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. Author manuscript; available in PMC: 2024 Apr 1.
Published in final edited form as: Autism Res. 2023 Feb 4;16(4):713–722. doi: 10.1002/aur.2895

Vasopressin, and not Oxytocin, Receptor Gene Methylation is Associated with Individual Differences in Receptive Joint Attention in Chimpanzees (Pan troglodytes)

William D Hopkins 1, Nicky Staes 2,3,4, Elaine E Guevara 2, Michele M Mulholland 1, Chet C Sherwood 2, Brenda J Bradley 2
PMCID: PMC10308317  NIHMSID: NIHMS1906886  PMID: 36738470

Abstract

Joint attention (JA) is an important milestone in human infant development and is predictive of the onset of language later in life. Clinically, it has been reported that children at risk for or with a diagnosis of autism spectrum disorder (ASD) perform more poorly on measures of JA compared to neurotypical controls. JA is not unique to humans but has also been reported in great apes and to a lesser extent in more distantly related monkeys. Further, individual differences in JA among chimpanzees are associated with polymorphisms in the vasopressin and oxytocin genes, AVPR1A and OXTR. Here, we tested whether individual variation in DNA methylation of OXTR and AVPR1A were associated with performance on JA tasks in chimpanzees. We found that individual differences in JA performance was associated with AVPR1A methylation, but not OXTR methylation in the chimpanzees. The collective results provide further evidence of the role of AVPR1A in JA abilities in chimpanzees. The results further suggest that methylation values for AVPR1A may be useful biomarkers for identifying individuals at risk for ASD or related neurodevelopmental disorders associated with impairments in JA abilities.

LAY SUMMARY:

This study examines how chimpanzee performance on joint attention tasks relate to the methylation of two genes associated with autism spectrum disorder (ASD). We found that chimpanzees that performed better on one task had lower methylation of the vasopressin receptor gene (AVPR1A). This indicates that AVPR1A methylation may be a promising ASD biomarker for predicting whether a given individual is at risk for developing impairments in nonverbal social communication.

Joint attention (JA) or joint engagement refers to the dyadic process in which preverbal individuals begin to respond to (receptive joint attention, RJA), and initiate (IJA) nonverbal bids of communication via the use of gaze, gesture and vocalizations (Adamson, 1996; Bates et al., 1975). Typically developing children progress through RJA then IJA skills and studies have shown that performance in these early JA abilities can predict language abilities at later points in development (Baldwin, 1995; Bottema-Beutel, 2016; Cetincelik et al., 2020; Charman et al., 2000; Morales et al., 2000). A number of studies have also shown that children with or at risk for the development of autism spectrum disorder (ASD) are less inclined to engage in or appropriately develop JA skills compared to neurotypical controls (Bottema-Beutel, 2016; Dawson et al., 2002; Mundy, 2018; Sullivan et al., 2007; Whalen et al., 2006; N. Yirmiya et al., 2006). However, the mechanisms that underlie differences in JA performance between ASD and neurotypical controls remains poorly understood. Furthermore, the role that different genetic and non-genetic factors play on individual variation and the developmental trajectory in JA performance in non-clinical populations of children is also largely unknown.

Two genes repeatedly linked to human social behavior and cognition as well as ASD are oxytocin receptor (OXTR) and arginine-vasopressin receptor 1a genes (AVPR1A; (Mundy & Bullen, 2021; Skuse & Gallagher, 2011; Wilczyński et al., 2019). Many studies have reported that OXTR genotype is related to higher risk of ASD diagnosis, and differences in social behavior and cognition (Skuse et al., 2014; Stavropoulos & Carver, 2013; Tops et al., 2011; M Wade et al., 2014; Wilczyński et al., 2019). Infants with the GG genotype had higher social cognition scores (including JA, empathy, cooperation, and self-recognition) compared to those with the AA or AG genotypes (M Wade et al., 2014). Related, in adults, those with the GG genotype had less difficulty processing social vocal communication (Tops et al., 2011). There have been fewer studies of the role of OXTR DNA methylation and ASD or social cognition and behavior, and results have been contradictory; studies have reported both hypermethylation and hypomethylation (Maud et al., 2018; Moerkerke et al., 2021). People diagnosed with ASD had higher methylation of several OXTR CpG sites measured from blood samples, and several measured in brain tissue (specifically the temporal cortex) compared to controls (Gregory et al., 2009). Andari and Rilling (2021) found hypermethylation of one CpG site in adults with ASD compared to controls, as well as a relationship between higher methylation and reduced social responsiveness. However, in children, researchers found decreased methylation of OXTR exon 1 and exon/intron 2 (Elagoz Yuksel et al., 2016) and at one particular site (in males only; Siu et al., 2021) in those diagnosed with ASD compared to controls.

Though far fewer studies have been published, AVPR1A genotypes have also been linked to ASD diagnoses as well as measures of social cognition (Wilczyński et al., 2019). Yirmiva et al. (2006) found that AVPR1A microsatellite haplotypes were associated with a higher risk of ASD and scores on three separate ASD trait measures. Yang et al. (2017) found that polymorphisms in the promotor region of AVPR1A were associated with worse social functioning as measured by multiple ASD social behavior scales. However, other studies showed no such associations (Wilczyński et al., 2019). No studies have examined AVPR1A DNA methylation and the relationship with social cognition in humans, nor have studies have examined the relationship with joint attention, specifically, in humans or animal models.

JA abilities are not uniquely human but have been reported in all great apes and, to a lesser extent, in more distantly related primate species. For instance, chimpanzees and other great apes will follow gaze and pointing gestures to objects and will return objects that are requested from them based on vocal and gestural cues (Clark et al., 2019; Hopkins et al., 2013; Leavens et al., 2008; Leavens & Racine, 2009). Chimpanzees and other great apes will also gesture to foods or objects that are otherwise out of their reach while alternating their gaze between the referent and a human experimenter, though there is some debate regarding nonhuman primates to engage in declarative pointing (Cartmill & Byrne, 2007; Clark et al., 2019; Gretscher et al., 2017; Leavens & Hopkins, 1998; Leavens, Hopkins, et al., 2004; Leavens, Hostetter, et al., 2004; Leavens et al., 2015; Leavens et al., 2005; Liebal et al., 2004; Liszkowski et al., 2004; Liszkowski et al., 2009; MacLean & Hare, 2013; Poss et al., 2006; Tanner & Byrne, 2010; Tomasello, 2008). Indeed, at least two measures of receptive joint attention (RJA) that significantly distinguish between children at risk for or with a diagnosis of ASD from neurotypical controls (herein referred to as the Dawson and Mundy tasks) have been used to assess RJA with chimpanzees (Hopkins et al., 2014a; Hopkins & Latzman, 2021). As in humans, chimpanzees show considerable individual variation in performance on the Dawson and Mundy tasks. Previous studies have reported that individual differences in chimpanzee performance on the Dawson and Mundy tasks are associated with polymorphisms in the vasopressin V1a receptor gene, AVPR1A (Hopkins et al., 2014a; Hopkins & Latzman, 2021).

Here, we examined individual differences in RJA performance in chimpanzees in relation to DNA methylation in AVPR1A and OXTR, the genes encoding the receptors for the neuropeptides vasopressin and oxytocin, respectively. Studies on epigenetics are relatively rare in nonhuman primates, including chimpanzees (Guevara et al., in press; Staes et al., in press). This is unfortunate in light of the fact that chimpanzees have a relatively immature brain at birth (Leigh, 2004) and prolonged period of infancy (Jones, 2011) compared to other primate species, making them ideal models of neurodevelopmental disorders. DNA methylation is a gene regulatory mechanism that is known to mediate long-term stable behavioral differences in response to social environment inputs during early life sensitive periods (Champagne & Curley, 2009; Tost et al., 2015). As defined by Staes et al. (in press), CpG methylation, or DNA methylation comprises the addition of a methyl chemical group to cytosine DNA bases within the context of CpG sites (CpGs), or cytosines next to guanine bases. Methylation can reflect and maintain a gene’s transcriptional status by altering transcription factor activity and chromatin structure. Because of the hypothesized role of vasopressin and oxytocin on social cognition and behavior, including joint attention (Francis et al., 2016; Hammock & Young, 2006; LoParo & Waldman, 2014; M. Wade et al., 2014; Zhang et al., 2017), we predicted that methylation in one or both of the receptor genes, AVPR1A and OXTR, would be associated with RJA performance in the chimpanzees. Specifically, we predicted that altered expression of either OXTR or AVPR1A (as reflected in lower methylation values) would be positively associated better RJA performance.

In addition, we also examined influence of early social rearing experiences on DNA methylation values for AVPR1A and OXTR. Previous studies in rodents and rhesus monkeys have reported that newborn offspring that experienced typical or adverse rearing experiences show differential expression of a wide range of genes, which in turn, influence the development of species typical behavior and the expression of some ASD-like behaviors, such as poor social skills and repetitive behaviors (Baker et al., 2017; Dettmer & Suomi, 2014). Within our sample of chimpanzees, there were three cohorts, which included individuals raised by their biological conspecific mothers (MR), those raised in a human nursery (NR) setting with same aged peers for the first three years of life (Bard, 1994) and a few wild-born chimpanzees. A number of previous studies have reported significant differences in social behavior and brain morphology between MR and NR chimpanzees (Bennett et al., 2021; Davenport & Rogers, 1970; Davenport et al., 1973; Hopkins et al., 2020; Menzel et al., 1970; Turner et al., 1969). Given the role that oxytocin and vasopressin play in mammalian social behavior, we hypothesized that MR and NR chimpanzee would differ in DNA methylation values for these two neuropeptides.

Methods

Subjects

Subjects included 54 chimpanzees (27 females, 27 males) from the National Center for Chimpanzee Care (NCCC) at The University of Texas MD Anderson Cancer Center. Blood samples and the magnetic resonance image scans were obtained during the subject’s annual physical exam and were collected prior to 2015 when captive chimpanzees were classified as endangered thereby placing limits on the collection of blood samples for purely research purposes. For most chimpanzees, collection of the behavioral data overlapped with the same period of time as the collection of blood samples (average of 0.45 years between collection times). Though 84 chimpanzees were included in the original blood collection, only the 54 with known rearing histories and behavioral data are included here. Age at the time of blood collection ranged from 12 to 59 years old (M = 26.22, SD = 10.05). Within this sample, there were 33 mother-reared and 21 nursery-reared chimpanzees. We defined a nursery-reared (NR) chimpanzee as an individual that was separated from his or her mother within the first 30 days of life due to unresponsive care, injury, or illness (see Bard, 1994; Bard et al., 1992 for details). These chimpanzees were placed in incubators, fed standard human infant formula and cared for by humans until they could sufficiently care for themselves. They were then placed with other infants of the same age until they were three years old (Bard, 1994; Bard et al., 1992). At three years of age, the nursery-reared chimpanzees were integrated into larger social groups of adult and sub-adult chimpanzees. Mother-reared (MR) chimpanzees were not separated from their mother during at least the first 2.5 years of life and were raised in ‘nuclear’ family groups of conspecifics, ranging in size from 4 to 20 individuals.

DNA extraction, methylation profiling, and data processing

Blood samples were collected from 84 chimpanzees from both NCCC (n=22) and Emory National Primate Research Center (formerly Yerkes; n=62) including 50 females and 34 males between 7 and 59 years of age (M=28.71, SD=11.83). Genomic DNA was extracted from 200 μl of blood samples using the QIAampDNA Mini Kit automated on a QiaCube (Qiagen). DNA concentrations were quantified using a Nanodrop 2000 (Thermo-Fisher Scientific) spectrophotometer. DNA samples were brought to a concentration of ~70 ng/μL. These samples then underwent bisulfite conversion prior to being run on the Illumina Infinium Methylation EPIC array at the Yale Center for Genome Analysis. Data was filtered to remove probes with spectral intensities not significantly different from background levels and normalized to account for the two probe types on the EPIC array using the illumina GenomeStudio software. In addition, because this array was designed to assay methylation levels at sites in the human genome, analyses were limited to CpG sites expected to also be successfully assayed in chimpanzees (Guevara et al. 2020). These CpG sites mapped to the chimpanzee genome (panTro2.1.4) with one or zero mismatches (Needhamsen et al. 2017). Raw intensity data for the remaining probes was then converted to beta values (proportion methylation), resulting in 19 and 17 CpG sites for OXTR and AVPR1A genes, respectively. Only data from 54 of these chimpanzees (with known rearing histories and complete behavioral data) are included in the subsequent analyses.

Receptive Joint Attention (RJA)

Mundy Task:

This task was designed to model those used in a previous study of human children by Mundy, Card and Fox (2007). Each chimpanzee received 24 test trials, divided over 4 sessions, with only one 6-trial session performed per day. Prior to beginning the task, the experimenter placed two PVC stations as high and far laterally apart on the cage mesh as possible, but within 1–2 meters of the focal subject. The experimenter positioned themselves in front of the subject an equal distance between the two PVC stations and engaged them in some basic husbandry training task. While the subject was actively engaged with the experimenter, the experimenter stopped interacting with the subject and pointed (full arm extended and maintained throughout the trial) and looked toward one of the PVC stations (the cued PVC) and said the chimpanzee’s name with increasing emphasis. If the subject looked at, oriented toward, or touched the cued PVC station during this time, they received a “1”, indicating a correct response. If the subject did not look at, orient toward, or touch the cued PVC, or if they instead looked at, oriented toward or touched the non-cued PVC pipe, then they received a score of “0” for that trial, indicating an incorrect response. This process was repeated for all six trials within a session, with each trial separated by the experimenter re-engaging the subject with the basic husbandry training task. The experimenter randomly alternated which of the PVC stations was the cued stimulus. The dependent measure was the proportion of correct responses across the 24 trials.

Dawson Task:

The methods for assessing RJA for this task have been described in detail elsewhere (Hopkins et al., 2014b). Briefly, at the onset of each trial, a human experimenter would engage in basic husbandry training activities with the focal subject. When the experimenter sensed that the focal chimpanzee was engaged and facing them, they would stop their action and initially look over the shoulder of the subject for 5 s, as if there were an object behind them. At the end of this cue, the chimpanzee’s behavior was recorded for 15 s. If they looked behind them, they were given a score of 3 and the trial ended. If the focal chimpanzee subject did not look behind them, the experimenter re-engaged the subject in husbandry training behavior. When the experimenter judged the subject to be engaged and facing them, they stopped and again looked over the focal subject’s shoulder and pointed as if there were an object behind the ape. Following this cue, the chimpanzee was again observed for 15 s, and if they looked behind them, they were given a score of 2 and the trial ended. As before, if the chimpanzee did not look behind them, the experimenter re-engaged the chimpanzee in husbandry training behavior. When the experimenter again sensed that the chimpanzee was engaged, they stopped and now looked over the focal subject’s shoulder, pointed and vocally prompted the chimpanzee to an object behind them. Following this cue, the chimpanzee’s response was recorded for 15 s and if they looked behind them, they were given a score of 1 and the trial ended. If the subject failed to look behind them at the end of this phase of the trial, they were given a score of 0. Each chimpanzee received 4 trials and the trials were administered across different days. We summed their performance across the 4 test trials to create a single composite score that ranged between 0 and 16 with higher values indicating better performance.

Statistical analysis

Statistical analyses were performed using SPSS. The methylation values for each gene were then (1) compared between sexes and rearing groups, and (2) correlated with each RJA performance measure as well as their average performance for both measures. Because the two JA tasks were on different scales of measurement, we converted them to standardized z-scores and then computed their average to derive the composite performance score (RJA_Mean). When testing for differences in methylation between rearing conditions and sexes, we performed multivariate analyses of covariance while controlling for age at the time of blood collection and genetic relatedness. Genetic relatedness was computed based on available pedigree information and reflected how related each subject is to all other chimpanzees within the colony that they were born. See Mulholland et al. (2020) for the methods used to calculate the relatedness coefficients.

Results

Sex and Rearing Effects on OXTR and AVPR1A Methylation

We identified 19 and 17 CpG sites for OXTR and AVPR1A genes, respectively. The specific CpG sites are shown in Tables 1 and 2. We first evaluated the influence of sex and rearing experiences on the methylation values for the AVPR1A and OXTR genes. For AVPR1A, the MANCOVA revealed no significant main effect for sex F(17,32)=1.437 p=0.184, rearing F(17,32)=1.362 p=0.220, nor a sex by rearing interaction F(17,32)=0.782 p=0.700. For OXTR, the MANCOVA also revealed no significant main effect for rearing F(19,30)=0.541 p=0.918, sex F(19,30)=1.283 p= 0.264, nor a sex by rearing interaction F(19,30)=1.208 p=0.314. Therefore, sex and rearing were not included as covariates for subsequent analyses.

Table 1.

AVPR1A CpG site information.

Site Chromosome Position Relation to Island Gene Region
1 cg04827692 chr12 63543831 Island 1stExon
2 cg09208611 chr12 63544319 Island 1stExon
3 cg10931900 chr12 63540400 N_Shelf 3’UTR
4 cg12807275 chr12 63543292 N_Shore Body
5 cg16352140 chr12 63544015 Island 1stExon
6 cg16668728 chr12 63544013 Island 1stExon
7 cg23335356 chr12 63547716 S_Shelf TSS1500
8 cg24501701 chr12 63544040 Island 1stExon
9 cg26727693 chr12 63544175 Island 1stExon
10 cg09040797 chr12 63544768 Island 1stExon;5’UTR
11 cg10862431 chr12 63544783 Island 1stExon;5’UTR
12 cg12516059 chr12 63545288 S_Shore 1stExon;5’UTR
13 cg13631391 chr12 63544945 Island 1stExon;5’UTR
14 cg19987210 chr12 63544752 Island 1stExon;5’UTR
15 cg21164131 chr12 63544923 Island 1stExon;5’UTR
16 cg23549160 chr12 63545956 S_Shore 1stExon;5’UTR
17 cg27032502 chr12 63544881 Island 1stExon;5’UTR
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Table 2.

OXTR CpG site information.

Site Chromosome Position Relation to Island Gene Region
1 cg00078085 chr3 8810592 Island 5’UTR
2 cg00247334 chr3 8811543 S_Shore TSS1500
3 cg00385883 chr3 8808259 N_Shore Body
4 cg02192228 chr3 8809536 Island Body
5 cg03257388 chr3 8809213 Island Body
6 cg03710862 chr3 8811728 S_Shore TSS1500
7 cg03987506 chr3 8810549 Island 5’UTR
8 cg04523291 chr3 8809501 Island Body
9 cg11171527 chr3 8810206 Island 5’UTR
10 cg14483142 chr3 8811758 S_Shore TSS1500
11 cg15317815 chr3 8809306 Island Body
12 cg17036624 chr3 8811601 S_Shore TSS1500
13 cg19619174 chr3 8810139 Island 5’UTR
14 cg25085537 chr3 8811739 S_Shore TSS1500
15 cg26455676 chr3 8797459 OpenSea Body
16 cg27501759 chr3 8809715 Island Body
17 cg09353063 chr3 8811092 Island 1stExon;5’UTR
18 cg17285225 chr3 8811004 Island 1stExon;5’UTR
19 cg23391006 chr3 8811279 Island 1stExon;5’UTR
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Associations Between Receptive Joint Attention, AVPR1A and OXTR Methylation

For AVPR1A, performance on the Dawson task was negatively correlated with methylation values of 8 CpG sites and positively correlated with methylation values of 1 CpG site. Mean_RJA was negatively correlated with methylation values of 5 CpG sites and positively correlated with methylation values of 1 CpG site. Performance on the Mundy task, however, was only positively correlated with methylation of one CpG site. In contrast, for OXTR, there were no significant correlations between performance on the JA tasks and methylation values. See Table 3 for specific CpG sites, correlation coefficients, and adjusted p-values (5% FDR; calculated using the R function p.adjust).

Table 3.

Partial Correlation Coefficients between each CpG site and each JA measure (df=50). All p-values are adjusted based on a 5% FDR.

AVPR1A CpG Site Mean_RJA Mundy Dawson
r adj. p-value r adj. p-value r adj. p-value
cg04827692 −0.233 0.171 −0.047 0.786 −0.304 0.070
cg09208611 −0.286 0.085 −0.052 0.778 −0.378 0.031 *
cg10931900 −0.24 0.164 −0.024 0.864 −0.333 0.048
cg12807275 −0.378 0.031 * −0.159 0.370 −0.425 0.020 *
cg16352140 0.219 0.184 0.234 0.171 0.13 0.464
cg16668728 −0.298 0.071 −0.133 0.464 −0.329 0.048 *
cg23335356 −0.031 0.847 0.095 0.555 −0.124 0.464
cg24501701 −0.319 0.056 −0.127 0.464 −0.365 0.034 *
cg26727693 −0.306 0.070 −0.228 0.171 −0.262 0.120
cg09040797 −0.384 0.031 * −0.125 0.464 −0.462 0.017 *
cg10862431 −0.302 0.070 −0.118 0.478 −0.347 0.044 *
cg12516059 −0.341 0.044 * −0.132 0.464 −0.393 0.029 *
cg13631391 0.477 <0.001 * 0.331 0.048 * 0.429 0.017 *
cg19987210 0.219 0.184 0.113 0.494 0.23 0.171
cg21164131 −0.363 0.034 * −0.174 0.322 −0.391 0.029 *
cg23549160 −0.173 0.322 0.034 0.842 −0.283 0.086
cg27032502 −0.346 0.044 * −0.106 0.517 −0.422 0.020 *
OXTR CpG Site Mean_RJA Mundy Dawson
r adj. p-value r adj. p-value r adj. p-value
cg00078085 0.085 0.810 −0.084 0.810 0.196 0.489
cg00247334 −0.071 0.859 −0.049 0.905 −0.064 0.859
cg00385883 0.104 0.810 0.21 0.431 −0.019 0.963
cg02192228 −0.14 0.726 −0.286 0.234 0.029 0.963
cg03257388 0.008 0.990 −0.099 0.810 0.093 0.810
cg03710862 0.079 0.821 0.168 0.606 −0.021 0.963
cg03987506 −0.057 0.870 −0.229 0.363 0.104 0.810
cg04523291 −0.129 0.762 −0.256 0.333 0.02 0.963
cg11171527 −0.028 0.963 −0.045 0.908 −0.004 0.990
cg14483142 −0.248 0.333 −0.338 0.114 −0.089 0.810
cg15317815 −0.042 0.908 0.109 0.810 −0.153 0.663
cg17036624 −0.101 0.810 −0.192 0.490 0.008 0.990
cg19619174 −0.138 0.726 −0.249 0.333 0.002 0.990
cg25085537 −0.361 0.114 −0.239 0.338 −0.338 0.114
cg26455676 −0.238 0.338 −0.352 0.114 −0.063 0.859
cg27501759 −0.392 0.114 −0.358 0.114 −0.285 0.234
cg09353063 0.164 0.610 0.09 0.810 0.168 0.606
cg17285225 −0.062 0.859 −0.213 0.431 0.084 0.810
cg23391006 −0.295 0.234 −0.415 0.114 −0.094 0.810
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*

indicates significant correlations

Discussion

Contrary to our hypothesis, results from this study revealed no effect of sex or rearing on methylation values for vasopressin and oxytocin receptor genes (AVPR1A and OXTR). However, as predicted, we found that performance on the two joint attention tasks and average RJA performance were significantly associated with AVPR1A CpG site methylation. Specifically, we found that performance on the Dawson task was negatively correlated with methylation values on 9 AVPR1A CpG sites including: cg09208611, cg12807275, cg16668728, cg24501701, cg09040797, cg10862431, cg12516059, cg21164131, and cg27032502, and positively correlated with methylation values of cg13631391. Chimpanzees that performed better on the Dawson measure had lower AVPR1A methylation for all but one of these CpG sites (cg13631391). Poor performance on the Dawson task is associated with higher AVPR1A methylation at these 9 sites, and increased methylation (or hypermethylation) can lead to gene inactivation or reduced gene expression. Unfortunately, we cannot determine the causal direction of this relationship; this could mean that higher methylation/reduced AVPR1A gene expression leads to the development of poor RJA skills or that poor RJA skills leads to hypermethylation, or that some other variable could cause changes in both RJA and AVPR1A methylation. However, this is consistent with previous studies in chimpanzees that have reported significant associations between performance on the Dawson joint attention task and polymorphisms in the AVPR1A gene (Hopkins et al., 2014a). Specifically, chimpanzee males that were homozygous for a sequence deletion in the 5’ flanking region of AVPR1A had poorer RJA skills (Hopkins et al., 2014a). Additionally, chimpanzees who performed poorly on the Dawson task had atypical (more rightward) gray matter volume asymmetries in the posterior superior temporal sulcus, a brain region known to be important for the processing of socially-relevant information (Hopkins, et al., 2014b). Thus, collectively, these findings strongly implicate the vasopressin pathway in receptive joint attention, as quantified by the Dawson task alone. Interestingly, there were far fewer associations between AVPR1A methylation and a second measure of RJA, the Mundy task. Like the Dawson task, performance on the Mundy task was positively associated with methylation values at cg13631391, but there were no other significant relationships. Unfortunately, there are no published papers on AVPR1A methylation that could help us explain why this one particular CpG site (cg13631391, genome location 63544945) would have the opposite relationship with RJA performance than the others. Additionally, in light of the fact that the Mundy and Dawson task are both considered measures of receptive joint attention, one would expect that there would be (1) a significant positive relationship with each other [there is, in fact, a moderate positive correlation: r (49)= 0.418, p = 0.002], and (2) more consistent associations between performance and the AVPR1A methylation values.

The lack of a stronger positive correlation between performance on the Mundy and Dawson tasks may reflect subtle differences in the two tasks. While both tasks require the chimpanzees to respond to communicative cues of a researcher, the scoring method and cues utilized are different. The Mundy task requires the chimpanzees to either look, orient, or point towards a cued target object on their immediate left or right (as indicated by the researcher’s simultaneous gaze, pointing and vocal cues). Higher scores indicate the number of trials the chimpanzees made correct responses. The Dawson task requires the chimpanzees to look behind them in the direction of the researcher’s gaze, or their gaze paired with either pointing, or pointing and vocalizing. Higher scores on the Dawson task indicate that chimpanzees required fewer cues to respond correctly (i.e. gaze following only would receive the highest score). The middle and low scores (requiring the researcher to point or point and vocalize, or not eliciting a correct response from the chimpanzee) are more congruent with scoring of the Mundy task. Therefore, it is more difficult to obtain a high score on the Dawson task compared to the Mundy task. Chimpanzees with higher Dawson scores (more likely to respond with fewer researcher cues) are more likely to have lower AVPR1A methylation across several CpG sites. Also, if the Mundy task included trials where cued objects were behind the chimpanzees, then perhaps the relationship with AVPR1A methylation would be more congruent with that of the Dawson performance.

Surprisingly, there were no significant relationships between JA performance (on any task) and OXTR methylation at any CpG sites. This is contrary to what has been found for humans, with several studies reporting either hyper- and hypomethylation of OXTR related to measures of social cognition (depending on age, sex, and ASD diagnosis (Andari & Rilling, 2021; Elagoz Yuksel et al., 2016; Maud et al., 2018; Moerkerke et al., 2021; Siu et al., 2021). Although we found no relationships between OXTR methylation and JA performance, it is possible that these relationships would be found in (1) a chimpanzee sample with more impaired JA abilities, and (2) that OXTR genotype may moderate the relationship between OXTR methylation and JA. Rijlaarsdam et al. (2017) examined the associations of OXTR methylation (averaged across 3 CpG sites: cg02192228, cg04523291, cg15317815 located within the CpG island), OXTR genotype, and prenatal stress exposure with ASD-related traits in children. They found no association between OXTR methylation and ASD traits or OXTR genotype and ASD traits when examined separately, however, there was a significant genotype by methylation interaction. Specifically, there was a stronger relationship between methylation and overall social responsiveness, social communication problems, social cognition, and ASD mannerisms for children with particular OXTR alleles (homozygous G-allele but not A-allele carriers; Rijlaarsdam et al., 2017). Future research should determine whether OXTR genotype moderates the relationship between JA performance and OXTR methylation in chimpanzees, and specifically examine these same three sites identified in children.

There are several limitations to this study. First, measures of methylation were obtained from blood samples which are not cell specific. That stated, previous studies in chimpanzees have reported that methylation values for the DRD2 gene obtained from blood correlate significantly and positively with methylation values obtained from prefrontal cortex and the cerebellum (Staes et al., in press). Second, the sample size was small and future studies would benefit from a larger cohort of subjects. In addition, although we had equal numbers of females and males, our sample was not comprised of equal numbers of mother- and nursery-reared individuals (female MR n=13, NR n=14; male MR n=20, NR n=7). Lastly, because of the correlational nature of the study, it is not clear whether performance on the JA tasks drives changes in AVPR1A methylation or vice versa.

Implications for Autism

Caveats and limitations aside, we believe the findings from this study have some implications for research on Autism Spectrum Disorder (ASD). According to the DSM-5, ASD is characterized by impairments in three broad behavioral categories or phenotypes, including (1) stereotyped or repetitive behaviors, (2) impairments in social behavior, and (3) socio-communicative deficits, particularly early in development. Because ASD is a neurodevelopmental disorder, there has been considerable effort devoted to identifying early behavioral and biological markers (including candidate genes) that predict whether a given individual may be at risk for the development of ASD (Constantino et al., 2017; Jones & Klin, 2013; Lord & Spence, 2006; Melke, 2008; Mundy, 2018; Osterling et al., 2002; Zwaigenbaum et al., 2005). The primary measure of socio-communicative impairment in preverbal children has been JA. To date, both the OXTR and AVPR1A receptor genes have been identified as risk genes for ASD (Hammock & Young, 2006; LoParo & Waldman, 2014). Our results suggest that rather than focus entirely on genetic polymorphisms, AVPR1A methylation may potentially serve as another biomarker for identifying individuals at risk for the development of ASD.

In summary, individual variation in AVPR1A methylation, but not OXTR methylation, was associated with measures of receptive joint attention, further implicating this gene in non-verbal, socio-communicative functions. Future studies on epigenetic processes, and interactions with genotype, in chimpanzees will provide invaluable data on how experiences shape the brain and cognition in primates, including humans.

Acknowledgement

This work was supported, in part, by NIH grants AG-067419, HD-103490, NS-073134, NS-42867, NS-092988 and NSF-2021711. MMM is funded by AG-078411. Chimpanzee maintenance at the National Center for Chimpanzee Care was previously funded by NIH/NCRR U42- OD-011197. All aspects of this research conformed to existing US and NIH federal policies on the ethical use of chimpanzees in research. Reprint requests may be sent to: William D. Hopkins, Department of Comparative Medicine, Keeling Center for Comparative Medicine and Research, Bastrop, Texas 78602 Email: wdhopkins@mdanderson.org

References

  1. Adamson LR (1996). Communication development during infancy. Westview. [Google Scholar]
  2. Andari E, & Rilling JK (2021). Genetic and epigenetic modulation of the oxytocin receptor and implications for autism. Neuropsychopharmacology, 46(1), 241. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Baker M, Lindell SG, Driscoll CA, Zhou Z, Yuan Q, Schwandt ML, Miller-Crews I, Simpson EA, Paukner A, Ferrari PF, Sindhu RK, Razaqyar M, Sommer WH, Lopez JF, Thompson RC, Goldman D, Heilig M, Higley JD, Suomi SJ, & Barr CS (2017, Oct 31). Early rearing history influences oxytocin receptor epigenetic regulation in rhesus macaques. Proc Natl Acad Sci U S A, 114(44), 11769–11774. 10.1073/pnas.1706206114 [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Baldwin DA (1995). Understanding the link between joint attention and language. In Moore C, & Dunham PJ (Ed.), Joint attention: Its origins and role in development (pp. 131–158). Erlbaum. [Google Scholar]
  5. Bard KA (1994). Evolutionary roots of intuitive parenting: Maternal competence in chimpanzees. Early Development and Parenting, 3(1), 19–28. 10.1002/edp.2430030104 [DOI] [Google Scholar]
  6. Bard KA, Platzman KA, Lester BM, & Suomi SJ (1992). Orientation to social and nonsocial stimuli in neonatal chimpanzees and humans. Infant Behavior and Development, 15(1), 43–56. 10.1016/0163-6383(92)90005-q [DOI] [Google Scholar]
  7. Bates E, Camaioni L, & Volterra V. (1975). Performatives prior to speech. Merrill-Palmer Quarterly, 21, 205–226. [Google Scholar]
  8. Bennett AJ, Pierre PJ, Wesley MJ, Latzman R, Schapiro SJ, Mareno MC, Bradley BJ, Sherwood CC, Mullholland MM, & Hopkins WD (2021, Nov). Predicting their past: Machine language learning can discriminate the brains of chimpanzees with different early-life social rearing experiences. Dev Sci, 24(6), e13114. 10.1111/desc.13114 [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Bottema-Beutel K. (2016). Associations between joint attention and language in autism spectrum disorder and typical development: A systematic review and meta-regression analysis. Autism Research, 10, 1021–1035. [DOI] [PubMed] [Google Scholar]
  10. Cartmill E, & Byrne RW (2007). Orangutans modify their gestural signaling according to their audience’s comprehension. Current Biology, 17, 1–14. [DOI] [PubMed] [Google Scholar]
  11. Cetincelik M, Rowland CF, & Snijders TM (2020). Do the Eyes Have It? A Systematic Review on the Role of Eye Gaze in Infant Language Development. Front Psychol, 11, 589096. 10.3389/fpsyg.2020.589096 [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Champagne FA, & Curley JP (2009). Epigenetic mechanims mediating the long-term effects of maternal care on development. Neuroscience and Biobehavioral Reviews, 33, 593–600. [DOI] [PubMed] [Google Scholar]
  13. Charman T, Baron-Cohen S, Swettenham J, Baird G, Cox A, & Drew A. (2000). Testing joint attention, imitation and play as infancy precursors to language and theory of mind. Cognitive Development, 15, 481–498. [Google Scholar]
  14. Clark H, Elsherif MM, & Leavens DA (2019, Oct). Ontogeny vs. phylogeny in primate/canid comparisons: A meta-analysis of the object choice task. Neurosci Biobehav Rev, 105, 178–189. 10.1016/j.neubiorev.2019.06.001 [DOI] [PubMed] [Google Scholar]
  15. Constantino JN, Kennon-McGill S, Weichselbaum C, Marrus N, Haider A, Glowinski AL, Gillespie S, Klaiman C, Klin A, & Jones W. (2017, Jul 20). Infant viewing of social scenes is under genetic control and is atypical in autism. Nature, 547(7663), 340–344. 10.1038/nature22999 [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Davenport RK, & Rogers CM (1970). Differential rearing of the chimpanzee: A project survey. In Bourne GH(Ed.), The Chimpanzee: A Series of Volumes on the Chimpanzee: Vol. 3. Immunology, Infections, Hormones, Anatomy, and Behavior of Chimpanzees (Vol. 3, pp. 337–360). University Park Press. [Google Scholar]
  17. Davenport RK, Rogers CM, & Rumbaugh DM (1973). Long-term cognitive deficits in chimpanzees associated with early impoverished rearing. Developmental Psychology, 9(3), 343–347. 10.1037/h0034877 [DOI] [Google Scholar]
  18. Dawson G, Munson J, Estes A, Osterling J, McPartland J, Toth K, Carver L, & Abbott R. (2002). Neurocognitive function and joint attention ability in young children with autism spectrum disorder versus developmental delay. Child Development 73(2), 345–358. https://srcd.onlinelibrary.wiley.com/doi/abs/10.1111/1467-8624.00411?sid=nlm%3Apubmed [DOI] [PubMed] [Google Scholar]
  19. Dettmer AM, & Suomi SJ (2014). Nonhuman primate models of neuropsychiatric disorders: Influences of early rearing, genetics and epigenetics. ILAR journal, 55(2), 361–371. [DOI] [PubMed] [Google Scholar]
  20. Elagoz Yuksel M, Yuceturk B, Karatas OF, Ozen M, & Dogangun B. (2016). The altered promoter methylation of oxytocin receptor gene in autism. Journal of Neurogenetics, 30(3–4), 280–284. [DOI] [PubMed] [Google Scholar]
  21. Francis SM, Kim SJ, Kistner-Griffin E, Guter S, Cook EH, & Jacob S. (2016). ASD and Genetic Associations with Receptors for Oxytocin and Vasopressin-AVPR1A, AVPR1B, and OXTR. Front Neurosci, 10, 516. 10.3389/fnins.2016.00516 [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Gregory SG, Connelly JJ, Towers AJ, Johnson J, Biscocho D, Markunas CA, Lintas C, Abramson RK, Wright HH, & Ellis P. (2009). Genomic and epigenetic evidence for oxytocin receptor deficiency in autism. BMC Medicine, 7(1), 1–13. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Gretscher H, Tempelmann S, Haun DB, Liebal K, & Kaminski J. (2017). Prelinguistic human infants and great apes show different communicative strategies in a triadic request situation. PLoS One, 12(4), e0175227. 10.1371/journal.pone.0175227 [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Guevara EE, Hopkins WD, Hof PR, Ely JJ, Bradley BJ, & Sherwood CC (in press). Epigenetic ageing of the prefrontal cortex and cerebellum in humans and chimpanzees. Epigenetics. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Hammock EA, & Young LJ (2006). Oxytocin, vasopressin and pair bonding: implications for autism. Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences, 361(1476), 2187–2198. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Hopkins WD, Keebaugh AC, Reamer LA, Schaeffer J, Schapiro SJ, & Young LJ (2014a, Jan 20). Genetic influences on receptive joint attention in chimpanzees (Pan troglodytes). Sci Rep, 4, 3774. 10.1038/srep03774 [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Hopkins WD, Keebaugh AC, Reamer LA, Schaeffer J, Schapiro SJ, & Young LJ (2014b). Genetic influences on receptive joint attention in chimpanzees (Pan troglodytes) . Scientific Reports 4(3774), 1–7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Hopkins WD, & Latzman RD (2021). Role of Oxytocin and Vasopressin V1a Receptor Variation on Personality, Social Behavior, Social Cognition, and the Brain in Nonhuman Primates with a Specific Emphasis in Chimpanzees. In Wilcznyski W& Brosnan SF(Eds.), Social Cooperation and Conflict: Biological Mechanisms at the Interface (pp. 134–160). Cambrdige University Press. [Google Scholar]
  29. Hopkins WD, Mulholland MM, Reamer LA, Mareno MC, & Schapiro SJ (2020, May 4). The role of early social rearing, neurological, and genetic factors on individual differences in mutual eye gaze among captive chimpanzees. Sci Rep, 10(1), 7412. 10.1038/s41598-020-64051-y [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Hopkins WD, Russell JL, McIntyre JM, & Leavens DA (2013). Are chimpanzees really so poor at understanding imperative pointing? Some new data and an alternative view of canine and ape social cognition. PlosOne, 8(11), e79338. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Jones JH (2011, Sep 27). Primates and the evolution of long, slow life histories. Curr Biol, 21(18), R708–717. 10.1016/j.cub.2011.08.025 [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Jones W, & Klin A. (2013, Dec 19). Attention to eyes is present but in decline in 2–6-month-old infants later diagnosed with autism. Nature, 504(7480), 427–431. 10.1038/nature12715 [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Leavens DA, & Hopkins WD (1998). Intentional communication by chimpanzee (Pan troglodytes): A cross-sectional study of the use of referential gestures. Developmental Psychology, 34, 813–822. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2080769/pdf/nihms30897.pdf [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Leavens DA, Hopkins WD, & Bard KA (2008). The heterochronic origins of explicit reference. In Zlatev J, Racine TP, Sinha C, & Itkonen E. (Eds.), The shared mind: Perspective on intersubjectivity (pp. 187–214). John Benjamins. [Google Scholar]
  35. Leavens DA, Hopkins WD, & Thomas R. (2004). Referential communication by chimpanzees (Pan troglodytes). Journal of Comparative Psychology, 118, 48–57. [DOI] [PubMed] [Google Scholar]
  36. Leavens DA, Hostetter AB, Wesley MJ, & Hopkins WD (2004). Tactical use of unimodal and bimodal communication by chimpanzees, Pan troglodytes. Animal Behaviour, 67, 467–476. [Google Scholar]
  37. Leavens DA, & Racine TP (2009). Joint attention in apes and humans: Are humans unique? . Journal of Consciousness Studies, 16, 240–267. [Google Scholar]
  38. Leavens DA, Reamer LA, Mareno MC, Russell JL, Wilson DC, Schapiro SJ, & Hopkins WD (2015). Distal communication by chimpanzees (Pan troglodytes): Evidence for common ground? Child Development, 86(5), 1623–1638. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Leavens DA, Russell JL, & Hopkins WD (2005). Intentionality as measured in the persistence and elaboration of communication by chimpanzees (Pan troglodytes). Child Development, 76(1), 291–306. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Leigh SR (2004, Mar). Brain growth, life history, and cognition in primate and human evolution. American Journal of Primatology, 62(3), 139–164. 10.1002/ajp.20012 [DOI] [PubMed] [Google Scholar]
  41. Liebal K, Pika S, Call J, & Tomasello M. (2004). To move or not to move: how apes adjust to the attentional state of others. Interaction Studies, 5, 199–219. [Google Scholar]
  42. Liszkowski U, Carpenter M, Henning A, Striano T, & Tomasello M. (2004). Twelve-month-olds point to share attention and interest. Developmental Science, 7, 297–307. [DOI] [PubMed] [Google Scholar]
  43. Liszkowski U, Schafer M, Carpenter M, & Tomasello M. (2009, May). Prelinguistic infants, but not chimpanzees, communicate about absent entities. Psychological science, 20(5), 654–660. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19476595 https://journals.sagepub.com/doi/pdf/10.1111/j.1467-9280.2009.02346.x [DOI] [PubMed] [Google Scholar]
  44. LoParo D, & Waldman ID (2014). The oxytocin receptor gene (OXTR) is associated with autism spectrum disorder: a meta-analysis. Molecular psychiatry, advanced online publication. [DOI] [PubMed] [Google Scholar]
  45. Lord C, & Spence SJ (2006). Autism spectrum disorders: Phenotype and diagnosis. In Moldin SO & Rubenstein JLR(Eds.), Understanding Autism: From Basic Neuroscience to Treatment. CRC Press. [Google Scholar]
  46. MacLean EL, & Hare B. (2013). Spontaneous triadic engagement in bonobos (Pan paniscus) and chimpanzees (Pan troglodytes) Journal of Comparative Psychology, 127(3), 245–255. [DOI] [PubMed] [Google Scholar]
  47. Maud C, Ryan J, McIntosh JE, & Olsson CA (2018). The role of oxytocin receptor gene (OXTR) DNA methylation (DNAm) in human social and emotional functioning: a systematic narrative review. BMC psychiatry, 18(1), 1–13. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Melke J. (2008). Autism: Which genes are involved?. Clinical Neuropsychiatry, 5(1), 63–69. [Google Scholar]
  49. Menzel EW, Davenport RK, & Rogers CM (1970). The development of tool using in wild-born and restriction-reared chimpanzees. Folia Primatologica, 12(4), 273–283. [DOI] [PubMed] [Google Scholar]
  50. Moerkerke M, Bonte M-L, Daniels N, Chubar V, Alaerts K, Steyaert J, & Boets B. (2021). Oxytocin receptor gene (OXTR) DNA methylation is associated with autism and related social traits–A systematic review. Research in Autism Spectrum Disorders, 85, 101785. [Google Scholar]
  51. Morales M, Mundy P, Delgado CEF, Yale M, Messinger D, Neal R, & Schwartz HK (2000). Responding to joint attention across the 6-through 24-month age period and early language acquisition Journal of Applied Developmental Psychology, 21(3), 283–298. [Google Scholar]
  52. Mulholland MM, Navabpour SV, Mareno MC, Schapiro SJ, Young LJ, & Hopkins WD (2020). AVPR1A variation is linked to gray matter covariation in the social brain network of chimpanzees. Genes, Brain and Behavior, 19, e12631. 10.1111/gbb.12631 [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Mundy P. (2018, Mar). A review of joint attention and social-cognitive brain systems in typical development and autism spectrum disorder. Eur J Neurosci, 47(6), 497–514. 10.1111/ejn.13720 [DOI] [PubMed] [Google Scholar]
  54. Mundy P, Block J, Delgado C, Pomares Y, Van Hecke AV, & Parlade MV (2007). Individual differences and the development of joint attention in infancy. Child Development, 78(3), 938–954. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Mundy P, & Bullen J. (2021). The Bidirectional Social-Cognitive Mechanisms of the Social-Attention Symptoms of Autism. Front Psychiatry, 12, 752274. 10.3389/fpsyt.2021.752274 [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Osterling JA, Dawson G, & Munson JA (2002). Early recognition of 1-year-old infants with autism spectrum disorders versus mental retardation. Development and psychopathology, 14, 239–251. [DOI] [PubMed] [Google Scholar]
  57. Poss SR, Kuhar C, Stoinski TS, & Hopkins WD (2006). Differential use of attentional and visual communicative signaling by orangutans (Pongo pygmaeus) and gorillas (Gorilla gorilla) in response to the attentional status of a human. American Journal of Primatology, 68, 978–992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. Rijlaarsdam J, van IJzendoorn MH, Verhulst FC, Jaddoe VW, Felix JF, Tiemeier H, & Bakermans-Kranenburg MJ (2017). Prenatal stress exposure, oxytocin receptor gene (OXTR) methylation, and child autistic traits: the moderating role of OXTR rs53576 genotype. Autism Research, 10(3), 430–438. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. Siu MT, Goodman SJ, Yellan I, Butcher DT, Jangjoo M, Grafodatskaya D, Rajendram R, Lou Y, Zhang R, & Zhao C. (2021). DNA methylation of the oxytocin receptor across neurodevelopmental disorders. Journal of autism and developmental disorders, 51(10), 3610–3623. [DOI] [PubMed] [Google Scholar]
  60. Skuse DH, & Gallagher L. (2011, 2011/05/01). Genetic Influences on Social Cognition. Pediatric Research, 69(8), 85–91. 10.1203/PDR.0b013e318212f562 [DOI] [PubMed] [Google Scholar]
  61. Skuse DH, Lori A, Cubelis JF, Lee I, Conneely KN, Puura K, Lehtimaki T, Binder EB, & Young LJ (2014). Common polymorphism in the oxytocin receptor gene (OXTR) is associated with human social recognition skills. Proceedings of the National Academcy of Sciences, 111(5), 1987–1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  62. Staes N, White CM, Guevara EE, Eens M, Hopkins WD, Schapiro SJG,SJM, Sherwood CC, & Bradley BJ (in press). Chimpanzee extraversion scores vary with epigenetic modification of dopamine receptor gene D2 (DRD2) and early rearing conditions. Epigenetics. [DOI] [PMC free article] [PubMed] [Google Scholar]
  63. Stavropoulos KK, & Carver LJ (2013). Research review: social motivation and oxytocin in autism–implications for joint attention development and intervention. Journal of Child Psychology and Psychiatry, 54(6), 603–618. [DOI] [PMC free article] [PubMed] [Google Scholar]
  64. Sullivan M, Finelli J, Marvin A, Garrett-Mayer E, Bauman M, & Landa R. (2007). Response to joint attention in toddlers at risk for autism spectrum disorder: A prospective study. Journal of autism and developmental disorders, 37, 37–48. [DOI] [PubMed] [Google Scholar]
  65. Tanner JE, & Byrne RW (2010, Jul). Triadic and collaborative play by gorillas in social games with objects. Anim Cogn, 13(4), 591–607. 10.1007/s10071-009-0308-y [DOI] [PubMed] [Google Scholar]
  66. Tomasello M. (2008). Origins of human communication. MIT Press. [Google Scholar]
  67. Tops M, Van Ijzendoorn MH, Riem MM, Boksem MA, & Bakermans-Kranenburg MJ (2011). Oxytocin receptor gene associated with the efficiency of social auditory processing. Frontiers in psychiatry, 2, 60. [DOI] [PMC free article] [PubMed] [Google Scholar]
  68. Tost H, Champagne FA, & Meyer-Lindenberg A. (2015, Oct). Environmental influence in the brain, human welfare and mental health. Nat Neurosci, 18(10), 1421–1431. 10.1038/nn.4108 [DOI] [PubMed] [Google Scholar]
  69. Turner CH, Davenport RK, & Rogers CM (1969). The effects of early deprivation on the social behavior of adolescent chimpanzees American Journal of Psychiatry, 125, 1531–1536. [DOI] [PubMed] [Google Scholar]
  70. Wade M, Hoffmann T, Wigg K, & Jenkins J. (2014). Association between the oxytocin receptor (OXTR) gene and children’s social cognition at 18 months. Genes, Brain and Behavior, 13(7), 603–610. [DOI] [PubMed] [Google Scholar]
  71. Wade M, Hoffmann TJ, Wigg K, & Jenkins JM (2014). Association between the oxytocin receptor (OXTR) gene and children’s social cognition at 18 months. Genes, Brain and Behavior, 13, 603–610. [DOI] [PubMed] [Google Scholar]
  72. Whalen C, Schreibman L, & Ingersoll B. (2006). The collateral effect of joint attention training on social initiations, positive affect, imitation, and spontaneous speech in young children with autism. Journal of autism and developmental disorders, 36, 655–664. [DOI] [PubMed] [Google Scholar]
  73. Wilczyński KM, Siwiec A, & Janas-Kozik M. (2019, 2019-May-31). Systematic Review of Literature on Single-Nucleotide Polymorphisms Within the Oxytocin and Vasopressin Receptor Genes in the Development of Social Cognition Dysfunctions in Individuals Suffering From Autism Spectrum Disorder [Systematic Review]. Frontiers in psychiatry, 10. 10.3389/fpsyt.2019.00380 [DOI] [PMC free article] [PubMed] [Google Scholar]
  74. Yang SY, Kim S, Hur GM, Park M, Park J-E, & Yoo HJ (2017). Replicative genetic association study between functional polymorphisms in AVPR1A and social behavior scales of autism spectrum disorder in the Korean population. Molecular autism, 8(1), 1–10. [DOI] [PMC free article] [PubMed] [Google Scholar]
  75. Yirmiya N, Gamliel I, Pilowsky T, Feldman R, Baron-Cohen S, & Sigman M. (2006, May). The development of siblings of children with autism at 4 and 14 months: social engagement, communication, and cognition. J Child Psychol Psychiatry, 47(5), 511–523. 10.1111/j.1469-7610.2005.01528.x [DOI] [PubMed] [Google Scholar]
  76. Yirmiya N, Rosenberg C, Levi S, Salomon S, Shulman C, Nemanov L, Dina C, & Ebstein R. (2006). Association between the arginine vasopressin 1a receptor (AVPR1a) gene and autism in a family-based study: mediation by socialization skills. Molecular psychiatry, 11(5), 488–494. [DOI] [PubMed] [Google Scholar]
  77. Zhang R, Zhang HF, Han JS, & Han SP (2017, Apr). Genes Related to Oxytocin and Arginine-Vasopressin Pathways: Associations with Autism Spectrum Disorders. Neurosci Bull, 33(2), 238–246. 10.1007/s12264-017-0120-7 [DOI] [PMC free article] [PubMed] [Google Scholar]
  78. Zwaigenbaum L, Bryson S, Rogers T, Roberts W, Brian J, & Szatmari P. (2005). Behavioral manifestations of autism in the first year of life. International Journal of Developmental Neuroscience, 23, 143–152. [DOI] [PubMed] [Google Scholar]

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