bioRxiv preprint doi: https://doi.org/10.1101/439869; this version posted February 1, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license.

1 Converging roles of glutamate receptors in

2 domestication and prosociality

1,2 1,2,3 3 Thomas O’Rourke and Cedric Boeckx

1 4 Universitat de Barcelona 2 5 Universitat de Barcelona Institute of Complex Systems 3 6 ICREA

7 February 1, 2019

8 Abstract

9 The present paper highlights the prevalence of signals of positive selec- 10 tion on genes coding for glutamate receptors—most notably kainate and 11 metabotropic receptors—in domesticated animals and anatomically mod- 12 ern humans. Relying on their expression in the central nervous system 13 and phenotypes associated with mutations in these genes, we claim that 14 regulatory changes in kainate and metabotropic receptor genes have led 15 to alterations in limbic function and Hypothalamic-Pituitary-Adrenal axis 16 regulation, with potential implications for the emergence of unique social 17 behaviors and communicative abilities in (self-)domesticated species.

18 1 Introduction

19 Under one account of recent human evolution, selective pressures on prosocial

20 behaviors led not only to a species-wide reduction in reactive aggression and the

21 extension of our social interactions [1,2], but also left discernible physical mark-

22 ers on the modern human phenotype, including our characteristically “gracile”

23 anatomy [3, 4].

24 It has long been noted that these morphological differences resemble those

25 of domesticated species when compared with their wild counterparts [5]. Ex-

26 perimental observation of domestication unfolding in wild farm-bred silver foxes

27 has unequivocally shown that selection for tameness alone can affect develop-

28 mental trajectories to bring about a suite of physiological and behavioral traits

29 indicative of the “domestication syndrome” [6]. This raises the possibility that

30 morphological changes in Homo sapiens resulted from selective pressures on

31 reduced reactivity to encounters with conspecifics. In turn, this predicts over-

32 lapping regions of selection and convergent physiological effects in the genomes

33 of domesticated species and modern humans.

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34 In a recent comparative study, we have shown that genes with signals of

35 positive selection pooled across different domesticated species — dog, cattle,

36 cat, and horse — have above-chance overlap with genes exhibiting signals of

37 selection in AMH, suggestive of convergent evolutionary processes [4]. Signals

38 on glutamate receptor genes were identified more consistently than any other

39 gene class across human and domesticate selective-sweep studies, and will be

40 the focus of this paper.

41 Glutamate is the primary excitatory neurotransmitter in the vertebrate ner-

42 vous system, essential for fast synaptic transmission and plasticity, learning,

43 memory, and modulation of Hypothalamic-Pituitary-Adrenal (HPA) activity.

44 [7]. The 26 glutamate receptors are primarily localized at synaptic nerve ter-

45 minals in the brain and are divisible into two broad families (ionotropic and

46 metabotropic). There are various widely used names for each receptor and

47 corresponding gene in the literature. For ease of reference, see Table 1.

Ionotropic NMDA AMPA Kainate HUGO Aliases HUGO Aliases HUGO Aliases GRIN1 NR1 GluN1 GRIA1 GLUR1 GLUA1 GRIK1 GLUR5 GLUK1 GRIN2A NR2A GluN2A GRIA2 GLUR2 GLUA2 GRIK2 GLUR6 GLUK2 GRIN2B NR2B GluN2B GRIA3 GLUR3 GLUA3 GRIK3 GLUR7 GLUK3 GRIN2C NR2C GluN2C GRIA4 GLUR4 GLUA4 GRIK4 KA1 GLUK4 GRIN2D NR2D GluN2D GRIK5 KA2 GLUK5 GRIN3A NR3A GluN3A GRIN3B NR3B GluN3B Delta GRID1 GLUD1 GRID2 GLUD2

Metabotropic Group I Group II Group III HUGO Aliases HUGO Aliases HUGO Aliases GRM1 mGluR1 mGlu1 GRM2 mGluR2 mGlu2 GRM4 mGluR4 mGlu4 GRM5 mGluR5 mGlu5 GRM3 mGluR3 mGlu3 GRM6 mGluR6 mGlu6 GRM7 mGluR7 mGlu7 GRM8 mGluR8 mGlu8

Table 1: Glutamate receptors. (Throughout the present study we use HUGO nomen- clature to refer to both receptor genes and proteins.)

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48 Given their importance for the normal functioning of the organism, glu-

49 tamate receptors are rarely subject to extensive structural changes from one

50 species to the next [8,9]. Despite this high structural conservation, there are

51 significant differences between humans and chimpanzees in the cortical expres-

52 sion of glutamate receptor genes [10, 11], suggesting that changes to regulatory

53 regions may have had important functional consequences for the emergence of

54 the human cognitive phenotype. Similarly, the vast majority of selective sweeps

55 or high-frequency changes on glutamate receptor genes in AMH relative to ar-

56 chaic Homo are found in regulatory regions that control gene expression [12, 13].

57 Like the tameness of domesticates towards carers, prosociality among hu-

58 mans necessitates a reduction in fearful and aggressive reactions to encounters

59 with conspecifics. Fear, anxiety, and aggression are stress responses, mediated

60 across vertebrates by the hypothalamic-pituitary-adrenal (HPA) axis [14, 15],

61 the hypofunction of which has been proposed to be a key mechanism in the

62 development of tame behaviors in domesticates [16, 17]. Here we articulate

63 the hypothesis that increased modulatory actions of glutamate receptors have

64 brought about attenuation of the HPA stress response in ours and domesti-

65 cated species. We first characterize the extent to which certain (sub)families

66 of glutamate receptor genes exhibit shared signals of selection in domesticates

67 and modern humans, comparing these with genes for other neurotransmitter

68 and nuclear hormone receptors. We then discuss the likely functional implica-

69 tions of these changes with reference to gene expression data and evidence from

70 developmental and psychiatric disorders.

71 2 Results

72 In earlier work, we have pointed out the intersection of glutamate receptor genes

73 showing signals of selection in humans, dogs, cats, cattle, and horses [4]. Here

74 we take into account a much broader range of human and domestication studies

75 showing changes in AMH, dogs, cats, cattle, horses, foxes, sheep, pigs, rabbits,

76 yaks, goats, guinea pigs, chickens, and ducks. We compare changes on the 26

77 glutamate receptor genes with those for genes encoding 462 other receptors from

78 equivalent classes (G-protein coupled receptors and ligand-gated ion channels),

79 as well the other major receptor superfamilies in the central nervous system

80 with potential relevance to domestication events (receptor kinases and nuclear

81 hormone receptors; see Supplementary Table S1)

82 Although we focus here on signals of selection on glutamate receptor genes,

83 changes to other glutamatergic signaling genes have also been identified in mod-

84 ern human and domestication studies. These include glutamate transporter,

85 accessory subunit, and related G-protein signaling cascade genes. We review

86 some of the most noteworthy of these in Supplementary Section S1.

87 At least one glutamate receptor gene shows signals of selection in all of

88 the species in Table 2. Overlapping signals of selection were most consistently

89 detected on kainate and Group II and III metabotropic receptor genes across

90 modern human and animal domestication studies (see Table 2 and Figure 1).

3 bioRxiv preprint certified bypeerreview)istheauthor/funder,whohasgrantedbioRxivalicensetodisplaypreprintinperpetuity.Itmadeavailableunder

AMH Dog Cattle Cat Horse Fox Yak Sheep Goat Pig Rabbit Guinea Pig Chicken Duck

[12, 13, 18, 19, 20, 21][22, 23, 24, 25, 26][27][28][29][30, 31][32, 33][34][35, 36, 37][38, 39, 40][41][42][43][44] doi: GRIN1 https://doi.org/10.1101/439869 GRIN2A q GRIN2B p q GRIN2C p GRIN2D u v GRIN3A u q u GRIN3B GRIA1 u GRIA2 u u u a

GRIA3 ; CC-BY-NC-ND 4.0Internationallicense this versionpostedFebruary1,2019. GRIA4 q GRIK1 GRIK2 uv q u u GRIK3 u uuuuu u q u GRIK4 p GRIK5 uup GRM1 u GRM2 uup GRM3 uu p GRM4 q v GRM5 The copyrightholderforthispreprint(whichwasnot GRM6 p p . GRM7 p u u GRM8 u u u uu GRID1 u GRID2 u

Table 2: Signals of selection, high-frequency changes, introgression, and differential expression of glutamate receptor genes in AMH and domesticated species. u Selective sweep study identifying differences between AMH and archaics or domesticates and their wild ancestors p High frequency changes differentiating AMH and archaics or domesticates and their wild ancestors v Differential brain expression between domesticated species and wild ancestors q Introgression study bioRxiv preprint doi: https://doi.org/10.1101/439869; this version posted February 1, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license.

GRM II/III 13

12 GRIK 11 GRM8 Glutamate 10

Serotonin 9

8 Adrenergic GRM7 7 Cholinergic GRIK3 6 GRIN3A

GABA of species No. 5 GRM6

Vasopressin/Oxytocin 4

3 GRM4 GRIN2D Purinergic 2 GRIK2 Dopamine GRIA2 1 GRM3 GRIN2B

Neuropeptides 0

0.0 0.5 1.0 1.5 2.0 GRM GRIK GRIN GRIA Mean signal per gene

(a) (b) Figure 1: Signals of selection, introgression, high-frequency changes, or expression dif- ferences on abundant neurotransmitter receptor and glutamate receptor genes, plotted by gene group. For full comparisons of receptor types, see supplementary Table S1 (a): Comparison of mean signals across major receptor types (b): Number of species for which signals are detected in at least two species per glutamate receptor gene.

91 Out of the thirty-two instances where differences were detected on function-

92 ing ionotropic glutamate receptor genes (NMDA, AMPA, or kainate), eighteen

93 were detected among the kainate receptor genes, and fourteen of these occurred

94 either on GRIK2 or GRIK3. GRIK3 exhibits signals of selection in modern

95 humans, dogs, cattle, sheep, and of introgression in yaks, while GRIK2 shows

96 signals of selection in dogs (accompanied by increased brain expression as com-

97 pared with wolves), rabbits, and ducks, and of introgression in yaks.

98 Metabotropic receptors are the other major subclass of glutamate receptor

99 genes that display consistently convergent signals among domesticated species

100 and modern humans, with members of Group II (GRM2 and GRM3 ) and, in

101 particular, Group III (GRM4, GRM6, GRM7, and GRM8 ) exhibiting signals

102 of selection across domesticate and human selective-sweep studies. Signals on

103 GRM8 have been detected in dogs, sheep, pigs, and humans. Relative to Ne-

104 anderthals and Denisovans, modern humans show signals of selection on GRM2

105 and GRM3 (this latter gene detected on both the Yoruba and KhoeSan branches

106 of our lineage).

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107 Eighteen out of the nineteen instances where signals of selection, expression

108 differences, high-frequency missense changes, or introgression were detected on

109 metabotropic glutamate receptor genes, these occurred in Group II or Group

110 III subfamilies. The only exception to this pattern is the detection of a selective

111 sweep on GRM1 in the chicken. Group II and III metabotropic receptors share

112 structural and functional similarities, which differentiate them from Group I

113 receptors. Most strikingly, Group II and III receptor subunits can form func-

114 tional heterodimers with each other across subfamilies, while they are unable to

115 do so with Group I subunits [45]. Moreover, activation of Group II and III re-

116 ceptors primarily inhibits adenylyl-cyclase signaling, whereas Group I receptors

117 potentiate this signaling cascade [46]. These facts suggest that Group II and III

118 metabotropic receptors form a class that is mechanistically distinct from Group

119 I. This, in turn, raises the possibility that signals of selection across these two

120 subfamilies may be instances of convergent evolutionary processes.

121 For the comparison between the 488 receptor genes and their relevant (sub)

122 families, we considered a gene to potentially be implicated in a domestication

123 event or in modern human evolution (to exhibit a ‘signal’) if it was identified in

124 at least one of the studies in Table 2. Detection of a single gene across different

125 studies of a single species were counted as a one signal, leaving a total of 401

126 putative signals detected across the 488 genes (a receptor-wide mean of 0.82

127 signals per gene). Receptor genes were subdivided into 106 distinct multigene

128 families (or 114 when subfamily divisions were included).

129 Group III metabotropic receptor genes exhibited signals at a rate higher

130 than those of any other multigene receptor (sub)families (mean of 2.75 sig-

131 nals per gene), including receptor genes for the most abundant neurotrans- 132 mitters in the brain, such as GABA (mean: 0.76; GABAA Beta mean: 1.33; 133 GABAB mean: 1.5), serotonin (mean: 0.83; HTR2 family: 1.33), dopamine 134 (mean: 0.6), (nor)epinephrine (mean: 0.78), or acetylcholine receptors (mean:

135 0.77). In general, signals on these receptor gene families tended to track the

136 neurotransmitter-wide average of 0.82. Signals on kainate receptor genes oc-

137 curred at a rate considerably higher than any of the above (sub)families (mean:

138 2.2). Of the 114 multigene (sub)families examined, only corticosteroid receptors

139 (mean: 2.5), and Adhesion G protein-coupled receptor (ADGR) subfamilies B

140 (mean 2.33) and D (mean 2.5) exhibited signals at higher rates (see Table S1).

141 Both the corticosteroid and ADGRD families contain only two receptor

142 genes, meaning that each family had a total of just five signals across the thirty

143 domestication and modern human evolution studies examined here. By contrast,

144 GRIK3 alone exhibited five signals of selection across these studies, and GRIK2

145 four. The small size of the corticosteroid and ADGRD receptor families may

146 well have contributed to the high mean signals highlighted here. To control for

147 this, we carried out a Monte Carlo simulation to determine the chance likelihood

148 that each of the receptor (sub)families under comparison here should the pre-

149 ponderance of signals that they do, given the family size. This analysis showed

150 that the prevalence of signals occurring on metabotropic family III or kainate

151 receptor (sub)families was unlikely to occur by chance (p<0.00001 and p=0.037,

152 respectively). By contrast, the chance likelihood of signals occurring at the rate

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153 they do on receptor families with comparable means (ADGRB, ADGRD, and

154 corticosteroid) was considerably higher (p=0.12, p=0.265, and p=0.265, respec-

155 tively). Given their ability to form functioning heterodimers, Group II and III

156 metabotropic receptors could be considered a single functional subfamily. The

157 fourteen signals occurring across these six genes was highly unlikely to have

158 occurred by chance, given the receptor-wide average (p = 0.003)

159 One-way ANOVA comparisons were carried out among all multigene receptor

160 (sub)families identified here in order to determine if subfamilies with the highest

161 mean signals showed significant divergence from those with lower means. Out of

162 the twenty-two pairwise comparisons that showed significant differences between

163 means, twenty involved metabotropic subfamily III, while the two other signif-

164 icant comparisons involved the kainate receptor family (see Table S2). When

165 one considers that alterations to neurotransmission are highlighted in many of

166 the domestication studies analysed here, these findings suggest that signals on

167 metabotrobic III and kainate receptor (sub)families are, at least, significantly

168 higher than background genome-wide signals of selection under domestication.

169 Averaging across multigene families allows for the identification of conver-

170 gent signals on distinct genes with similar functional properties. However, this

171 does not allow for analysis of single-gene receptor families, and it may also

172 obscure above-chance convergent signals on individual genes within multigene

173 families. GRIK3 was one of only two genes exhibiting changes in five species,

174 the other being ADGRB3 (Likelihood according to Monte Carlo simulation:

175 p=0.004). The ADGRB3 subunit (also known as BAI3), like kainate receptors,

176 is bound by C1ql proteins, modulates excitatory transmission, as per kainate

177 and metabotropic glutamate receptors, and is implicated in similar neurodevel-

178 opmental and stress disorders as genes from these (sub) families [47, 48, 49].

179 GRIK2 and GRM8 were two of only five genes that were identified in four

180 domesticates (including modern humans in the case of GRM8 ) (Likelihood ac-

181 cording to Monte Carlo simulation: p=0.043). KIT, a gene involved in the

182 differentiation of neural crest precursor cells into melanocytes, and important

183 in selection for coat color in domesticated species [17], was also identified in

184 four different species. Three glutamate receptor genes (GRM7, GRIN3A, and

185 GRIA2 ) were identified among the ten genes with changes detected in three

186 species. Functional enrichment (Gene Ontology) analyses of these seventeen

187 genes with signals in three or more species showed glutamate receptor signaling

188 to be the most highly-enriched pathway in the Biological Process category, with

189 glutamatergic activity being in three of the top five pathways highlighted under

190 Molecular Function. An extended functional analysis of the 92 genes showing

191 signals of selection in two or more species highlighted ‘Glutamatergic synapse’

192 as the second most prominent KEGG pathway, behind the more general (and

193 subsuming) category ‘Neuroactive ligand-receptor interaction’.

194 In several of the studies cited in Table 2, signals of selection on glutamate

195 receptor genes have been suggested as potentially important for behavioral

196 changes during the domestication process [23, 27, 28, 29, 30, 39, 44]. How-

197 ever, such suggestions often form part of broader discussion on changes to genes

198 related to the central nervous system (CNS) under domestication, and no mech-

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199 anistic details are provided. Furthermore, discussion is usually limited to high-

200 lighting the potential importance of glutamatergic-signaling changes in learning,

201 memory, or excitatory transmission in a single domesticated species under study,

202 and tends to focus on cortical regions.

203 To our knowledge, no study to date has sought to explore the extent to

204 which glutamate receptor genes show signals of selection across a large number

205 of domesticated species. More significantly, we are unaware of any previous

206 study that has identified kainate and metabotropic receptor genes as the most

207 prevalent targets of selective sweeps under domestication and in recent human

208 evolution. The consistency with which these receptor genes are identified across

209 domestication studies makes them prime candidates for being involved in the

210 emergence of tameness.

211 If an argument is to be made for the convergent involvement of kainate and

212 metabotropic glutamate receptor genes in domesticated tameness and human

213 prosociality, evidence should point to the shared participation of these recep-

214 tors in modulating the stress response across these species. Table 3 summarizes

215 evidence from human, model organism, and animal gene-behavior-correlation

216 studies that kainate and Group II and III metabotropic receptors highlighted

217 here are implicated in developmental, neuropsychiatric, stress, and mood disor-

218 ders, as well as divergent tame and agonistic phenotypes in non-human species.

219 (Detailed discussion of these studies can be found in Supplementary section S2.)

220 Schizophrenia is among the disorders most regularly associated with mu-

221 tations on these metabotropic and kainate receptor genes. In humans, pre-

222 natal stress is a risk factor for the development of schizophrenia in adult off-

223 spring [50, 51]. Pharmacological agonists of Group II metabotropic receptors

224 reduce schizophrenia-like phenotypes in adult offspring of prenatally stressed

225 mice [52]. Furthermore, high glucocorticoid inputs to the hippocampus reduce

226 the expression of kainate receptors, and schizophrenics have been found express

227 significantly reduced kainate receptors in this region [53, 54]. More broadly,

228 heightened stress experienced during pregnancy can lead to a “persistently hy-

229 peractive” HPA axis in offspring, increasing children’s propensity to develop

230 Attention Deficit Hyperactivity Disorder (ADHD), as well as adult anxiety and

231 reactivity to stress, while in rats, prenatal stress decreases the propensity to

232 play in juvenile offspring and impairs sociality and extinction of conditioned

233 fear lasting into adulthood [55, 56, 57].

234 Prenatal stress can, then, contribute to the emergence of the same neurode-

235 velopmental, neuropsychiatric, stress, and mood disorders commonly associated

236 with altered expression of metabotropic and kainate receptor genes. We hy-

237 pothesize that selective sweeps on these genes are markers of convergent posi-

238 tive selection on an attenuated stress response in both ancient modern humans

239 and early domesticated species. We propose that enhanced prenatal modulation

240 by these receptors of stress responses to human contact in (pre-)domesticated

241 and archaic human females provided an important first step in the emergence

242 tameness and prosociality. In section 3, we explore the neurobiological evidence

243 for this proposal, focusing on the roles of kainate and metabotropic glutamate

244 receptors in the stress-response cascade.

8 bioRxiv preprint certified bypeerreview)istheauthor/funder,whohasgrantedbioRxivalicensetodisplaypreprintinperpetuity.Itmadeavailableunder doi: https://doi.org/10.1101/439869 GENE Associated Human phenotypes Tame and aggressive animal phenotypes DD/ID ADHD ASD SCZ BPD OCD ANX MDD SR/Fear Retention of dog-like polymorphisms on GRIK2 GRIK2 * ******** in tame Czechoslovakian Wolf-Dog hybrid [58]

GRIK3 * *** *** Signals of selection on GRIK3 differentiating cattle with agonistic and tame behaviors [59] a ; CC-BY-NC-ND 4.0Internationallicense

GRIK5 * ** * this versionpostedFebruary1,2019.

GRM2 * ** ****

GRM3 * ******* Fixed missense mutation on GRM3 differentiating aggressive from tame foxes [30] GRM4 * *** ***

Lower nucleotide variability on GRM7 in docile GRM7 * ******* Apennine Brown Bear [60] The copyrightholderforthispreprint(whichwasnot .

Lower nucleotide variability on GRM8 in docile GRM8 * *** *** Apennine Brown Bear [60]

Table 3: Human and Domesticated phenotypes associated with kainate and metabotropic receptor genes. Detailed discussion of these associations, including references can be found in Supplementary section S2. DD/ID - Developmental Delay/Intellectual Disability, ADHD - Attention Deficit Hyperactivity Disorder, ASD - Autism Spectrum Disorder, SCZ - Schizophrenia, BPD - Bipolar Dis- order, OCD - Obsessive Compulsive Disorder, ANX - Anxiety Disorder, MDD - Major Depression, SR/Fear - Startle Response/Fear.

Note: Widespread use of non-selective Group II agonists that act on both GRM2 and GRM3 subunits in model organisms makes it difficult to always separate subunit associations with disorders. Where a disorder has been associated with Group II receptors, an asterisk is placed in the row for both GRM2 and GRM3. bioRxiv preprint doi: https://doi.org/10.1101/439869; this version posted February 1, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license.

245 3 Discussion

246 Alterations to the HPA axis are considered to be essential for the emergence

247 of tameness in different (indeed competing) theories of domestication [17, 61].

248 Glutamatergic signaling acts as a prominent regulator of HPA activity and has

249 been identified among the top enriched pathways across studies of aggression [7,

250 62, 63, 64]. The association of kainate and Group II/III metabotropic receptor

251 genes with multiple stress disorders implicates them in altered HPA-axis activity.

252 Given the predominantly modulatory, as opposed to excitatory, functions of

253 both kainate and Group II and III metabotropic receptors [46, 65], we argue

254 that selective sweeps on their respective genes are markers of decreased HPA

255 reactivity in humans and (pre-)domesticated species.

256 Below, we propose a mechanism for how these receptor subfamilies modulate

257 glutamatergic signaling to alter developmental trajectories and, subsequently,

258 the HPA stress response in both humans and domesticated species. Our ar-

259 gument relies on three pieces of evidence: First, that alterations to the HPA

260 axis are common across domesticated species versus their wild counterparts,

261 and in non-reactive versus reactively aggressive humans; second, evidence that

262 the genes highlighted here are extensively expressed in limbic and hypothalamic

263 brain regions crucial for controlling the stress response; and third, evidence that

264 disturbance of this expression alters the stress response.

265 Alterations to the stress response in domesticated species

266 and modern humans

267 In response to stress, corticotrophin releasing hormone (CRH) is synthesized in

268 the paraventricular nucleus (PVN) of the hypothalamus. This induces adreno-

269 corticotrophin (ACTH) release from the anterior pituitary gland, which, in turn,

270 stimulates the release of glucocorticoids (GCs: primarily cortisol and corticos-

271 terone) from the adrenal gland [66]. GCs are “the principal end-products of

272 the HPA axis”, which help to maintain homeostatic balance in the organism

273 [67]. They also provide feedback directly to neurons in the PVN [14, 68], or via

274 other brain regions, particularly limbic structures, including the hippocampus,

275 thereby modulating CRH release and the HPA stress response [69, 67]. Thus,

276 GC measures can be an accurate indicator of stress response in vertebrates, once

277 basal and stress-response measures can be differentiated [70].

278 Domesticated foxes, sheep, bengalese finches, and ducks have lower basal GC

279 levels than their wild ancestors or other closely related wild comparators [71, 72,

280 73, 74, 75, 76, 77]. In the duck and the fox, differences are particularly marked

281 in prenatal and juvenile development, respectively [76, 77, 71]. Compared to

282 their wild ancestors, Guinea pigs and chickens have a lower spike in GCs in

283 response to stress [78, 79]. Although there is no extant ancestral comparator

284 of neuroendocrine function in AMH, our species has considerably lower basal

285 plasma cortisol levels than chimpanzees and most other primates [80].

286 Within the human population, variability in GC levels correlate with dif-

287 ferent individual stress responses, which mirrors findings in laboratory rats.

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288 Acute GC increases accompany bouts of reactive aggression, while chronically

289 high basal levels have been found to correlate with increased anxiety and ma-

290 jor depression, and may be implicated in reduced aggressive tendencies [15].

291 Chronically low GC levels can correlate with antisocial personality disorder,

292 callous, unemotional tendencies, and externalizing behaviors in children, as well

293 as aggressive delinquency in adults. Proactively aggressive or non-aggressive

294 children tend to have a lower spike in GC levels in response to frustrating tasks

295 than reactively aggressive children [81]. Psychopathic adults (who often ex-

296 hibit pathological proactive aggression) tend to have no cortisol reactivity to

297 frustrating tasks [15].

298 The above studies suggest that, from early development into adulthood,

299 lower basal GC levels are shared by domesticates and modern humans relative to

300 closely related extant wild species. Moreover decreased GC spikes in response to

301 stress are common to domesticates and non-aggressive or proactively aggressive

302 modern humans versus reactively aggressive individuals. These findings are

303 consistent with the view that prosocial selective pressures have led to a reduction

304 in reactive over and above proactive aggression in recent human evolution [1]. It

305 could be considered that proactive aggressors within modern human populations

306 exhibit a pathological version of the non-reactive phenotype that has been under

307 positive selection and is associated with HPA-axis hypofunction under stress.

308 Kainate and metabotropic receptor expression in brain re-

309 gions crucial for HPA regulation

310 The HPA axis is centrally regulated by the limbic system, primarily through

311 amygdalar processing of perceptual inputs, which are relayed via the bed nu-

312 cleus of the stria terminalis (BNST) to the paraventricular nucleus (PVN) in the

313 hypothalamus. The limbic system also mediates feedback mechanisms, whereby

314 glucocorticoids and mineralocorticoids act upon receptors in the hippocampus

315 and medial prefrontal cortex, which connect to the PVN via the BNST and

316 lateral septum. Feedback also occurs directly on cells in the PVN to modu-

317 late HPA reactivity. Feedforward mechanisms, further potentiating the stress

318 response, are relayed from the amygdala to the PVN via the BNST. [82, 69, 68].

319 Glutamatergic and GABAergic signaling are the central mediators of each

320 of these aspects of HPA (re)activity, and the kainate and metabotropic receptor

321 subfamilies discussed here play prominent roles in modulating release of both

322 neurotransmitters. These receptors are extensively expressed in limbic regions

323 crucial for modulating the stress response. Figure 2 highlights these expression

324 patterns, including both Group II and III metabotropic receptors, given their

325 shared structural and functional properties. A detailed overview of what is

326 known about kainate and Group II and III metabotropic receptor expression

327 in the developing and adult brain can be found in Supplementary section S3.

328 In the subsection that follows, we propose a mechanism by which metabotropic

329 and kainate receptors modulate, and are modulated by, HPA activity.

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Figure 2: Kainate and metabotropic receptor expression in brain regions crucial for HPA regulation. (Most detailed brain-expression data come from rodent studies. Where available, we have used data from human fetal or postmortem studies. Broadly, there are cross-species parallelisms in kainate and metabotropic expression. Similarities and differences are discussed in Supplementary section S3.) bioRxiv preprint doi: https://doi.org/10.1101/439869; this version posted February 1, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license.

330 Control of HPA function by metabotropic and kainate glu-

331 tamate receptors

332 The PVN is the crucial hypothalamic mediator of psychogenic stressors that

333 drive HPA activity. Glutamate acting directly on parvocellular neurons of the

334 PVN stimulates CRH release, whereas GABA inhibits this [7]. This means

335 that modulation of glutamatergic signaling by both kainate and metabotropic

336 glutamate receptors may serve to inhibit direct activation of the PVN.

337 GRIK2, GRIK3, and GRIK5 are all expressed in the PVN and surround-

338 ing regions in adult rats, although GRIK1 is the most abundantly expressed

339 kainate receptor subunit mRNA in the PVN proper [83]. GRIK5 is extensively

340 expressed on parvocellular neurons [84]. Presynaptic activation of GRIK1 sub-

341 units in the PVN has been shown to modulate HPA activity by inhibiting CRH

342 from parvocellular neurons [62]. Similarly, agonism of presynaptic kainate re-

343 ceptors in hypothalamic neurons facilitates inhibitory GABAergic signaling [85].

344 In vitro antagonism of Group II metabotropic receptors in hypothalamic

345 slices has been shown to increase CRH signaling, whereas no other metabotropic

346 receptor agonists or antagonists had this effect. Mice administered with Group

347 II antagonists in vivo experienced an increase in corticosterone that mimicked

348 the response to the forced-swim (behavioral despair) test [86]. Given the pre-

349 dominant presynaptic and glial modulatory functions of Group II receptors, the

350 above evidence implicates Group II receptors in the attenuation of central gluta-

351 matergic inputs to the hypothalamus (likely in the PVN), attenuating the HPA

352 stress response. Group III metabotropic receptors have also been implicated

353 in modulating excitatory inputs to the lateral hypothalamus [87], while Group

354 I metabotropic receptors stimulate both oxytocin and vasopressin release from

355 the SON [88].

356 Agonism of Group II metabotropic receptors disrupts the fear-potentiated

357 startle response in mice, suggesting that these receptors regulate the learning

358 of fearful experiences [89]. Knockout of GRM2 has been shown to correlate

359 with increased stress in social interactions [90]. In macaques captured from

360 the wild, six-week chronic intravenous administration of a Group II agonist

361 reduced basal cortisol levels by as much as 50% compared to controls [91]. This

362 same agonist has been shown to act on GRM3 receptors in adrenal gland cells,

363 leading to a reduction in aldosterone and cortisol via inhibition of the adenylyl

364 cyclase / cAMP signaling pathway [92]. Yet another Group II agonist attenuates

365 aggressive tendencies, hyperactivity, and deficits in the inhibition of the startle

366 response of mice reared in isolation [93]

367 It has been proposed that Group II metabotropic receptors in the central

368 amygdala dampen the stress response by modulating the release of glutamate,

369 in turn leading to an increase in GABAergic signaling and overall dampen-

370 ing of excitatory inputs to the PVN. Agonism of these receptors also leads to

371 an increase in activity in the predominantly inhibitory BNST, and in the the

372 PVN in response to stress, suggesting modulation of the HPA by suppression

373 of excitatory signaling. At the same time, activation of Group II receptors is

374 downregulated in the hippocampus [94]. Excitatory feedback outputs from the

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375 hippocampus likely act on inhibitory neurons of the BNST that, in turn, relay

376 to the hypothalamus [82]. Thus, decreased Group II modulation of these out-

377 puts in response to stress can have the effect of enabling increases of inhibitory

378 signals to dampen the HPA cascade. Within the BNST itself, activation Group

379 II and III receptors has been shown to suppress excitatory transmission [95].

380 Mice lacking the Group III receptor GRM8 display increased age- and sex-

381 dependent anxiety-like behaviors and startle response [96, 97]. However, in con-

382 trast to GRM2, knockout of GRM8 can enhance social interactions, suggesting

383 that this receptor has opposing effects depending on the nature of the stressor.

384 In another contrast with GRM2 and the Group II subfamily as a whole, ablation

385 of GRM7 can make mice less fearful and less aggressive [98, 99, 100] correlat-

386 ing with a severe reduction in neuronal activity in the BNST. This suggests

387 that GRM7 serves to enhance overall excitability of BNST neurons project-

388 ing to the PVN (and thus the stress response), perhaps through modulation of

389 glutamatergic release innervating GABA inhibitory interneurons [100]. Activa-

390 tion of GRM4 reduces anxiety-like behaviors in mice, while knockout enhances

391 fear-conditioning responses and increases anxiety in adult but not juvenile mice

392 [101]. Such anxiety-related effects are thought to be brought about by alter-

393 ations to amygdalar function, whereby either excitatory or inhibitory signaling

394 is modulated by Group III receptors.

395 Although the above behavioral correlates of Group II and III receptor (ant-)

396 agonism and ablation are partially contrasting, they indicate that both sub-

397 families are important for modulating the stress response, including aggressive

398 reactivity. This tendency is clear in Group II metabotropic receptors, while the

399 actions of Group III receptors are more varied according to the specific subunits

400 and brain regions activated. Studies in rodents suggest that GRM8 and GRM7

401 have broadly opposite effects on anxiety levels, with GRM8 activation tending

402 to be closer to Group II metabotropic receptors in its anxiolytic effects, while

403 GRM7 seems to be more anxiety- (and aggression-) inducing [102]. This sug-

404 gests that the numerous signals of selection on GRM8 across domesticates and

405 similar signals on Group II receptors in humans may be markers of convergent

406 selection for a decreased stress response. This said, evidence also points more

407 clearly towards activation of Group II receptors in potentiating prosocial behav-

408 iors. Future investigation of differences in brain region expression of Group II

409 and III receptors in domesticated species may help to shed more light on their

410 contributions of each to the modulation of the stress response.

411 The kainate receptors we have examined here are abundantly expressed in

412 limbic regions that modulate HPA-axis function via glucocorticoid (GC) feed-

413 back (in particular the hippocampus and medial prefrontal cortex, but also more

414 moderately in the amygdala [see Figure 2]). GCs promote glutamate release in

415 these feedback regions, and the different affinities of mineralocorticoid recep-

416 tors (MRs; bound by GCs at low concentrations) and glucocorticoid receptors

417 (GRs; bound at higher concentrations) enable the modulation of stress feedback

418 signaling from basal or moderate to acute levels [67, 68].

419 Glucocorticoids differentially modulate the expression of kainate receptor

420 mRNA in the hippocampus depending on whether MRs or GRs are bound [103,

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421 53]. Adrenalectomy (lowering corticosteroid levels) leads to increased expression

422 of GRIK2 in DG and CA3, and of GRIK3 in DG [53] (although no change has

423 also been reported for GRIK2 in CA3 [103]). Single dose treatment with low

424 levels of corticosterone following adrenalectomy — thought to bind MRs —

425 increases GRIK3 and high affinity subunit (GRIK4 and GRIK5 ) mRNA in

426 DG, as well as GRIK5 across the hippocampus [103]. MR binding has been

427 reported both to lower and raise GRIK2 levels in the hippocampus [53, 103].

428 Acute corticosterone treatment in adrenalectomized rats lowers kainate re-

429 ceptor mRNA expression to levels of untreated controls [103]. Similarly, chronic

430 treatment leads to lower expression of GRIK3 and GRIK4 in hippocampal

431 structures, although no changes were noted for GRIK2 or GRIK5 [53]. These

432 divergent MR/GR- mediated patterns of expression can help to elucidate the

433 mechanism by which the genes under selection in domesticates and humans are

434 expressed in a manner that can modulate the stress-induced feedback response.

435 Kainate receptor activation at CA3-CA1 synapses serves to inhibit gluta- 436 mate transmission via Gi/o signaling, especially when synapses are immature. 437 At mossy fiber synapses connecting DG and CA3 (areas of high kainate recep-

438 tor expression throughout life), kainate receptors inhibit glutamatergic signaling

439 when glutamate is released at high levels, while facilitating release at lower lev- 440 els, again via a Gi/o-coupled mechanism [104]. Similar biphasic modulation has 441 been detected in the neocortex and amygdalae of rodents. Thus, when GCs are

442 circulating at low levels, during basal or low stress, MR binding should lead

443 to higher kainate receptor expression and facilitation of glutamatergic signal-

444 ing in feedback regions. At higher GC levels (as when under acute stress) GR

445 binding will tend to reduce kainate receptor expression, thus diminishing these

446 receptors’ potency in modulating glutamate release. In contrast, postsynaptic

447 expression of AMPA and NMDA is enhanced under acute stress and corticos-

448 terone treatment [105].

449 Because there are no direct hippocampal, prefrontal, or amygdalar connec-

450 tions to the PVN, feedback from these regions are instead relayed via the BNST,

451 lateral septum, and ventromedial hypothalamus (VMH), which are all predomi-

452 nantly GABAergic [106, 7]. For the amygdala, which emits primarily inhibitory

453 outputs to intermediary regions, this results in “GABA-GABA disinhibitory”

454 downstream signals, increasing excitatory inputs to the PVN [69]. In the case of

455 kainate receptor expression, which is predominant in the hippocampus and me-

456 dial prefrontal cortex, increased facilitation of glutamate release during basal or

457 low-level stress is likely to primarily innervate GABAergic neurons along path-

458 ways relaying to the PVN. Similarly, downregulation of kainate receptor expres-

459 sion by GR binding during acute stress serves to diminish the alternate modu-

460 latory effect of kainate receptors during intense glutamatergic release. This, in

461 turn, should allow for NMDA and AMPA receptor signaling to be potentiated,

462 leading to a dampening of the HPA stress response, again via the innervation

463 of inhibitory neurons of the BNST, septum and VMH, which relay to the PVN.

464 In contrast to prefrontal and hippocampal feedback regions, the effect of

465 glucocorticoids on parvocellular and magnocellular neurons of the hypothalamus

466 is to downregulate glutamatergic signaling via the release of endocannabinoids,

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467 in turn promoting the release of GABA [107]. Kainate receptors have been

468 implicated in the mobilization of endocannabinoid signaling in distinct brain

469 regions, as well as in the promotion of GABAergic signaling in the PVN [62,

470 108, 109].

471 Figure3 presents a schema of the modulatory actions of metabotropic and

472 kainate receptors in the stress-response cascade.

K mPFC A R mGluR II

Hippocampus

KAR mGluR II

Amygdala

mGluR III mGluR II

mGluR III GRM7 K A Septum K BNST R A R mGluR II / III KAR – Kainate receptor mGluR I/II/III – Metabotropic glutamate receptor family I/II/III Excitatory (glutamate) mGluR I KAR mGluR II Inhibitory (GABA) Modulatory PVN Pituitary Adrenal Gland OXT Hypo- CRH thalamus SON ACTH mGluR I CORT Figure 3: Modulatory Actions of Metabotropic and Kainate Receptors

473 Increased metabotropic and kainate-mediated attenuation of central and

474 feedback stress responses may plausibly have conferred selective advantages in

475 human evolution, not only via the reduction of stress and enabling of prosocial

476 cooperation, but also by enabling subsequent increases in GRIK2, GRIK3, and

477 GRIK5 expression: Firstly, Group II and III metabotropic glutamate receptor

478 modulation of amygdalar fear processing in response to stressors, in combina-

479 tion with kainate and Group II metabotropic receptor inhibition of CRH release

480 in the PVN can lead to a signaling cascade that results in lower glucocorticoid

481 feedback in limbic structures. This, in turn may lead to increased expression

482 of kainate receptors in the hippocampus, prefrontal cortex, and elsewhere, en-

483 abling subsequent selection on improvements in plasticity and learning, as well

484 as further resources for limbic modulation of the stress response.

485 4 Conclusion

486 We have argued here that, on balance, selective pressures have led to a modu-

487 lation of glutamatergic signaling in order to attenuate the HPA stress response,

488 and that this has had the corollary effect of increasing synaptic plasticity in

489 limbic feedback regions that play a crucial role in memory and learning. We

490 have not dealt in detail with G-protein signaling cascades activated by kainate,

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491 Group II, and Group III receptors. A more in-depth view of convergence may

492 be gained by exploring the extent to which the same signaling cascades (in par- 493 ticular Gi/o signaling) are activated in homologous brain regions across species 494 regardless of the receptor subtype initially bound.

495 Given the important roles that serotonin and oxytocin play in promoting

496 social and empathetic behaviors across different species, it has been proposed

497 that convergent tameness in domesticates and prosociality in modern humans

498 is driven by alterations to these systems [3]. The present analysis of modern

499 human-archaic and domesticate-wild differences in glutamatergic receptor genes

500 suggests that any such modifications (particularly to oxytocinergic signaling) are

501 more likely to be dependent on upstream changes to glutamatergic signaling.

502 Glutamate mediates the release of oxytocin and vasopressin from the SON and

503 PVN [110].

504 Serotonin modulates glutamatergic activity in the brain, often inhibiting ex-

505 citatory potentials and stimulating GABAergic inhibitory signaling [111]. This

506 regulation from outside the glutamatergic system could potentially produce

507 comparable modulation of the stress-response to the regulation from within

508 that we propose for metabotropic and kainate receptors. In studies of genetic

509 differences between tame and aggressive foxes, changes to serotonergic signaling

510 accompany those of the glutamatergic system, with genetic changes often po-

511 tentially relevant to both synapses [30, 31]. Similarly, domestication of the pig

512 appears to have involved important changes across both systems [39]. Signals

513 of selection associated with serotonergic signaling have also been identified in

514 a tame strain of rat and the domesticated goat [112, 35]. It should be noted,

515 however, that glutamatergic signaling can also control the release of serotonin

516 from the dorsal raphe nucleus [113].

517 One may reasonably ask whether Group II and III metabotropic and kainate

518 receptors share functional or structural qualities that have made them more

519 likely to come under selection than NMDA, AMPA, or Group I metabotropic

520 receptor (sub)families in domesticate species and modern humans. These recep-

521 tors, particularly NMDA, have been implicated in many disorders and pheno-

522 types reviewed here for metabotropic and kainate receptors [114, 115, 116, 117,

523 118, 119, 120, 63]. Even within receptor families, specific subunits (and combi-

524 nations of them) or splice variants can have diametrically opposing functional

525 properties from others that are nominally similar [121, 122].

526 The similar modulatory properties, overlapping expression patterns, and

527 shared phenotypical associations of those genes that are most consistently de-

528 tected across domestication and modern human studies has led us to hypothesize

529 an overarching role for kainate and Group II and III metabotropic receptors in

530 the modulation of the stress response. However, there is no reason, in principle,

531 why other glutamate receptor families could not have contributed to the emer-

532 gence of tame behaviors. In fact, signals are detected on NMDA receptors in

533 two species for each of GRIN2B (fox and yak), GRIN2D (AMH and fox), and

534 on three species in the case of GRIN3A (AMH, yak, and duck; see Table 2).

535 Each of these genes’ respective subunits are highest expressed during embryonic

536 and early postnatal stages, and have been associated with the maintenance of

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537 immature dendritic spines during development [123] If similar patterns of selec-

538 tion should be detected on NMDA receptors across other domesticates, a case

539 could be feasibly be made for their contributing to the juvenile cognitive phe-

540 notype typically retained by domesticate species into adulthood. On the other

541 hand, the only case of potentially convergent selection on an AMPA receptor

542 gene occurs on GRIA2 (AMH, cat, and pig), which is a crucial AMPA subunit

543 at mature synapses [124].

544 The diversity of roles played by kainate receptors in the CNS, including

545 extensive excitatory, inhibitory, ionotropic, metabotropic, and modulatory ac-

546 tivities [65], provides a wide range of possible functions upon which natural

547 selection can act. Selective pressures seem to have honed varied specializations

548 for kainate receptors in different brain regions. Group II and III metabotropic

549 receptor subunits can have opposing actions within a single brain region, and

550 to stressful stimuli being processed. This suggests that these subunits often

551 have complementary modulatory functions within their subfamilies. Nonethe-

552 less, there are considerable overlaps of function, and these subunits primarily

553 inhibit adenylyl-cyclase signaling. Each receptor subfamily acts, broadly, to

554 dampen stress responses. These overlaps in function undoubtedly contribute to

555 numerous signals of selection being spread across different metabotropic recep-

556 tor genes in distinct species.

557 In the future, it may be worthwhile examining the extent to which the glu-

558 tamatergic changes discussed here could have impacted the vocal abilities of the

559 relevant species, including ours. Although the extent of archaic humans’ vocal-

560 learning abilities is not known, this capacity is highly striatum-dependent, as

561 can be seen in the neurology of Tourette’s syndrome. Glutamatergic signaling

562 alterations in the striatum have been implicated in Tourette’s syndrome, includ-

563 ing genes with AMH-specific changes. Vocal learning deficits in humans who

564 carry a mutation on the FOXP2 gene are thought to arise, in part, from abnor-

565 malities in the striatum [125]. Knock-in experiments of the humanized FOXP2

566 allele in mice have shown the principal structural changes to take place in the

567 striatum, where MSN dendrites are longer and respond to stimulation with in-

568 creased long term depression [126]. FOXP2 is also expressed in glutamatergic

569 projection neurons of the motor cortex and is highly expressed during the de-

570 velopment of corticostriatal and olivocerebellar circuits, important for motor

571 control [126, 127]. Several glutamate receptor genes discussed above, such as

572 GRIK2 and GRM8, have been identified as a transcriptional target of FOXP2 in

573 the developing human brain [128]. Significant changes to glutamatergic expres-

574 sion have also been found in the vocal nuclei of vocal-learning birds, and in the

575 domesticated bengalese finch compared to its its wild ancestor the white-rumped

576 munia [9, 129, 130]. These changes are thought to play a role in the more com-

577 plex singing capabilities of the bengalese finch. Glutamate receptor genes form

578 part of the most highly co-expressed module in the periaqueductal gray of bats,

579 a mammalian species that displays strong evidence of vocal-learning capabilities

580 [131].

581 Finally, an important question arising from the evidence presented above is

582 how glutamatergic involvement in the modulation of the stress response relates

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583 to the hypofunction of the neural crest, proposed to account for the suite of phe-

584 notypic changes that make up the domestication syndrome [17]. At this point,

585 the evidence from selective sweep studies strongly points to the involvement of

586 glutamatergic signaling in domestication. Our comparison of different receptor

587 types does not allow evaluation of arguments that a “mild neurocristopathy"

588 drives the emergence of the domesticated phenotype. One neural crest-related

589 gene (KIT ) was detected in studies of cattle, sheep, pigs, and yaks. This gene

590 is involved in melanocyte differentiation, and evidence points to its importance

591 in selection for coat colour: Signals occurring on KIT in Clydesdale horses and

592 Birman cats have been implicated in their breed-specific coat patters [29, 28]. As

593 such, selection on KIT is unlikely to be related to the unifying domesticated trait

594 of tameness, as proposed here for modulatory glutamatergic signaling. Whether

595 this extends to other neural-crest related genes, in line with arguments against

596 the universality of the effects predicted by the neural crest hypothesis (see [132])

597 remains to be determined.

598 There are various possible explanations for how glutamatergic signaling may

599 interact with, or even bypass, the neural crest to bring about the broader phe-

600 notypical features of the domestication syndrome. We present two alternatives

601 in Supplementary Section S4 that future work could put to the test. On consid-

602 ering these two alternative accounts of glutamatergic signaling in the emergence

603 of the domestication syndrome (NCC-interacting versus NCC-independent), we

604 prefer to be cautious about attributing too many functional consequences to the

605 signals of selection highlighted here. We consider that a mild neurocristopathy

606 will almost certainly explain some physical trait changes in domesticate species,

607 and that this may serve to entrench earlier selection for tameness via reduced

608 inputs to stress-hormone cells in the adrenal glands. Future investigations may

609 help to determine whether these reductions result from upstream modulation

610 of glutamatergic signaling. In some species, changes to glutamatergic signal-

611 ing may also have acted to directly alter the development of physical traits,

612 independently of genetic or epigenetic alterations to the neural crest, driven by

613 domestication.

614 5 Materials and Methods

615 Based on our previous work showing overlapping signals of selection on glutamatergic-

616 signaling genes in domesticates and anatomically modern humans [4], we ex-

617 tended our comparative analysis across a broad range of domesticated species.

618 In order to delimit the comparison to a clearly-defined gene set within the gluta-

619 matergic system, we selected the 26 glutamate receptor genes as our cross-species

620 comparator (Table 1).

621 For our comparison, we included all domesticated species for which whole-

622 genome sequences were available. In species for which no studies of selective

623 sweeps were available, we included studies of decreased heterozygosity differenti-

624 ating tame and aggressive strains (fox) and/or studies detailing brain-expression

625 differences between tame and wild or aggressive lineages (guinea pig, fox, and

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626 rat). We also included a study of introgressed genes from cattle to yaks, which

627 identified genes likely to have been subject to positive selection. Finally, we in-

628 cluded for comparison high-frequency (near-fixed) changes differentiating mod-

629 ern from archaic humans. (Table 2.)

630 We extracted all instances of selective sweeps, introgression, brain-expression,

631 and high-frequency changes on glutamate receptor genes from the domestica-

632 tion and modern-human studies listed in Table 2. We compiled these genes for

633 comparison according to the receptor (sub)families of which they are members.

634 To evaluate whether signals detected on glutamate receptor genes occurred at a

635 rate significantly higher than those for comparable receptor classes, we compiled

636 signals of selection occurring on ligand-gated ion channel receptor and G-protein

637 coupled receptor genes. We excluded olfactory, vomeronasal, and taste receptor

638 genes from our comparison, given the large cross-species variability in function-

639 ing receptors encoded by these genes, driven, in large part, by species-specific

640 dietary and environmental specializations. We also excluded orphan g-protein

641 coupled receptors from our analysis, given that, for the most part, their endoge-

642 nous ligands and broad functions remain uncharacterized. Because of an earlier

643 observation that domestication events may have affected Erb-b2 signaling [4], as

644 well as extensive evidence for effects on stress-hormone levels, we also included

645 receptor kinase and nuclear hormone receptor genes for comparison.

646 Following the compilation of signals on 488 receptor genes across thirty do-

647 mestication studies, we confirmed that this data, when categorized according

648 to receptor subfamilies, passed the assumptions required for use of a one-way

649 ANOVA (residuals-versus-fit and Levene’s test for homogeneity of variance). We

650 then carried out the one-way ANOVA in R, showing significant differences in

651 signals of selection between certain receptor subfamilies. Following this, we used

652 Monte Carlo random sampling (100,000 simulations) to determine the chance

653 likelihood of signals occurring at the rates they do on single genes and gene

654 (sub)families.

655 In order to determine potentially shared functions of kainate and metabotropic

656 receptor gene (sub)families that showed the strongest signals of convergence

657 across humans and domesticates, we investigated associations with phenotypes

658 relevant to tameness and prosociality by doing an exhaustive literature search

659 (Pubmed). These included associations with the startle response and neurode-

660 velopmental, neuropsychiatric, stress, and mood disorders, summarized in Table

661 3.

662 Finally, we carried out a meta-analysis (summarized in Figure 2, details

663 in Supplementary Material) to determine the brain expression of kainate and

664 Group II and III metabotropic receptor genes.

665 Author contributions

666 Data collection and analysis: TOR, CB; proposed mechanism: TOR; draft

667 preparation: TOR, with input and revisions from CB; project supervision: CB.

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668 Acknowledgements

669 We would like to thank Pedro Tiago Martins for invaluable help in preparing

670 Tables1 and2, and Figure1. We kindly thank Bridget D. Samuels and Kay

671 Sušelj for help in choosing and carrying out the statistical analyses. We thank

672 Yan Li for sharing unpublished data relevant to the study in [23]. We would

673 also like to thank Adam S. Wilkins, Stefanie Sturm, Alejandro Andirkó, and

674 Pedro Tiago Martins for helpful comments on earlier drafts of this text.

675 Funding statement

676 CB acknowledges support from the Spanish Ministry of Economy and Com-

677 petitiveness (grant FFI2016-78034-C2-1-P/FEDER), Marie Curie International

678 Reintegration Grant from the European Union (PIRG-GA-2009-256413), Fun-

679 dació Bosch i Gimpera, MEXT/JSPS Grant-in-Aid for Scientific Research on In-

680 novative Areas 4903 (Evolinguistics: JP17H06379), and Generalitat de Catalunya

681 (2017-SGR-341). TOR acknowledges support from the Generalitat de Catalunya

682 (FI 2019 fellowship).

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