Does the Fraternal Birth Order Effect Influence Handedness?

The fraternal birth order effect (FBOE) is the phenomenon whereby the probability that a man has a same-sex sexual orientation in adulthood increases with each biological older brother. Several studies have found evidence that the FBOE is limited to right-handed men, and left-handed men do not show an FBOE. Recent debates about the appropriate methods for quantifying the FBOE center on distinguishing the FBOE from other effects, such as the female fecundity effect (FFE), whereby mothers more prone to bearing gay sons are also more fecund. The FBOE and FFE are confounded in that a real FFE will result in data consistent with the FBOE under some analyses. Here, we applied some recent proposed analytic methods for the FBOE to the property of handedness. A straightforward application of Khovanova's technique to the binary trait of handedness yielded support for a fraternal birth order effect consistent with the maternal immune hypothesis, in that the ratios of handedness differed between men with one older brother only, and men with one younger brother only, while no such effect was seen in women. This effect was not seen, however, when the confounding effects of parental age were controlled for. Models including factors to simultaneously test multiple posited effects find significant female fecundity effects, as well as paternal age and birth order effects on handedness in men, but no FBOE. The effects seen in women were different, with no fecundity or parental age effects, but birth order and sex of older siblings had effects. We conclude, based on this evidence, that many of the factors thought to contribute to sexual orientation in men may also have an influence on handedness, and further note that parental age is a potential confound which may be overlooked by some analyses of the FBOE.

Epigenetic regulation of gonadal and brain aromatase expression in a cichlid fish with environmental sex determination.

A fit animal must develop testes or ovaries, with brain and physiology to match. In species with alternative male morphs this coordination of development across tissues operates within sexes as well as between. For Pelvicachromis pulcher, an African cichlid in which early pH exposure influences both sex and alternative male morph, we sequence both copies of aromatase (cyp19a1), a key gene for sex determination. We analyze gene expression and epigenetic state, comparing gonad and brain tissue from females, alternative male morphs, and fry. Relative to brain, we find elevated expression of the A-copy in the ovaries but not testes. Methylation analysis suggests strong epigenetic regulation, with one region specifying sex and another specifying tissue. We find elevated brain expression of the B-copy with no sex or male morph differences. B-copy methylation follows that of the A-copy rather than corresponding to B-copy expression. In 30-day old fry, we see elevated B-copy expression in the head, but we do not see the expected elevated A-copy expression in the trunk that would reflect ovarian development. Interestingly, the A-copy epialleles that distinguish ovaries from testes are among the most explanatory patterns for variation among fry, suggesting epigenetic marking of sex prior to differentiation and thus laying the groundwork for mechanistic studies of epigenetic regulation of sex and morph differentiation.

Modulation of complex spike activity differs between zebrin-positive and -negative Purkinje cells in the pigeon cerebellum.

The cerebellum is organized into parasagittal zones defined by its climbing and mossy fiber inputs, efferent projections, and Purkinje cell (PC) response properties. Additionally, parasagittal stripes can be visualized with molecular markers, such as heterogeneous expression of the isoenzyme zebrin II (ZII), where sagittal stripes of high ZII expression (ZII+) are interdigitated with stripes of low ZII expression (ZII-). In the pigeon vestibulocerebellum, a ZII+/- stripe pair represents a functional unit, insofar as both ZII+ and ZII- PCs within a stripe pair respond best to the same pattern of optic flow. In the present study, we attempted to determine whether there were any differences in the responses between ZII+ and ZII- PCs within a functional unit in response to optic flow stimuli. In pigeons of either sex, we recorded complex spike activity (CSA) from PCs in response to optic flow, marked recording sites with a fluorescent tracer, and determined the ZII identity of recorded PCs by immunohistochemistry. We found that CSA of ZII+ PCs showed a greater depth of modulation in response to the preferred optic flow pattern compared with ZII- PCs. We suggest that these differences in the depth of modulation to optic flow stimuli are due to differences in the connectivity of ZII+ and ZII- PCs within a functional unit. Specifically, ZII+ PCs project to areas of the vestibular nuclei that provide inhibitory feedback to the inferior olive, whereas ZII- PCs do not. NEW & NOTEWORTHY Although the cerebellum appears to be a uniform structure, Purkinje cells (PCs) are heterogeneous and can be categorized on the basis of the expression of molecular markers. These phenotypes are conserved across species, but the significance is undetermined. PCs in the vestibulocerebellum encode optic flow resulting from self-motion, and those that express the molecular marker zebrin II (ZII+) exhibit more sensitivity to optic flow than those that do not express zebrin II (ZII-).

The SETDB2 locus: evidence for a genetic link between handedness and atopic disease.

The gene SETDB2, which mediates aspects of laterality in animal model systems, has recently been linked with human handedness as measured continuously on a scale from strong left to strong right. By contrast, it was marginally associated with a left-right dichotomous measure, and it showed no evidence of association with absolute handedness strength independent of direction. We genotyped the SETDB2 handedness-associated single nucleotide polymorphism, rs4942830, in a large healthy population likewise phenotyped for continuous, absolute, and dichotomous handedness variables. Our results demonstrated significant effects of rs4942830 genotype on continuous handedness, and weaker, marginal effects on dichotomous handedness, but no effects on absolute handedness. These results help to establish the locus marked by the SNP rs4942830 as a strong candidate for mediating human handedness. Intriguingly, rs4942830 is also in complete linkage disequilibrium with rs386770867, a polymorphism recently shown to affect human serum levels of IgE production and other atopic phenotypes. These findings implicate this locus in the longstanding links of handedness with asthma and other atopic diseases.

A genetic locus for paranoia.

The psychological effects of brain-expressed imprinted genes in humans are virtually unknown. Prader-Willi syndrome (PWS) is a neurogenetic condition mediated by genomic imprinting, which involves high rates of psychosis characterized by hallucinations and paranoia, as well as autism. Altered expression of two brain-expressed imprinted genes, MAGEL2 and NDN, mediates a suite of PWS-related phenotypes, including behaviour, in mice. We phenotyped a large population of typical individuals for schizophrenia-spectrum and autism-spectrum traits, and genotyped them for the single-nucleotide polymorphism rs850807, which is putatively functional and linked with MAGEL2 and NDN Genetic variation in rs850807 was strongly and exclusively associated with the ideas of reference subscale of the schizophrenia spectrum, which is best typified as paranoia. These findings provide a single-locus genetic model for analysing the neurological and psychological bases of paranoid thinking, and implicate imprinted genes, and genomic conflicts, in human mentalistic thought.

Damage-induced alarm cues influence lateralized behaviour but not the relationship between behavioural and habenular asymmetry in convict cichlids (Amatitlania nigrofasciata).

Cerebral lateralization, the partitioning of functions into a certain hemisphere of the brain, is ubiquitous among vertebrates. Evidence suggests that the cognitive processing of a stimulus is performed with a specific hemisphere depending in part upon the emotional valence of the stimulus (i.e. whether it is appetitive or aversive). Recent work has implicated a predominance of right-hemisphere processing for aversive stimuli. In fish with laterally placed eyes, the preference to view an object with a specific eye has been used as a proxy for assessing cerebral lateralization. The habenula, one of the most well-known examples of an asymmetrical neural structure, has been linked to behavioural asymmetry in some fish species. Here, we exposed convict cichlid fish (Amatitlania nigrofasciata) to both a social and non-social lateralization task and assessed behavioural lateralization in either the presence or absence of an aversive stimulus, damage-induced alarm cues. We also assessed whether behavioural asymmetry in these tests was related to asymmetry of the habenular nuclei. We found that when alarm cues were present, fish showed increased left-eye (and by proxy, right hemisphere) preference for stimulus viewing. In addition, females, but not males, showed stronger eye preferences when alarm cues were present. We did not find a relationship between behavioural lateralization and habenular lateralization. Our results conflict with previous reports of concordance between behavioural and habenular lateralization in this fish species. However, our results do provide support for the hypothesis of increased right-hemisphere use when an organism is exposed to aversive stimuli.

Patient-perceived content and formatting expectations for prescription container labeling.

OBJECTIVES: The objectives of the study were to identify patient expectations for prescription label content and formatting and to explore how United States Pharmacopeia Chapter 17 Standards for prescription container labeling meet patient expectations. DESIGN: Focus group. SETTING: St. Louis, Missouri, in July and August 2014. PARTICIPANTS: Patients 18 years and older who were taking at least 2 chronic prescription medications and managing their medications independently. MAIN OUTCOME MEASURE: Qualitative themes. INTERVENTION: Not applicable. METHODS: Five focus groups (17 total participants) were conducted in St. Louis in 2014. Focus groups were audio-recorded and consent was obtained from the participants. The audio files were professionally transcribed. Atlas.ti software (version 7.5.3) was used to analyze the transcript data, which were then coded to identify key themes. To ensure consistency of interpretation, a constant comparative analytic framework approach was used. RESULTS: Analysis produced 6 themes related to patient perceptions and expectations of prescription label content and formatting: importance of drug name, dose, and directions; lack of side effects on the label; improved organization and larger font size; using the color red; lack of familiarity with auxiliary labels; and the importance of pharmacy information. Themes focused on how patients use prescription labels and the relative value of different aspects of prescription container labeling. CONCLUSIONS: Patient-perceived prescription content and formatting expectations for prescription container labeling were generally consistent with published USP Chapter 17 guidelines. The importance of pharmacy phone numbers, white space, and highlighting were noteworthy.

Practice makes proficient: pigeons (Columba livia) learn efficient routes on full-circuit navigational traveling salesperson problems.

Visiting multiple locations and returning to the start via the shortest route, referred to as the traveling salesman (or salesperson) problem (TSP), is a valuable skill for both humans and non-humans. In the current study, pigeons were trained with increasing set sizes of up to six goals, with each set size presented in three distinct configurations, until consistency in route selection emerged. After training at each set size, the pigeons were tested with two novel configurations. All pigeons acquired routes that were significantly more efficient (i.e., shorter in length) than expected by chance selection of the goals. On average, the pigeons also selected routes that were more efficient than expected based on a local nearest-neighbor strategy and were as efficient as the average route generated by a crossing-avoidance strategy. Analysis of the routes taken indicated that they conformed to both a nearest-neighbor and a crossing-avoidance strategy significantly more often than expected by chance. Both the time taken to visit all goals and the actual distance traveled decreased from the first to the last trials of training in each set size. On the first trial with novel configurations, average efficiency was higher than chance, but was not higher than expected from a nearest-neighbor or crossing-avoidance strategy. These results indicate that pigeons can learn to select efficient routes on a TSP problem.

Cognitive-behavioral phenotypes of Williams syndrome are associated with genetic variation in the GTF2I gene, in a healthy population.

BACKGROUND: Individuals with Williams syndrome, a neurogenetic condition caused by deletion of a set of genes at chromosomal location 7q11.23, exhibit a remarkable suite of traits including hypersociality with high, nonselective friendliness and low social anxiety, expressive language relatively well-developed but under-developed social-communication skills overall, and reduced visual-spatial abilities. Deletions and duplications of the Williams-syndrome region have also been associated with autism, and with schizophrenia, two disorders centrally involving social cognition. Several lines of evidence have linked the gene GTF2I (General Transcription Factor IIi) with the social phenotypes of Williams syndrome, but a role for this gene in sociality within healthy populations has yet to be investigated. RESULTS: We genotyped a large set of healthy individuals for two single-nucleotide polymorphisms in the GTF2I gene that have recently been significantly associated with autism, and thus apparently exhibit functional effects on autism-related social phenotypes. GTF2I genotypes for these SNPs showed highly significant association with low social anxiety combined with reduced social-communication abilities, which represents a metric of the Williams-syndrome cognitive profile as described from previous studies. CONCLUSIONS: These findings implicate the GTF2I gene in the neurogenetic basis of social communication and social anxiety, both in Williams syndrome and among individuals in healthy populations.

The imprinted gene LRRTM1 mediates schizotypy and handedness in a nonclinical population.

Imprinted genes have been posited to have important roles in human brain development and cognition, but their effects in nonclinical populations have yet to be investigated. Single-nucleotide polymorphisms (SNPs) of the imprinted gene LRRTM1 have previously been associated with schizophrenia risk and with handedness in individuals with dyslexia. We tested the hypothesis that genetic variation (SNPs) and epigenetic variation (methylation) in this gene are associated with schizotypy and handedness in a nonclinical population. Risk alleles of the three schizophrenia-linked SNPs were associated with significantly and substantially higher levels of total schizotypy. Variation in SNP genotypes was not associated with handedness, but levels of methylation in a block of CpG sites in the putative LRRTM1 promoter region were associated with more-mixed handedness. These findings provide evidence of continuity between schizophrenia and schizotypy with regard to the psychological effects of allelic variation in this imprinted gene, and show that epigenetic variation in an imprinted gene mediates the development and expression of human handedness.

Inbreeding is associated with lower 2D: 4D digit ratio.

OBJECTIVES: While consanguineous marriage has been shown to result in a small increase in risk of recessive Mendelian disorders among offspring, far less research has been conducted on the effects of inbreeding on complex traits. These effects, thought to result from increased developmental instability due to loss of heterozygosity, are expected to be found more pervasively than rare recessive Mendelian traits and are expected to result in increased developmental noise. Here, we test for a direct effect of inbreeding on 2D : 4D, a putative indicator of prenatal hormonal environment. METHODS: We compared the 2D : 4D ratios of 122 male and 108 female consanguineous (children of first cousin marriages) high school and university students to those of 142 male and 122 females controls. RESULTS: Across hands and sex, consanguineous parentage was consistently associated with lower, more masculine-typical, digit ratios. Digit ratios were 1.3-1.9 times more variable among the consanguineous group than the control group. While socio-economic status cannot explain the effects seen in our data, we found that lower, more masculinized, digit ratios were associated with lower family income. CONCLUSIONS: Our results suggest that consanguineous marriages are associated with a fetal environment that influences morphological development and may have associated behavioral sequelae.

Sex, drugs, and zebrafish: Acute exposure to anxiety-modulating compounds in a modified novel tank dive test.

This study investigated the effects of anxiogenic and anxiolytic drugs on zebrafish (Danio rerio) behaviour using a modified novel tank dive test with higher walls and a narrower depth. Zebrafish were administered chondroitin sulfate, beta-carboline, delta-9-tetrahydrocannabinol (THC), ethanol, and beta-caryophyllene, and their behaviours were evaluated for geotaxis, swimming velocity, and immobility. Both anxiogenic and anxiolytic compounds generally increased bottom-dwelling behaviour, suggesting that the tank's modified dimensions significantly influence zebrafish responses. EC50 values for ethanol showed a lower threshold for velocity reduction compared to zone preference. Chondroitin sulfate uniquely caused a sex-specific increase in male swimming velocity, whereas no other sex-differences were observed with any compound. Interestingly, the presence of drug-treated fish did not alter the behaviour of observer fish, suggesting limited social buffering effects. The findings underscore the complexity of zebrafish behavioural phenotypes and highlight the need for considering tank dimensions and multiple behavioural parameters to accurately assess the effects of anxiety-modulating drugs. This study demonstrates the utility of the modified novel tank dive test in providing nuanced insights into the behavioural effects of different pharmacological agents in zebrafish.

Genes underlying altruism.

William D. Hamilton postulated the existence of 'genes underlying altruism', under the rubric of inclusive fitness theory, a half-century ago. Such genes are now poised for discovery. In this article, we develop a set of intuitive criteria for the recognition and analysis of genes for altruism and describe the first candidate genes affecting altruism from social insects and humans. We also provide evidence from a human population for genetically based trade-offs, underlain by oxytocin-system polymorphisms, between alleles for altruism and alleles for non-social cognition. Such trade-offs between self-oriented and altruistic behaviour may influence the evolution of phenotypic diversity across all social animals.

Zebrafish (Danio rerio) shoaling in light and dark conditions involves a complex interplay between vision and lateral line.

We know little about how - or even if in some species - fish shoal in darkness. We hypothesized that 'dark shoaling' occurs in zebrafish and therefore must depend upon lateral line sensory input. Shoaling in groups of five adult zebrafish was analyzed with motion tracking software. We measured average inter-individual distance, time near the arena wall (thigmotaxis zone) and total distance traveled under normal room light, and in near-complete darkness (infrared light at 850 nm). These observations were repeated in fish treated with cobalt chloride (CoCl2), which ablates lateral line function. In untreated controls, dark shoaling was reduced compared to in light, but nonetheless still present. Elimination of lateral line sensory input by CoCl2 treatment similarly reduced, but did not eliminate, shoaling under both light and dark. Our findings indicate that normal zebrafish shoaling in light or dark requires both visual and lateral line inputs, with neither alone sufficient for normal shoaling.

Estrogen receptor 1 promoter polymorphism and digit ratio in men.

OBJECTIVES: The 2D:4D digit ratio, the relative lengths of the index and ring fingers in humans, is a widely used proxy measure for prenatal testosterone exposure. Varying distributions of androgen and estrogen receptors on the second and fourth digits, both of which regulate digit development, appears to be the basis for this effect. Polymorphism in a tandem repeat in the gene coding for the estrogen receptor α (ESR1) in zebra finches (Taeniopygia guttata) not only explains a significant amount of variation in digit ratio but also seems to explain the significant correlation between digit ratio and sexual behavior in these birds. Here, we investigate the effect of TA polymorphism in ESR1 on 2D:4D and aggressive behavior in men. METHODS: We genotyped ESR1 polymorphism in samples collected for a previous study in which we had demonstrated an association between androgen receptor polymorphism and aggression, but not 2D:4D. RESULTS: We found a significant effect of ESR1 TA repeat number on left hand 2D:4D ratio. More TA repeats were associated with higher, more feminized, digit ratios. We found no effect on right hand 2D:4D. We also found an effect of ESR1 polymorphism on aggressive behavior. Greater heterozygosity in TA(n) was associated with lower physical aggression. CONCLUSIONS: Our results suggest that a significant amount of left hand 2D:4D variation and aggressive behavior is due to this variation in ESR1, and that some of the correlation between digit ratio and social behavior is due to pleiotropic effects of ESR1 variation on the two traits.

Aggression, digit ratio and variation in androgen receptor and monoamine oxidase a genes in men.

Variation in prenatal exposure to androgens is thought to be responsible for some of the individual differences in aggressive behavior among adults. A putative indicator of prenatal testosterone exposure, 2D:4D (the index to ring finger length) ratios have shown a weak correlation with aggression. Variation in sensitivity of the androgen receptor, resulting from polymorphism in the AR gene, is also thought to influence the relative expression of sexually dimorphic traits within each sex, including aggressive behavior and 2D:4D. Here we examine variation in aggression, 2D:4D, and polymorphism in the AR and MAO-A genes in a sample of 188 men. We find no evidence of AR gene influence on right hand 2D:4D, and a weak trend towards more feminine-typical left hand 2D:4D in men with more sensitive androgen receptors. Men with more sensitive androgen receptors tended to score lower on many of the subscales of the Aggression Questionnaire and Indirect Aggression Questionnaire. We found no influence of MAO-A allele on either digit ratio or aggressive behavior. We conclude that more masculine-typical 2D:4D does not reflect greater sensitivity to testosterone through variation in this locus on the AR gene, and that AR alleles conferring greater sensitivity to testosterone are associated with lower, not higher propensity to aggression.

Sex differences in the relationship between aggressiveness and the strength of handedness in humans.

Cerebral lateralisation, the partitioning of cognitive functioning into one hemisphere of the brain, was once considered unique to humans; however, recent research in a variety of taxa suggests that lateralisation is an evolutionarily ancient adaptation. Handedness is the most obvious manifestation of cerebral lateralisation in humans. Much of the literature on handedness has focused on the direction, rather than the strength, of this lateralisation. From both genetic and evolutionary perspectives it may be more informative to study degrees of cerebral lateralisation rather than direction. Strong evidence suggests that the strength may be more closely associated with individual differences in behaviour in humans than the direction, and individual variation in the degree of lateralisation has been found to correlate with personality-like characteristics such as aggressiveness in fish. The association between different patterns of lateralisation and personality characteristics may help explain how variation in the strength of lateralisation is evolutionarily stable in natural populations. The present study investigated the relationship between aggression and strength of handedness in humans. We found a significant interaction between sex and lateralisation with respect to aggression. In males, trait aggression was significantly higher in strong-handers than in mixed-handers, while no difference was seen in females. This finding highlights the importance of considering sex as a factor when investigating relationships between cerebral lateralisation and personality characteristics. Potential causes and consequences of the sex interaction as well as future directions for research are discussed.

Epigenetic Regulation and Environmental Sex Determination in Cichlid Fishes.

Studying environmental sex determination (ESD) in cichlids provides a phylogenetic and comparative approach to understand the evolution of the underlying mechanisms, their impact on the evolution of the overlying systems, and the neuroethology of life history strategies. Natural selection normally favors parents who invest equally in the development of male and female offspring, but evolution may favor deviations from this 50:50 ratio when environmental conditions produce an advantage for doing so. Many species of cichlids demonstrate ESD in response to water chemistry (temperature, pH, and oxygen concentration). The relative strengths of and the exact interactions between these factors vary between congeners, demonstrating genetic variation in sensitivity. The presence of sizable proportions of the less common sex towards the environmental extremes in most species strongly suggests the presence of some genetic sex-determining loci acting in parallel with the ESD factors. Sex determination and differentiation in these species does not seem to result in the organization of a final and irreversible sexual fate, so much as a life-long ongoing battle between competing male- and female-determining genetic and hormonal networks governed by epigenetic factors. We discuss what is and is not known about the epigenetic mechanism behind the differentiation of both gonads and sex differences in the brain. Beyond the well-studied tilapia species, the 2 best-studied dwarf cichlid systems showing ESD are the South American genus Apistogramma and the West African genus Pelvicachromis. Both species demonstrate male morphs with alternative reproductive tactics. We discuss the further neuroethology opportunities such systems provide to the study of epigenetics of alternative life history strategies and other behavioral variation.

Cognitive Empathy as Imagination: Evidence From Reading the Mind in the Eyes in Autism and Schizotypy.

How is cognitive empathy related to sociality, imagination, and other psychological constructs? How is it altered in disorders of human social cognition? We leveraged a large data set (1,168 students, 62% female) on the Reading the Mind in the Eyes test (RMET), the Autism Quotient (AQ), and the Schizotypal Personality Questionnaire (SPQ-BR) to test the hypotheses that the RMET, as a metric of cognitive empathy, reflects mainly social abilities, imagination, or both. RMET showed the expected female bias in performance, though only for eyes that expressed emotions and not for neutral expressions. RMET performance was significantly, and more strongly, associated with the AQ and SPQ subscales that reflect aspects of imagination (AQ-Imagination and SPQ-Magical Ideation) than aspects of social abilities (AQ-Social, AQ-Communication, and SPQ-Interpersonal subscales). These results were confirmed with multiple regression analysis, which also implicated increased attention (AQ-Attention Switching and, marginally non-significantly, AQ-Attention to Detail) in RMET performance. The two imagination-related correlates of RMET performance also show the strongest sex biases for the AQ and SPQ: male biased in AQ-Imagination, and female biased in SPQ-Magical Ideation, with small to medium effect sizes. Taken together, these findings suggest that cognitive empathy, as quantified by the RMET, centrally involves imagination, which is underdeveloped (with a male bias) on the autism spectrum and overdeveloped (with a female bias) on the schizotypy spectrum, with optimal emotion-recognition performance intermediate between the two. The results, in conjunction with previous studies, implicate a combination of optimal imagination and focused attention in enhanced RMET performance.