The oxytocin receptor gene, an integral piece of the evolution of Canis familaris from Canis lupus

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Jessica Lee Oliva
Yen T Wong
Jean-Loup Rault
Belinda Appleton
Alan Lill


Previous research in canids has revealed both group (dog versus wolf) and individual differences in object choice task (OCT) performance. These differences might be explained by variation in the oxytocin receptor (OXTR) gene, as intranasally administered oxytocin has recently been shown to improve performance on this task by domestic dogs. This study looked at microsatellites at various distances from the OXTR gene to determine whether there was an association between this gene and: i) species (dog/wolf) and ii) good versus bad OCT performers. Ten primer sets were designed to amplify 10 microsatellites that were identified at various distances from the canine OXTR gene. We used 94 (52 males, 42 females) blood samples from shelter dogs, 75 (33 males, 42 females) saliva samples from pet dogs and 12 (6 males, 6 females) captive wolf saliva samples to carry out our analyses. Significant species differences were found in the two markers closest to the OXTR gene, suggesting that this gene may have played an important part in the domestic dogs’ evolution from the wolf. However, no significant, meaningful differences were found in microsatellites between good versus bad OCT performers, which suggests that other factors, such as different training and socialisation experiences, probably impacted task performance.

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Agnetta B., Hare B., Tomasello M. 2000. Cues to food location that domestic dogs (Canis familiaris) of different ages do and do not use. Animal Cognition 3: 107-112.

Amico, J. A., Challinor, S. M., Cameron, J. L. 1990. Pattern of Oxytocin Concentrations in the Plasma and Cerebrospinal Fluid of Lactating Rhesus Monkeys (Macaca mulatto): Evidence for Functionally Independent Oxytocinergic Pathways in Primates. Journal of Clinical Endocrinology and Metabolism 71(6): 1531-1535.

Bakermans-Kranenburg M.J., van Ijzendoorn M.H. 2008. Oxytocin receptor (OXTR) and serotonin transporter (5-HTT) genes associated with observed parenting. Social Cognitive and Affective Neuroscience 3(2): 128-134. doi: 10.1093/scan/nsn004

Bartz J.A., Zaki J., Bolger N., Ochsner K.N. 2011. Social effects of oxytocin in humans: context and person matter. Trends in Cognitive Science 15(7): 301-309.

Born J., Lange T., Kern W., McGregor G.P., Bickel U., Fehm H.L. 2002. Sniffing neuropeptides: a transnasal approach to the human brain. Nature Neuroscience 5(6): 514-516.

Campbell I. 2007. Chi-squared and Fisher-Irwin tests of two-by-two tables with small sample recommendations. Statistics in Medicine 26(19): 3661-3675. doi: 10.1002/sim.2832

Chen F.S., Barth M.E., Johnson S.L., Gotlib I.H., Johnson, S.C. 2011. Oxytocin receptor (OXTR) polymorphisms and attachment in human infants. Frontiers in Psychology 2. doi: 10.3389/fpsyg.2011.00200

Christensen, J. C., Shiyanov, P. A., Estepp, J. R., Schlager, J. L. 2014. Lack of association between human plasma oxytocin and interpersonal trust in a prisoner’s dilemma paradigm. PLoS ONE 9(12): e116172. doi:10.1371/journal.pone.0116172

Csaba G. 2000. Hormonal imprinting: its role during the evolution and development of hormones and receptors. Cell Biology International 24(7): 407-414. doi: 10.1006/cbir.2000.0507

Csaba G. 2008. Hormonal imprinting: phylogeny, ontogeny, diseases and possible role in present-day human evolution. Cell Biochemistry and Function 26(1): 1-10. doi: 10.1002/cbf.1412

Dadds M.R., Moul C., Cauchi A., Dobson-Stone C., Hawes D.J., Brennan J., Urwin R., Ebstein R.E. 2014. Polymorphisms in the oxytocin receptor gene are associated with the development of psychopathy. Developmental Psychopathology 26(1): 21-31. doi: 10.1017/S0954579413000485

Dal Monte O., Noble P. L., Turchi J., Cummins A., Averbeck B.B. 2014. CSF and blood oxytocin concentration changes following intranasal delivery in Macaque. PLoS ONE 9(8): e103677. doi: 10.1371/journal.pone.0103677

Denes A. 2015. Genetic and individual influences on predictors of disclosure: exploring variation in the oxytocin receptor gene and attachment security. Communication Monographs 82(1): 113-133.

Elgier, A. M., Jakovcevic, A., Barrera, G., Mustaca, A. E., Bentosela, M. 2009. Communication between domestic dogs (Canis familiaris) and humans: dogs are good learners. Behavioural processes 81(3): 402-408. doi: 10.1016/j.beproc.2009.03.017

Elgier, A. M., Jakovcevic, A., Mustaca, A. E., Bentosela, M. 2012. Pointing following in dogs: are simple or complex cognitive mechanisms involved? Animal Cognition 15: 1111-1119. doi: 10.1007/s10071-012-0534-6

Engelmann M., Wotjak C.T., Ebner K., Landgraf R. 2000. Behavioural impact of intraseptally released vasopressin and oxytocin in rats. Experimental Physiology 85S: 125S-130S.

Francis D.D., Young L.J., Meaney M.J., Insel T.R. 2002. Naturally occurring differences in maternal care are associated with the expression of oxytocin and vasopressin (V1a) receptors: gender differences. Journal of Neuroendocrinology 14(5): 349-353.

Guastella A.J., MacLeod C. 2012. A critical review of the influence of oxytocin nasal spray on social cognition in humans: evidence and future directions. Hormones and Behavior 61(3): 410-418. doi: 10.1016/j.yhbeh.2012.01.002

Guastella A.J., Mitchell P.B., Dadds M.R. 2008. Oxytocin increases gaze to the eye region of human faces. Biological Psychiatry 63(1): 3-5. doi: 10.1016/j.biopsych.2007.06.026

Handlin L., Hydbring-Sandberg E., Nilsson A., Ejdebäck M., Jansson A., Uvnäs-Moberg K. 2011. Short-term interaction between dogs and their owners: effects of oxytocin, cortisol, insulin and heart-rate - an exploratory study. Anthrozoös 24(3): 301-315.

Hare B., Brown M., Williamson C., Tomasello M. 2002. The domestication of social cognition in dogs. Science 298(5598): 1634-1636. doi: 10.1126/science.1072702

Hare, B., Rosati, A., Kaminski, J., Bräuer, J., Call, J., Tomasello, M. 2010. The domestication hypothesis for dogs' skills with human communication: a response to Udell et al. (2008) and Wynne et al. (2008). Animal Behaviour 79, e1-e6.

Heim C., Young L.J., Newport D.J., Mletzko T., Miller A.H., Nemeroff C.B. 2009. Lower CSF oxytocin concentrations in women with a history of childhood abuse. Molecular Psychiatry 14(10): 954-958. doi: 10.1038/mp.2008.112

Hernádi A., Kis A., Kanizsár O., Tóth K., Miklósi B., Topál J. 2015. Intranasally administered oxytocin affects how dogs (Canis familiaris) react to the threatening approach of their owner and an unfamiliar experimenter. Behavioural Processes 119: 1-5. doi: 10.1016/j.beproc.2015.07.001
IBM Corp. 2013. SPSS Statistics for Windows, Version 22.0. IBM Corp., Armonk.

Jacob S., Brune C.W., Carter C.S., Leventhal B.L., Lord C., Cook E.H. Jr. 2007. Association of the oxytocin receptor gene (OXTR) in Caucasian children and adolescents with autism. Neuroscience Letters 417(1): 6-9. doi: 10.1016/j.neulet.2007.02.001

Jakovcevic A., Elgier A.M., Mustaca A.E., Bentosela M. 2010. Breed differences in dogs’ (Canis familiaris) gaze to the human face. Behavioural Processes 84: 602-607. doi: 10.1016/j.beproc.2010.04.003

Keri S., Benedek G. 2009. Oxytocin enhances the perception of biological motion in humans. Cognitive Affective and Behavioral Neuroscience 9(3): 237-241. doi: 10.3758/CABN.9.3.237

Kirchhofer, K. C., Zimmermann, F., Kaminski, J., Tomasello, M. 2012. Dogs (Canis familiaris), but not chimpanzees (Pan troglodytes), understand imperative pointing. PloS one 7(2), e30913. doi: 10.1371/journal.pone.0030913

Kis A., Bence M., Lakatos G., Pergel E., Turcsán B., Pluijmakers J., Vas J., Elek Z., Brúder I., Földi L., Sasvári-Székely M., Miklósi A., Rónai Z., Kubinyi E. 2014. Oxytocin receptor gene polymorphisms are associated with human directed social behavior in dogs (Canis familiaris). PloS one 9(1): e83993. doi: 10.1371/journal.pone.0083993

Kis A., Hernádi A., Kanizsár O., Gácsi M., Topál J. 2015. Oxytocin induces positive expectations about ambivalent stimuli (cognitive bias) in dogs. Hormones and Behavior 69: 1-7. doi: 10.1016/j.yhbeh.2014.12.004

Kosfeld M., Heinrichs M., Zak P.J., Fischbacher U., Fehr E. 2005. Oxytocin increases trust in humans. Nature 435(7042): 673-676. doi: 10.1038/nature03701

Lazarowski, L., Dorman, D.C. 2015. A comparison of pet and purpose-bred research dog (Canis familiaris) performance on human-guided object-choice tasks. Behavioural Processes 110: 60-67. doi: 10.1016/j.beproc.2014.09.021
Leng, G., Ludwig, M. 2016. Intranasal Oxytocin: Myths and Delusions. Biological Psychiatry 79(3): 243–250.

Lim M.M., Young L.J. 2006. Neuropeptidergic regulation of affiliative behavior and social bonding in animals. Hormones and Behavior 50(4): 506-517 doi: 10.1016/j.yhbeh.2006.06.028

Lucht M.J., Barnow S., Sonnenfeld C., Rosenberger A., Grabe H.J., Schroeder W., Völzke H., Freyberger H.J., Herrmann F.H., Kroemer H., Rosskopf D. 2009. Associations between the oxytocin receptor gene (OXTR) and affect, loneliness and intelligence in normal subjects. Progress in Neuro-psychopharmacology 33(5): 860-866. doi: 10.1016/j.pnpbp.2009.04.004

Ludwig M., Leng G. 2006. Dendritic peptide release and peptide-dependent behaviours. Nature Reviews Neuroscience 7(2): 126-136. doi: 10.1038/nrn1845

Macdonald K.S. 2012. Sex, receptors, and attachment: a review of individual factors influencing response to oxytocin. Frontiers in Neuroscience 6. doi: 10.3389/fnins.2012.00194

McCullough, M. E., Churchland, P. S., Mendez, A. J. 2013. Problems with measuring peripheral oxytocin: Can the data on oxytocin andhuman behavior be trusted? Neuroscience and Biobehavioral Reviews 37: 1485– 1492.

Miklósi Á., Kubinyi E., Topál J., Gácsi M., Virányi Z., Csányi V. 2003. A simple reason for a big difference: wolves do not look back at humans, but dogs do. Current Biology 13(9): 763-766.

Miklósi Á., Polgárdi R., Topál J., Csányi V. 1998. Use of experimenter-given cues in dogs. Animal Cognition 1: 113-121.

Miklósi, Á., Pongrácz, P., Lakatos, G., Topál, J., Csányi, V. 2005. A comparative study of the use of visual communicative signals in interactions between dogs (Canis familiaris) and humans and cats (Felis catus) and humans. Journal of comparative psychology 119(2): 179-186. doi: 10.1037/0735-7036.119.2.179

Miller S.C., Kennedy C., DeVole D., Hickey M., Nelson T., Kogan L. 2009. An examination of changes in oxytocin levels in men and women before and after interaction with a bonded dog. Anthrozoös 22(1): 31-42.

Mitsui S., Yamamoto M., Nagasawa M., Mogi K., Kikusui T., Ohtani N., Ohta M. 2011. Urinary oxytocin as a noninvasive biomarker of positive emotion in dogs. Hormones and Behavior 60(3): 239-243. doi: 10.1016/j.yhbeh.2011.05.012

Montaldo H.H., Meza-Herrera C.A. 1998. Use of molecular markers and major genes in the genetic improvement of livestock. Electronic Journal of Biotechnology 1(2): 83-89. doi: 10.2225/vol1-issue2-fulltext-4

Nagasawa M., Kikusui T., Onaka T., Ohta M. 2009. Dog's gaze at its owner increases owner's urinary oxytocin during social interaction. Hormones and Behavior 55(3): 434-441. doi: 10.1016/j.yhbeh.2008.12.002

Nagasawa M., Mitsui S., En S., Ohtani N., Ohta M., Sakuma Y., Onaka T., Mogi K., Kikusui T. 2015. Oxytocin-gaze positive loop and the coevolution of human-dog bonds. Science 348(6232): 333-336. doi: 10.1126/science.1261022

NCBI. 2012. OXTR oxytocin receptor [Canis lupus familiaris (dog)], annotation release 103. [ONLINE] Available at:

Neumann, I. D., Maloumby, R., Beiderbeck, D. I., Lukas, M., Landgraf, R. 2013. Increased brain and plasma oxytocin after nasal and peripheral administration in rats and mice. Psychoneuroendocrinology 38: 1985-1993.

Odendaal J.S., Meintjes R.A. 2003. Neurophysiological correlates of affiliative behaviour between humans and dogs. Veterinary Journal 165(3): 296-301.

Oliva J.L., Rault J-L., Appleton B., Lill A. 2015. Oxytocin enhances the appropriate use of human social cues by the domestic dog (Canis familiaris) in an object choice task. Animal Cognition 18: 767-775. doi: 10.1007/s10071-015-0843-7

Parker H.G., Shearin A.L., Ostrander E.A. 2010. Man's best friend becomes biology's best in the show: genome analysis in the domestic dog. Annual Review of Genetics 44: 309-336.

Rault J-L. 2016. Effects of positive and negative human contacts and intranasaloxytocin on cerebrospinal fluid oxytocin. Psychoneuroendocrinology, 69: 60–66.

Reid P. J. 2009. Adapting to the human world: dogs' responsiveness to our social cues. Behavioural processes, 80(3): 325-333. doi: 10.1016/j.beproc.2008.11.002

Riem M.M., Pieper S., Out D., Bakermans-Kranenburg M.J., van Ijzendoorn M.H. 2011. Oxytocin receptor gene and depressive symptoms associated with physiological reactivity to infant crying. Social Cognitive and Affective Neuroscience 6(3): 294-300. doi: 10.1093/scan/nsq035

Robinson I.C. 1983. Neurohypophysial peptides in cerebrospinal fluid. Progress in Brain Research 60: 129-145. doi: 10.1016/S0079-6123(08)64381-2

Robinson I.C., Jones P.M. 1982. Oxytocin and neurophysin in plasma and CSF during suckling in the guinea-pig. Neuroendocrinology 34(1): 59-63.

Rodrigues S.M., Saslow L.R., Garcia N., John O.P., Keltner D. 2009. Oxytocin receptor genetic variation relates to empathy and stress reactivity in humans. Proceedings of the National Academy of Sciences USA 106(50): 21437-21441. doi: 10.1073/pnas.0909579106

Romero T., Nagasawa M., Mogi K., Hasegawa T., Kikusui T. 2014. Oxytocin promotes social bonding in dogs. Proceedings of the National Academy of Sciences 111(25): 9085-9090. doi: 10.1073/pnas.1322868111

Romero T., Nagasawa M., Mogi K., Hasegawa T., Kikusui T. 2015. Intranasal administration of oxytocin promotes social play in domestic dogs. Communicative and Integrative Biology 8(3): e1017157.

RSPCA. 2010. RSPCA Australia discussion paper: puppy farms (pp. 11)
Saphire-Bernstein S., Way B.M., Kim H.S., Sherman D.K., Taylor S.E. 2011. Oxytocin receptor gene (OXTR) is related to psychological resources. Proceedings of the National Academy of Sciences USA 108(37): 15118-15122.

Schuelke M. 2000. An economic method for the fluorescent labeling of PCR fragments. Nature Biotechnology 18(2): 233-234. doi: 10.1038/72708
Scott, J.P. 1962. Critical periods in behavioral development. Science 138(3544): 949-958.

Soproni, K., Miklósi, A., Topál, J., Csányi, V. 2002. Dogs' (Canis familiaris) responsiveness to human pointing gestures. Journal of comparative psychology, 116(1): 27-34.

Striepens N., Kendrick K. M., Hanking V., Landgraf R., Wullner U., Maier W., Hurlemann R. 2013. Elevated cerebrospinal fluid and blood concentrations of oxytocin following its intranasal administration in humans. Scientific Reports 3: 3440. doi: 10.1038/srep03440

Sutter N.B., Ostrander E.A. 2004. Dog star rising: the canine genetic system. Nature Reviews Genetics 5(12):900-910 doi: 10.1038/nrg1492

Szeto A., McCabe P.M., Nation D.A., Tabak M.S., Rossetti M.A., McCullough M.E., Schneiderman N., Mendez A.J. 2011. Evaluation of enzyme immunoassay and radioimmunoassay methods for the measurement of plasma oxytocin. Psychosomatic Medicine 73(5): 393-400. doi: 10.1097/PSY.0b013e31821df0c2

Tanaka K., Osako Y., Yuri K. 2010. Juvenile social experience regulates central neuropeptides relevant to emotional and social behaviors. Neuroscience 166(4): 1036-1042. doi: 10.1016/j.neuroscience.2010.01.029

Toonen R.J., Hughes S. 2001. Increased throughput for fragment analysis on an ABI PRISM 377 automated sequencer using a membrane comb and STRand software. Biotechniques 31: 1320-1324.

Tost H., Kolachana B., Hakimi S., Lemaitre H., Verchinski B.A., Mattay V.S., Weinberger D.R., Meyer-Lindenberg A. 2010. A common allele in the oxytocin receptor gene (OXTR) impacts prosocial temperament and human hypothalamic-limbic structure and function. Proceedings of the National Academy of Sciences USA 107(31): 13936-13941 doi: 10.1073/pnas.1003296107

Udell M.A., Giglio R.F., Wynne C.D. 2008a. Domestic dogs (Canis familiaris) use human gestures but not nonhuman tokens to find hidden food. Journal of Comparative Psychology 122(1): 84-93. doi: 10.1037/0735-7036.122.1.84

Untergasser A., Cutcutache I., Koressaar T., Ye J., Faircloth B.C., Remm M., Rozen S.G. 2012. Primer3--new capabilities and interfaces. Nucleic Acids Research, 40(15): e115.

Udell M.A.R., Dorey N.R., Wynne C.D.L. 2008b. Wolves outperform dogs in following human social cues. Animal Behaviour 76: 1767-1773.

Udell, M. A., Dorey, N. R., & Wynne, C. D. 2010a. What did domestication do to dogs? A new account of dogs' sensitivity to human actions. Biological reviews of the Cambridge Philosophical Society, 85(2): 327-345. doi: 10.1111/j.1469-185X.2009.00104.x

Udell M.A.R., Dorey N.R., Wynne C.D.L. 2010b. The performance of stray dogs (Canis familiaris) living in a shelter on human-guided object-choice tasks. Animal Behaviour 79: 717-725.

Udell M. A. R., Wynne, C. D. L. 2010. Ontogeny and phylogeny: both are essential to human-sensitive behaviour in the genus Canis. Animal Behaviour 79: e9-e14.

Veening J.G., de Jong T., Barendregt H.P. 2010. Oxytocin-messages via the cerebrospinal fluid: behavioral effects; a review. Physiology and Behavior 101(2): 193-210. doi: 10.1016/j.physbeh.2010.05.004

Virányi Z., Gácsi M., Kubinyi E., Topál J., Belényi B., Ujfalussy D., Miklósi Á. 2008. Comprehension of human pointing gestures in young human-reared wolves (Canis lupus) and dogs (Canis familiaris). Animal Cognition 11(3): 373-387. doi: 10.1007/s10071-007-0127-y

Vorherr H., Bradbury M.W., Hoghoughi M., Kleeman C.R. 1968. Antidiuretic hormone in cerebrospinal fluid during endogenous and exogenous changes in its blood level. Endocrinology 83(2): 246-250.

Wang G., Zhai W., Yang H., Fan R., Cao X., Zhong L., Wang L., Liu F., Wu H., Cheng L., Poyarkov A.D., Poyarkov N.A., Tang S., Zhao W., Gao Y., Lv X., Irwin D.M., Savolainen P., Wu C., Zhang Y. 2013. The genomics of selection in dogs and the parallel evolution between dogs and humans. Nature Communications 4. doi: 10.1038/ncomms2814

Weaver B. 2013. Assumptions/Restrictions for Chi-square Tests on Contingency Tables. Retrieved March 27, 2015

Wobber V., Hare B., Koler-Matznick J., Wrangham R., Tomasello M. 2009. Breed differences in domestic dogs' (Canis familiaris) comprehension of human communicative signals. Interaction Studies 10(2): 206-224.

Wu S., Jia M., Ruan Y., Liu J., Guo Y., Shuang M., Gong X., Zhang Y., Yang X., Zhang D. 2005. Positive association of the oxytocin receptor gene (OXTR) with autism in the Chinese Han population. Biological Psychiatry 58(1): 74-77. doi: 10.1016/j.biopsych.2005.03.013