Plasticity Alleles Research Articles

Genetic basis of variation in thermal developmental plasticity for Drosophila melanogaster body pigmentation.

Seasonal differences in insect pigmentation are attributed to the influence of ambient temperature on pigmentation development. This thermal plasticity is adaptive and heritable, and thereby capable of evolving. However, the specific genes contributing to the variation in plasticity that can drive its evolution remain largely unknown. To address this, we analysed pigmentation and pigmentation plasticity in Drosophila melanogaster. We measured two components of pigmentation in the thorax and abdomen: overall darkness and the proportion of length covered by darker pattern elements (a trident in the thorax and bands in the abdomen) in females from two developmental temperatures (17 or 28°C) and 191 genotypes. Using a GWAS approach to identify the genetic basis of variation in pigmentation and its response to temperature, we identified numerous dispersed QTLs, including some mapping to melanogenesis genes (yellow, ebony, and tan). Remarkably, we observed limited overlap between QTLs for variation within specific temperatures and those influencing thermal plasticity, as well as minimal overlap between plasticity QTLs across pigmentation components and across body parts. For most traits, consistent with selection favouring the retention of plasticity, we found that lower plasticity alleles were often at lower frequencies. The functional analysis of selected candidate QTLs and pigmentation genes largely confirmed their contributions to variation in pigmentation and/or pigmentation plasticity. Overall, our study reveals the existence and underlying basis of extensive and trait-specific genetic variation for pigmentation and pigmentation plasticity, offering a rich reservoir of raw material for natural selection to shape the evolution of these traits independently.

The relationship of maternal rank, 5-HTTLPR genotype, and MAOA-LPR genotype to temperament in infant rhesus monkeys (Macaca mulatta).

Temperament is a construct whose manifestations are quantifiable from an early age, and whose origins have been proposed as "biological." Our goal was to determine whether maternal rank and infant genotype are associated with five measures of temperament in 3- to 4-month old rhesus monkeys (Macaca mulatta), all of whom were born and reared by their mothers in large, outdoor, half-acre cages. Maternal rank was defined as the proportion of animals outranked by each female, and the two genes of interest to us were monoamine oxidase and serotonin transporter, both of which are polymorphic in their promoter regions (MAOA-LPR and 5-HTTLPR, respectively), with one allele of each gene considered a "plasticity" allele, conferring increased sensitivity to environmental events. Our large sample size (n = 2014-3140) enabled us to examine the effects of individual genotypes rather than combining genotypes as is often done. Rank was positively associated with Confident temperament, but only for animals with the 5-repeat allele for MAOA-LPR. Rank had no other effect on temperament. In contrast, genotype had many different effects, with 5-HTTLPR associated with behavioral inhibition, and MAOA-LPR associated with ratings-based measures of temperament. We also examined the joint effect of the two genotypes and found some evidence for a dose-response: animals with the plasticity alleles for both genes were more likely to be behaviorally inhibited. Our results suggest phenotypic differences between animals possessing alleles for MAOA-LPR that show functional equivalence based on in vitro tests, and our data for 5-HTTLPR revealed differences between short/short homozygotes and long/short heterozygotes, strongly suggesting that combining genotypes for statistical analysis should be avoided if possible. Our analysis also provides evidence of sex differences in temperament, and, to our knowledge, the only evidence of differences in temperament based on specific pathogen-freestatus. We suggest several directions for future research.

Monoaminergic Multilocus Genetic Variants Interact with Stressful Life Events in Predicting Changes in Adolescent Anxiety Symptoms: A One-year Longitudinal Study

Research suggests that genetic variants linked to monoaminergic neurotransmitter function moderate the association between stress and anxiety symptoms, but examining gene-environment (G × E) interactions with individual genes limits power. As one of polygenetic approaches, the multilocus genetic profile score is derived theoretically from combining the effects of multiple candidate genes based on the "biological plausibility". Using this approach, the current study examined the interaction between monoaminergic multilocus genetic variants and stressful life events on the changes in adolescent anxiety symptoms across a one-year timespan. In a Chinese Han adolescent sample which was derived from three vocational high schools (N = 587; T1: Mage = 16.47 ± 1.53 years; 50.8%, girls), the monoaminergic multilocus genetic profile score was calculated using 5-HTR2C rs6318, TPH2 rs4570625 and DRD2 rs1800497 polymorphisms. Results showed that this monoaminergic multilocus genetic profile score interacted with stressful life events in predicting changes in anxiety symptoms. Consistent with the G×E hypothesis of differential susceptibility, adolescents with more monoaminergic plasticity alleles not only suffered more from high levels of stressful life events, which increased the risk for anxiety symptoms, but also benefited more from low levels of stressful life events, which decreased the risk for anxiety symptoms. There were no significant G × E interactions when individual polymorphisms were examined in isolation. The results highlight the importance of examining aggregated influences of multiple genes in G × E interactions underlying the longitudinal development of adolescent anxiety symptoms.

Parenting Interacts With Plasticity Genes in Predicting Behavioral Outcomes in Preschoolers.

Public health and pediatric nurses typically focus on supporting parenting to reduce the likelihood of children's behavioral problems. Studies have identified interactions between early exposures to stress in caregiving and child genotype in predicting children's behavioral problems, such that certain genotypes connote greater differential susceptibility or plasticity to environmental stressors. We sought to uncover the interaction between observational measures of parent-child relationship quality and genotype in predicting early-onset behavioral problems in 24-month-olds, using prospective methods. We conducted a secondary analysis of data collected on a subsample of 176 women and their infants enrolled during pregnancy in the ongoing Alberta Pregnancy Outcomes and Nutrition (APrON) cohort study. Inclusion criteria required mothers to be ≥18 years of age, English speaking and ≤22 weeks gestational age at enrollment. Genetic data were obtained from blood leukocytes and buccal epithelial cell samples, collected from infants at three months of age. For each child, the presence of plasticity alleles was determined for BDNF, CNR1, DRD2/ANKK1, DRD4, DAT1, 5-HTTLPR, and MAOA and an overall index was calculated to summarize the number of plasticity alleles present. Observational assessments of parent-child relationship quality (sensitivity, controlling, and unresponsiveness) were conducted at six months of age. Children's internalizing (e.g., emotionally reactive, anxious/depressed, somatic complaint, withdrawn) and externalizing (e.g., aggression, inattention) behaviors were assessed at 24 months of age. After extracting genetic data, a maximum likelihood method for regressions was employed with Akaike Information Criterion (AIC) for model selection. When parents were less responsive and children possessed more plasticity alleles, children were more likely to be emotionally reactive, anxious/depressed, report somatic complaints, and withdrawn, while when parents were less responsive and children possessed fewer plasticity alleles, children were less likely to display these internalizing behaviors, in a differentially susceptible manner. Furthermore, when parents were more responsive, and children possessed more plasticity alleles, children were less likely to display internalizing behaviors (P = 0.034). Similarly, children who possessed either the CNR1-A plasticity allele (P = 0.010) or DAT1 9-repeat plasticity allele (P = 0.036) and experienced more/less parental control displayed more/fewer externalizing problems, respectively, in a differentially susceptible manner. The plasticity index score interacted with parental unresponsiveness in predicting anxiety and depressive behavioral problems in children, while individual genetic variants interacted with parental controlling behavior in predicting aggression and inattention in children, suggestive of differential susceptibility to caregiving. Especially in the context of nursing interventions designed to support childrearing and children's development, nurses need to be aware of the interactions between child genotype and parenting in understanding how well interventions will work in promoting optimal child behavior.

When Does Religion Matter With Regard to Crime? Examining the Relationship Between Genetics, Religiosity, and Criminal Behavior

Religiosity has been shown to be a predictor of initial criminal offending, reoffending, and desistance. To date, however, research has generally failed to assess the role that biological factors play in moderating the religiosity–crime relationship. The present study utilizes a nationally representative sample of male adolescents ( N = 4,053), to explore whether variants of the dopamine transporter gene (DAT1) and the monoamine oxidase A gene (MAOA) interact with religiosity to affect self-reported criminal offending. Results of negative binomial regressions demonstrate that religiosity interacts with these genes to influence offending among males, net of controls. Importantly, once potential confounding variables are accounted for, a statistically significant effect of religiosity on offending among males is only evident for those who carry plasticity alleles for both DAT1 and MAOA (vs. carrying one or zero plasticity alleles). Thus, among males, whether religiosity is important for criminal offending depends partly on the individual genotype. Implications for theory and policy are discussed.

Mice engineered to mimic a common Val66Met polymorphism in the BDNF gene show greater sensitivity to reversal in environmental contingencies

•A common human polymorphism in the gene that encodes brain derived neurotrophic factor (BDNF), Val66Met, is considered a marker of vulnerability for mental health issues and has been associated with cognitive impairment. An alternate framework has been proposed in which “risk alleles” are reinterpreted as “plasticity alleles” that confer vulnerability in adverse environments and positive effects in neutral or positive environments (Belsky et al., 2009). These frameworks produce divergent predictions for tests of learning and cognitive flexibility. Here, we examined multiple aspects of learning and cognitive flexibility in a relatively new BDNF Val66Met mouse model (BDNF Val68Met, Warnault et al., 2016), including multiple choice discrimination and reversal, go/no-go learning and reversal, and appetitive extinction learning. We found that mice homozygous for the Met allele show more efficient reversal learning in two different paradigms, but learn at rates comparable to Val homozygotes on the multiple choice discrimination task, a go/no-go task, and in appetitive extinction. Our results dissociate reversal performance from go/no-go learning and appetitive extinction and support the plasticity allele framework that suggests BDNF Met carriers are potentially more sensitive to changes in the environment.

Association between maternal childhood maltreatment and mother-infant attachment disorganization: Moderation by maternal oxytocin receptor gene and cortisol secretion

This study examined maternal oxytocin receptor (OXTR, rs53576) genotype and cortisol secretion as moderators of the relation between maternal childhood maltreatment history and disorganized mother-infant attachment in the Strange Situation Procedure (SSP). A community sample of 314 mother-infant dyads completed the SSP at infant age 17 months. Self-reported maltreatment history more strongly predicted mother-infant attachment disorganization score and disorganized classification for mothers with more plasticity alleles of OXTR (G), relative to mothers with fewer plasticity alleles. Maltreatment history also more strongly predicted mother-infant attachment disorganization score and classification for mothers with higher SSP cortisol secretion, relative to mothers with lower SSP cortisol secretion. Findings indicate that maltreatment history is related to disorganization in the next generation, but that this relation depends on maternal genetic characteristics and cortisol.

Maternal DRD2, SLC6A3, and OXTR genotypes as potential moderators of the relation between maternal history of care and maternal cortisol secretion in the context of mother-infant separation

A mother’s cortisol secretion is importantly associated with her own mental health and her infant’s cortisol secretion. This study investigated the influences of maternal history of care and maternal DRD2, SLC6A3, and OXTR genotypes on maternal cortisol in the context of infant stress. A community sample of 296 mother-infant dyads completed a maternal separation at infant age 17 months. Maternal salivary cortisol, buccal cells, and self-reported history of care were collected. Multilevel models revealed that history of care had a greater influence on maternal baseline cortisol (but not cortisol trajectory) for mothers with more plasticity alleles of SLC6A3 (10R) and OXTR (G), relative to mothers with fewer or no plasticity alleles. Findings indicate that a mother’s history of care is related to her cortisol secretion in anticipation of infant stress, but that this relation depends on her genetic characteristics. Findings are discussed in relation to the maternal protective system and anticipatory cortisol secretion.

Genetic Moderation of Intervention Efficacy: Dopaminergic Genes, TheIncredible Years, and Externalizing Behavior in Children.

This study investigated whether children scoring higher on a polygenic plasticity index based on five dopaminergic genes (DRD4, DRD2, DAT1, MAOA, and COMT) benefited the most from the Incredible Years (IY) parent program. Data were used from a randomized controlled trial including 341 Dutch families with 4- to 8-year-old children (55.7% boys) showing moderate to high levels of problem behavior. IY proved to be most effective in decreasing parent-reported (but not observed) externalizing behavior in boys (but not girls) carrying more rather than fewer dopaminergic plasticity alleles; this Gene×Intervention effect was most pronounced in the case of boys whose parents' manifested the most positive change in parenting in response to the intervention. These results proved robust across a variety of sampling specifications (e.g., intention to treat, ethnicity).

Genetic Differential Susceptibility to Socioeconomic Status and Childhood Obesogenic Behavior: Why Targeted Prevention May Be the Best Societal Investment.

Genes may work by modulating the way individuals respond to environmental variation, and these discrete and differential genes vs environmental interactions may not be readily captured in simple association studies. To determine whether children carrying the 7-repeat allele of the DRD4 gene living under adverse economic conditions have worse-than-average fat intake compared with those living in a healthy environment. Data from an established prospective birth cohort (Maternal Adversity, Vulnerability, and Neurodevelopment) were used to study 4-year-old children from Montreal, Quebec, Canada and Hamilton, Ontario, Canada. A total of 190 children (94 girls and 96 boys) had height and weight measured and complete food diaries and were therefore eligible for the study. The study is derived from a birth cohort started in June 2003 and still ongoing. The last age of follow-up was at 6 years. Social environment was characterized based on the gross family income, and DNA was genotyped for the 7-repeat allele of the DRD4 gene. Fat intake. The 5 steps to distinguish the differential susceptibility from other types of interaction were followed, and the study confirms that differential susceptibility is a relevant model to address the association between the 7-repeat allele of DRD4 and food choices in girls. Of the 190 children, 112 did not have the DRD4 7-repeat allele and 78 did. Baseline characteristics did not differ in these 2 groups. Although not different in several confounders, such as maternal educational level, maternal smoking during gestation, birth weight, and breastfeeding duration, girls carrying the 7-repeat allele of the DRD4 gene and living in adverse socioeconomic conditions have increased fat intake compared with girls who are noncarriers (DRD4 7+ mean, 33.95% of calories derived from fat; 95% CI, 28.76%-39.13%; DRD4 7- mean, 28.76%; 95% CI, 26.77%-30.83%). However, girls carrying the 7-repeat allele of the same gene and living in better socioeconomic conditions have decreased fat intake compared with noncarriers (DRD4 7+ mean, 29.03% of calories derived from fat; 95% CI, 26.69%-31.51%; DRD4 7- mean, 31.88%; 95% CI, 30.28%-33.58%). Alleles previously considered to be obesity risk alleles might in fact function as plasticity alleles, determining openness to environmental modification and/or intervention, as seen in the girls in this study. This finding has important implications for obesity prevention and social pediatrics.

Genes, Parenting, Self-Control, and Criminal Behavior.

Self-control has been found to predict a wide variety of criminal behaviors. In addition, studies have consistently shown that parenting is an important influence on both self-control and offending. However, few studies have examined the role that biological factors may play in moderating the relationship between parenting, self-control, and offending. Using a sample of adolescent males drawn from the National Longitudinal Study of Adolescent Health (N = 3,610), we explore whether variants of the monoamine oxidase A gene (MAOA) and the dopamine transporter (DAT1) gene interact with parenting to affect self-control and offending. Results reveal that parenting interacts with these genes to influence self-control and offending, and that the parenting-by-gene interaction effect on offending is mediated by self-control. The effects of parenting on self-control and offending are most pronounced for those who carry plasticity alleles for both MAOA and DAT1. Thus, MAOA and DAT1 may be implicated in offending because they increase the negative effects of parenting on self-control. Implications for theory are discussed.

Genetic susceptibility to family environment: BDNF Val66met and 5-HTTLPR influence depressive symptoms.

Functional genetic polymorphisms associated with Brain-Derived Neurotrophic Factor (BDNF) and serotonin (5-HTTLPR) have demonstrated associations with depression in interaction with environmental stressors. In light of evidence for biological connections between BDNF and serotonin, it is prudent to consider genetic epistasis between variants in these genes in the development of depressive symptoms. The current study examined the effects of val66met, 5-HTTLPR, and family environment quality on youth depressive symptoms in adolescence and young adulthood in a longitudinal sample oversampled for maternal depression history. A differential susceptibility model was tested, comparing the effects of family environment on depression scores across different levels of a cumulative plasticity genotype, defined as presence of both, either, or neither plasticity alleles (defined here as val66met Met and 5-HTTLPR 'S'). Cumulative plasticity genotype interacted with family environment quality to predict depression among males and females at age 15. After age 15, however, the interaction of cumulative plasticity genotype and early family environment quality was only predictive of depression among females. Results supported a differential susceptibility model at age 15, such that plasticity allele presence was associated with more or less depressive symptoms depending on valence of the family environment, and a diathesis-stress model of gene-environment interaction after age 15. These findings, although preliminary because of the small sample size, support prior results indicating interactive effects of 5-HTTLPR, val66met, and environmental stress, and suggest that family environment may have a stronger influence on genetically susceptible women than men.

Plasticity genes do not modify associations between physical activity and depressive symptoms.

Physical activity is inversely associated with depression in adolescents, but the overall associations are fairly weak, suggesting individual differences in the strength of the associations. The aim of this study was to investigate whether plasticity genes modify the reciprocal prospective associations between physical activity and depressive symptoms found previously. In a prospective population-based study (N = 1,196), physical activity and depressive symptoms were assessed three times, around the ages of 11, 13.5, and 16. Structural Equation Modeling was used to examine reciprocal effects of physical activity and depressive symptoms over time. The plasticity genes examined were 5-HTTLPR, DRD2, DRD4, MAOA, TPH1, 5-HTR2A, COMT, and BDNF. A cumulative gene plasticity index consisting of three groups (low, intermediate, and high) according to the number of plasticity alleles carried by the adolescents was created. Using a multigroup approach, we examined whether the associations between physical activity and depressive symptoms differed between the three cumulative plasticity groups, as well as between the individual polymorphisms. We found significant cross-sectional and cross-lagged paths from physical activity to depressive symptoms and vice versa. Neither the cumulative plasticity index nor the individual polymorphisms modified the strengths of these associations. Associations between adolescents' physical activity and depressive symptoms are not modified by plasticity genes.

Genetic sensitivity to the caregiving context: The influence of 5httlpr and BDNF val66met on indiscriminate social behavior

Evidence that gene×environment interactions can reflect differential sensitivity to the environmental context, rather than risk or resilience, is increasing. To test this model, we examined the genetic contribution to indiscriminate social behavior, in the setting of a randomized controlled trial of foster care compared to institutional rearing. Children enrolled in the Bucharest Early Intervention Project (BEIP) were assessed comprehensively before the age of 30months and subsequently randomized to either care as usual (CAUG) or high quality foster care (FCG). Indiscriminate social behavior was assessed at four time points, baseline, 30months, 42months and 54months of age, using caregiver report with the Disturbances of Attachment Interview (DAI). General linear mixed-effects models were used to examine the effect of the interaction between group status and functional polymorphisms in Brain Derived Neurotrophic Factor (BDNF) and the Serotonin Transporter (5htt) on levels of indiscriminate behavior over time. Differential susceptibility, relative to levels of indiscriminate behavior, was demonstrated in children with either the s/s 5httlpr genotype or met 66 BDNF allele carriers. Specifically children with either the s/s 5httlpr genotype or met66 carriers in BDNF demonstrated the lowest levels of indiscriminate behavior in the FCG and the highest levels in the CAUG. Children with either the long allele of the 5httlpr or val/val genotype of BDNF demonstrated little difference in levels of indiscriminate behaviors over time and no group×genotype interaction. Children with both plasticity genotypes had the most signs of indiscriminate behavior at 54months if they were randomized to the CAUG in the institution, while those with both plasticity genotypes randomized to the FCG intervention had the fewest signs at 54months. Strikingly children with no plasticity alleles demonstrated no intervention effect on levels of indiscriminate behavior at 54months. These findings represent the first genetic associations reported with indiscriminate social behavior, replicate previous gene×gene×environment findings with these polymorphisms, and add to the growing body of literature supporting a differential susceptibility model of gene×environment interactions in developmental psychopathology.

Gene-Environment Interaction and the Intergenerational Transmission of Parenting: Testing the Differential-Susceptibility Hypothesis

The current study evaluated the differential-susceptibility hypothesis in explaining the intergenerational transmission of parenting, using data from the National Longitudinal Study of Adolescent Health (Add Health). Exposure to maternal parenting was measured prospectively when respondents were adolescents and parental stress was measured when they were parents themselves, some 14 years later, on average. Cumulative-genetic plasticity was measured by dominantly coding the presence of putative plasticity alleles from four genes: the 10R allele of DAT1, the A1 allele of DRD2, the 7R allele of DRD4, and the short allele of 5HTTLPR. Results showed that the more plasticity alleles individuals carried (range 0-4), the more that parenting experienced in adolescence predicted future parenting experience. Those respondents with the most plasticity alleles not only experienced the highest levels of parental stress when exposed to negative maternal parenting in adolescence but the lowest levels when exposed to positive maternal parenting in adolescence. These results indicate that differential susceptibility is operative in the case of the intergenerational transmission of parenting, which could explain why estimates of such transmission have proven so modest in studies which fail to consider GXE interactions.

Cumulative-genetic plasticity, parenting and adolescent self-regulation

The capacity to control or regulate one's emotions, cognitions and behavior is central to competent functioning, with limitations in these abilities associated with developmental problems. Parenting appears to influence such self-regulation. Here the differential-susceptibility hypothesis is tested that the more putative 'plasticity alleles' adolescents carry, the more positively and negatively influenced they will be by, respectively, supportive and unsupportive parenting. One thousand, five hundred and eighty-six (1586) adolescents (n = 754 males; n = 832 females) enrolled in the American Add Health project were scored in terms of how many of 5 putative 'plasticity alleles' they carried - the 10R allele of DAT1, the A1 allele of DRD2, the 7R allele of DRD4, the short allele of 5HTTLPR, and the 2R/3R alleles of MAOA. Then the effect of the resultant index (ranging from 0 to 5) of cumulative-genetic plasticity in moderating effects of parenting on adolescent self-regulation was evaluated. Consistent with differential susceptibility, the more plasticity alleles males (but not females) carried, the more and less self-regulation they manifested under, respectively, supportive and unsupportive parenting conditions. Adolescent males appear to vary for genetic reasons in their susceptibility to parenting vis-à-vis self-regulation, perhaps due to epistatic and/or epigenetic processes. G×E research may benefit from compositing candidate genes. To afford comparative evaluation of differential-susceptibility vs. diathesis-stress models of environmental action, future G×E work should focus on positive as well as negative environmental conditions and developmental outcomes.