biases result from individuals using clues about the social structure of their population to determine what cultural variants to adopt.  This determination is made without reference to the content of the variant.  There are two major categories of context biases: model-based biases, and frequency-dependent biases.


Model-based biases result when an individual is biased to choose a particular "cultural model" to imitate.  There are four major categories of model-based biases: prestige bias, skill bias, success bias, and similarity bias. [ 5 ] [ 58 ]  A "prestige bias" results when individuals are more likely to imitate cultural models that are seen as having more  prestige .  A measure of prestige could be the amount of deference shown to a potential cultural model by other individuals.  A "skill bias" results when individuals can directly observe different cultural models performing a learned skill and are more likely to imitate cultural models that perform better at the specific skill.  A "success bias" results from individuals preferentially imitating cultural models that they determine are most generally successful (as opposed to successful at a specific skill as in the skill bias.)  A "similarity bias" results when individuals are more likely to imitate cultural models that are perceived as being similar to the individual based on specific traits.


Frequency-dependent biases result when an individual is biased to choose particular cultural variants based on their perceived frequency in the population.  The most explored frequency-dependent bias is the "conformity bias."  Conformity biases result when individuals attempt to copy the mean or the mode cultural variant in the population. Another possible frequency dependent bias is the "rarity bias."  The rarity bias results when individuals preferentially choose cultural variants that are less common in the population.  The rarity bias is also sometimes called a "nonconformist" or "anti-conformist" bias.


In DIT, the evolution of culture is dependent on the evolution of social learning.  Analytic models show that social learning becomes evolutionarily beneficial when the environment changes with enough frequency that genetic inheritance can not track the changes, but not fast enough that individual learning is more efficient. [ 59 ]  For environments that have very little variability, social learning is not needed since genes can adapt fast enough to the changes that occur, and innate behaviour is able to deal with the constant environment. [ 60 ]  In fast changing environments cultural learning would not be useful because what the previous generation knew is now outdated and will provide no benefit in the changed environment, and hence individual learning is more beneficial. It is only in the moderately changing environment where cultural learning becomes useful since each generation shares a mostly similar environment but genes have insufficient time to change to changes in the environment. [ 61 ]  While other species have social learning, and thus some level of culture, only humans, some birds and chimpanzees are known to have cumulative culture. [ 62 ]  Boyd and Richerson argue that the evolution of cumulative culture depends on observational learning and is uncommon in other species because it is ineffective when it is rare in a population.  They propose that the environmental changes occurring in the  Pleistocene  may have provided the right environmental conditions. [ 61 ]   Michael Tomasello argues that cumulative cultural evolution results from a  ratchet effect  that began when humans developed the cognitive architecture to understand others as mental agents. [ 62 ]  Furthermore, Tomasello proposed in the 80s that there are some disparities between the observational learning mechanisms found in humans and great apes - which go some way to explain the observable difference between great ape traditions and human types of culture (see  Emulation (observational learning) ).


Although  group selection  is commonly thought to be nonexistent or unimportant in genetic evolution, [ 63 ] [ 64 ] [ 65 ]  DIT predicts that, due to the nature of cultural inheritance, it may be an important force in cultural evolution.  Group selection occurs in cultural evolution because conformist biases make it difficult for novel cultural traits to spread through a population (see above section on transmission biases). Conformist bias also helps maintain variation between groups.  These two properties, rare in genetic transmission, are necessary for group selection to operate. [ 66 ]   Based on an earlier model by Cavalli-Sforza and Feldman, [ 67 ]  Boyd and Richerson show that conformist biases are almost inevitable when traits spread through social learning, [ 68 ]  implying that group selection is common in cultural evolution.  Analysis of small groups in New Guinea imply that cultural group selection might be a good explanation for slowly changing aspects of social structure, but not for rapidly changing fads. [ 69 ]  The ability of cultural evolution to maintain intergroup diversity is what allows for the study of cultural phylogenetics. [ 70 ]


In 1876,  Friedrich Engels  wrote a manuscript titled  The Part Played by Labour in the Transition from Ape to Man , accredited as a founding document of DIT; [ 71 ]  “The approach to gene-culture coevolution first developed by Engels and developed later on by anthropologists…” is described by  Stephen Jay Gould  as “…the best nineteenth-century case for gene-culture coevolution.” [ 72 ]  The idea that human cultures undergo a similar evolutionary process as genetic evolution also goes back to  Darwin . [ 73 ]  In the 1960s,  Donald T. Campbell  published some of the first theoretical work that adapted principles of evolutionary theory to the evolution of cultures. [ 74 ]  In 1976, two developments in cultural evolutionary theory set the stage for DIT. In that year  Richard Dawkins's   The Selfish Gene  introduced ideas of cultural evolution to a popular audience.  Although one of the best-selling science books of all time, because of its lack of mathematical rigor, it had little effect on the development of DIT. Also in 1976, geneticists  Marcus Feldman  and  Luigi Luca Cavalli-Sforza  published the first dynamic models of gene–culture coevolution. [ 75 ]   These models were to form the basis for subsequent work on DIT, heralded by the publication of three seminal books in the 1980s.


The first was Charles Lumsden and  E.O. Wilson's   Genes, Mind and Culture . [ 76 ]   This book outlined a series of mathematical models of how genetic evolution might favor the selection of cultural traits and how cultural traits might, in turn, affect the speed of genetic evolution.  While it was the first book published describing how genes and culture might coevolve, it had relatively little effect on the further development of DIT. [ 77 ]  Some critics felt that their models depended too heavily on genetic mechanisms at the expense of cultural mechanisms. [ 78 ]   Controversy surrounding Wilson's  sociobiological theories  may also have decreased the lasting effect of this book. [ 77 ]


The second 1981 book was  Cavalli-Sforza  and Feldman's  Cultural Transmission and Evolution: A Quantitative Approach . [ 47 ]   Borrowing heavily from  population genetics  and  epidemiology , this book built a mathematical theory concerning the spread of cultural traits. It describes the evolutionary implications of  vertical transmission , passing cultural traits from parents to offspring; oblique transmission, passing cultural traits from any member of an older generation to a younger generation; and  horizontal transmission , passing traits between members of the same population.


The next significant DIT publication was  Robert Boyd  and  Peter Richerson 's 1985  Culture and the Evolutionary Process . [ 55 ]  This book presents the now-standard mathematical models of the evolution of social learning under different environmental conditions, the population effects of social learning, various forces of selection on cultural learning rules, different forms of biased transmission and their population-level effects, and conflicts between cultural and genetic evolution.  The book's conclusion also outlined areas for future research that are still relevant today. [ 79 ]


In their 1985 book, Boyd and Richerson outlined an agenda for future DIT research. This agenda, outlined below, called for the development of both theoretical models and empirical research. DIT has since built a rich tradition of theoretical models over the past two decades. [ 80 ]  However, there has not been a comparable level of empirical work.


In a 2006 interview Harvard biologist  E. O. Wilson  expressed disappointment at the little attention afforded to DIT:


"...for some reason I haven't fully fathomed, this most promising frontier of scientific research has attracted very few people and very little effort." [ 81 ]


Kevin Laland  and  Gillian Ruth Brown  attribute this lack of attention to DIT's heavy reliance on formal modeling.


"In many ways the most complex and potentially rewarding of all approaches, [DIT], with its multiple processes and cerebral onslaught of sigmas and deltas, may appear too abstract to all but the most enthusiastic reader. Until such a time as the theoretical hieroglyphics can be translated into a respectable empirical science most observers will remain immune to its message." [ 82 ]


Economist  Herbert Gintis  disagrees with this critique, citing empirical work as well as more recent work using techniques from  behavioral economics . [ 83 ]  These behavioral economic techniques have been adapted to test predictions of cultural evolutionary models in laboratory settings [ 84 ] [ 85 ] [ 86 ]  as well as studying differences in cooperation in fifteen small-scale societies in the field. [ 87 ]


Since one of the goals of DIT is to explain the distribution of human cultural traits,  ethnographic  and  ethnologic  techniques may also be useful for testing hypothesis stemming from DIT. Although findings from traditional ethnologic studies have been used to buttress DIT arguments, [ 47 ] [ 55 ]  thus far there have been little ethnographic fieldwork designed to explicitly test these hypotheses. [ 69 ] [ 87 ] [ 88 ]


Herb Gintis has named DIT one of the two major conceptual theories with potential for unifying the behavioral sciences, including economics, biology, anthropology, sociology, psychology and political science. Because it addresses both the genetic and cultural components of human inheritance, Gintis sees DIT models as providing the best explanations for the ultimate cause of human behavior and the best paradigm for integrating those disciplines with evolutionary theory. [ 89 ]  In a review of competing evolutionary perspectives on human behavior, Laland and Brown see DIT as the best candidate for uniting the other evolutionary perspectives under one theoretical umbrella. [ 90 ]


Two major topics of study in both  sociology  and  cultural anthropology  are human cultures and cultural variation.
However, Dual Inheritance theorists charge that both disciplines too often treat culture as a static superorganic entity that dictates human behavior. [ 18 ] [ 91 ]  Cultures are defined by a suite of common traits shared by a large group of people. DIT theorists argue that this doesn't sufficiently explain variation in cultural traits at the individual level.  By contrast, DIT models human culture at the individual level and views culture as the result of a dynamic evolutionary process at the population level. [ 18 ] [ 92 ]


Evolutionary psychologists study the evolved architecture of the human mind. They see it as composed of many different programs that process information, each with assumptions and procedures that were specialized by natural selection to solve a different adaptive problem faced by our hunter-gatherer ancestors (e.g., choosing mates, hunting, avoiding predators, cooperating, using aggression). [ 93 ]  These evolved programs contain content-rich assumptions about how the world and other people work. When ideas are passed from mind to mind, they are changed by these evolved inference systems (much like messages get changed in a game of telephone). But the changes are not usually random. Evolved programs add and subtract information, reshaping the ideas in ways that make them more "intuitive", more memorable, and more attention-grabbing. In other words, "memes" (ideas) are not precisely like genes. Genes are normally copied faithfully as they are replicated, but ideas normally are not. It's not just that ideas mutate every once in a while, like genes do. Ideas are transformed every time they are passed from mind to mind, because the sender's message is being interpreted by evolved inference systems in the receiver. [ 94 ] [ 95 ]  It is useful for some applications to note, however, that there are ways to pass ideas which are more resilient and involve substantially less mutation, such as by mass distribution of printed media.


There is no necessary contradiction between evolutionary psychology and DIT, but evolutionary psychologists argue that the psychology implicit in many DIT models is too simple; evolved programs have a rich inferential structure not captured by the idea of a "content bias". They also argue that some of the phenomena DIT models attribute to cultural evolution are cases of "evoked culture"—situations in which different evolved programs are activated in different places, in response to cues in the environment. [ 96 ]


Sociobiologists  try to understand how maximizing genetic fitness, in either the modern era or past environments, can explain human behavior. When faced with a trait that seems maladaptive, some sociobiologists try to determine how the trait actually increases genetic fitness (maybe through kin selection or by speculating about early evolutionary environments).  Dual inheritance theorists, in contrast, will consider a variety of genetic and cultural processes in addition to natural selection on genes.


Human behavioral ecology  (HBE) and DIT have a similar relationship to what ecology and evolutionary biology have in the biological sciences.  HBE is more concerned about ecological process and DIT more focused on historical process. [ 97 ]   One difference is that human behavioral ecologists often assume that culture is a system that produces the most adaptive outcome in a given environment.  This implies that similar behavioral traditions should be found in similar environments.  However, this is not always the case.  A study of African cultures showed that cultural history was a better predictor of cultural traits than local ecological conditions. [ 98 ]


Memetics , which comes from the  meme  idea described in  Dawkins's   The Selfish Gene , is similar to DIT in that it treats culture as an evolutionary process that is distinct from genetic transmission.  However, there are some philosophical differences between memetics and DIT. [ 17 ]  One difference is that memetics' focus is on the selection potential of discrete replicators (memes), where DIT allows for transmission of both non-replicators and non-discrete cultural variants.  DIT does not assume that replicators are necessary for cumulative adaptive evolution. DIT also more strongly emphasizes the role of genetic inheritance in shaping the capacity for cultural evolution.  But perhaps the biggest difference is a difference in academic lineage.  Memetics  as a label is more influential in popular culture than in academia. Critics of memetics argue that it is lacking in empirical support or is conceptually ill-founded, and question whether there is hope for the memetic research program succeeding. Proponents point out that many cultural traits are discrete, and that many existing models of cultural inheritance assume discrete cultural units, and hence involve memes. [ 99 ]


Israeli psychologist  Liane Gabora  has criticised DIT. [ 100 ] [ 101 ] [ 102 ]  She argues that traits that are  not  transmitted by way of a self-assembly code (as in genetic evolution) is misleading, because this second use does not capture the algorithmic structure that makes an inheritance system require a particular kind of mathematical framework. [ 103 ]


Other criticisms of the effort to frame culture in tandem with evolution have been leveled by  Richard Lewontin , [ 104 ]   Niles Eldredge , [ 105 ]  and  Stuart Kauffman . [ 106 ]


In  genetic epidemiology ,  endophenotype  (or  intermediate phenotype [ 1 ] ) is a term used to separate behavioral  symptoms  into more stable  phenotypes  with a clear  genetic  connection. By seeing the EP notion as a special case of a larger collection of multivariate genetic models, which may be fitted using currently accessible methodology, it is possible to maximize its valuable potential lessons for etiological study in  psychiatric disorders . [ 2 ]
The concept was coined by Bernard John and Kenneth R. Lewis in a 1966 paper attempting to explain the  geographic distribution  of  grasshoppers . They claimed that the particular geographic distribution could not be explained by the obvious and external " exophenotype " of the grasshoppers, but instead must be explained by their microscopic and internal "endophenotype". [ 3 ]  The endophenotype idea represents the influence of two important conceptual currents in biology and psychology research. An adequate technology would be required to perceive the endophenotype, which represents an unobservable latent entity that cannot be directly observed with the unaided naked eye. In the investigation of anxiety and affective disorders, the endophenotype idea has gained popularity. [ 4 ]


The next major use of the term was in  psychiatric genetics , to bridge the gap between high-level symptom presentation and low-level genetic variability, such as  single nucleotide polymorphisms . [ 5 ]  It is therefore more applicable to more heritable disorders, such as bipolar disorder and schizophrenia. [ 6 ]  Through their impact on the growth and operation of the vital components of the nervous system, such as neurons, transmitter systems, and neural networks, genes have an impact on complex behavior. Therefore, heritable differences in mental abilities may be caused by changes in the code describing the shape and operation of the underlying neural network. One significant expression of this idea is believed to be the many cognitive deficiencies seen in ADHD, making them ideal candidates for an endophenotype approach. [ 7 ]  Since then, the concept has expanded to many other fields, such as the study of  ADHD , [ 8 ]   addiction , [ 9 ]   Alzheimer's disease , [ 10 ]   obesity [ 11 ]  and  cystic fibrosis . [ 12 ]  Some other terms which have a similar meaning but do not stress the genetic connection as highly are "intermediate phenotype", " biological marker ", "subclinical trait", "vulnerability marker", and "cognitive marker". [ 13 ] [ 14 ]  The strength of an endophenotype is its ability to differentiate between potential diagnoses that present with similar symptoms. [ 15 ]


In psychiatry research, the accepted criteria which a biomarker must fulfill to be called an endophenotype include: [ 5 ] [ 16 ] [ 17 ]


In the case of  schizophrenia , the overt symptom could be a  psychosis , but the underlying phenotypes are, for example, a lack of  sensory gating  and a decline in  working memory . Both of these traits have a clear genetic component and can thus be called endophenotypes. [ 5 ]  A strong candidate for schizophrenia endophenotype is  prepulse inhibition , the ability to inhibit the reaction to startling stimuli. [ 18 ]  However, several other task-related candidate endophenotypes have been proposed for schizophrenia, [ 19 ]  and even resting measures extracted from  EEG , such as, power of frequency bands [ 20 ]  and EEG microstates. [ 21 ]


Endophenotypes are quantitative, trait-like deficits that are typically assessed by laboratory-based methods rather than by clinical observation.


The four primary criteria for an endophenotype are that it is present in  probands  with the disorder, that it is not state-related (that is, it does not occur only during clinical episodes) but instead is present early in the disease course and during periods of remission, that it is observed in unaffected family members at a higher rate than in the general population, and that it is heritable. [ 22 ]  The behavioral syndrome of schizophrenia is no longer thought to be a singular disease with a single underlying cause, as is once again becoming clear. Instead, it could have a number of different etiologies, and the symptoms could have many different origins. Such heterogeneity may explain some of the challenges in determining the genetics of schizophrenia and may also account for the clinical observations of schizophrenia treatment response variability. [ 23 ]


Some distinct genes that could underlie certain endophenotypic traits in schizophrenia include:


In  bipolar disorder , one commonly identified endophenotype is a deficit in  face emotion labeling , which is found in both individuals with bipolar disorder and in individuals who are "at risk" (i.e., have a first degree relative with bipolar disorder). [ 15 ]   Using  fMRI , this endophenotype has been linked to dysfunction in the dorsolateral and ventrolateral  prefrontal cortex ,  anterior cingulate cortex ,  striatum , and  amygdala . [ 27 ]  A polymorphism in the  CACNA1C  gene coding for the  voltage-dependent calcium channel   Ca v 1.2  has been found to be associated with deficits in facial emotion recognition. [ 28 ]


The endophenotype concept has also been used in  suicide  studies. Personality characteristics can be viewed as endophenotypes that may exert a  diathesis  effect on an individual's susceptibility to suicidal behavior. Although the exact identification of these endophenotypes is controversial, certain traits such as  impulsivity  and  aggression  are commonly cited risk factors. [ 29 ]
One such genetic basis for one of these at-risk endophenotypes has been suggested in 2007 to be the gene coding for the  serotonin  receptor  5-HT 1B , known to be relevant in aggressive behaviors. [ 30 ]