Parental care is essential for the survival of mammals, yet the mechanisms underlying its evolution remain largely unknown. Here we show that two sister species of mice, Peromyscus polionotus and Peromyscus maniculatus, have large and heritable differences in parental behaviour. Using quantitative genetics, we identify 12 genomic regions that affect parental care, 8 of which have sex-specific effects, suggesting that parental care can evolve independently in males and females. Furthermore, some regions affect parental care broadly, whereas others affect specific behaviours, such as nest building. Of the genes linked to differences in nest-building behaviour, vasopressin is differentially expressed in the hypothalamus of the two species, with increased levels associated with less nest building. Using pharmacology in Peromyscus and chemogenetics in Mus, we show that vasopressin inhibits nest building but not other parental behaviours. Together, our results indicate that variation in an ancient neuropeptide contributes to interspecific differences in parental care.
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Lukas, D. & Clutton-Brock, T. H. The evolution of social monogamy in mammals. Science 341, 526–530 (2013)
Lim, M. M. et al. Enhanced partner preference in a promiscuous species by manipulating the expression of a single gene. Nature 429, 754–757 (2004)
Okhovat, M., Berrio, A., Wallace, G., Ophir, A. G. & Phelps, S. M. Sexual fidelity trade-offs promote regulatory variation in the prairie vole brain. Science 350, 1371–1374 (2015)
Wang, Z., Ferris, C. F. & De Vries, G. J. Role of septal vasopressin innervation in paternal behavior in prairie voles (Microtus ochrogaster). Proc. Natl Acad. Sci. USA 91, 400–404 (1994)
Bosch, O. J. & Neumann, I. D. Both oxytocin and vasopressin are mediators of maternal care and aggression in rodents: from central release to sites of action. Horm. Behav. 61, 293–303 (2012)
Dulac, C., O’Connell, L. A. & Wu, Z. Neural control of maternal and paternal behaviors. Science 345, 765–770 (2014)
Scott, N., Prigge, M., Yizhar, O. & Kimchi, T. A sexually dimorphic hypothalamic circuit controls maternal care and oxytocin secretion. Nature 525, 519–522 (2015)
Turner, L. M. et al. Monogamy evolves through multiple mechanisms: evidence from V1aR in deer mice. Mol. Biol. Evol. 27, 1269–1278 (2010)
Birdsall, D. A. & Nash, D. Occurrence of successful multiple insemination of females in natural populations of deer mice (Peromyscus maniculatus). Evolution 27, 106–110 (1973)
Dewsbury, D. A. Aggression, copulation, and differential reproduction of deer mice (Peromyscus maniculatus) in a semi-natural enclosure. Behaviour 91, 1–23 (1984)
Dewsbury, D. A. & Lovecky, D. V. Copulatory behavior of old-field mice (Peromyscus polionotus) from different natural populations. Behav. Genet. 4, 347–355 (1974)
Foltz, D. W. Genetic evidence for long-term monogamy in a small rodent, Peromyscus polionotus. Am. Nat. 117, 665–675 (1981)
Dewsbury, D. A. An exercise in the prediction of monogamy in the field from laboratory data on 42 species of muroid rodents. Biologist 63, 138–162 (1981)
Peterson, B. K., Weber, J. N., Kay, E. H., Fisher, H. S. & Hoekstra, H. E. Double digest RADseq: an inexpensive method for de novo SNP discovery and genotyping in model and non-model species. PLoS ONE 7, e37135 (2012)
Andolfatto, P. et al. Multiplexed shotgun genotyping for rapid and efficient genetic mapping. Genome Res. 21, 610–617 (2011)
Royle, N. J ., Smiseth, P. T & Kölliker, M. The Evolution of Parental Care (Oxford Univ. Press, 2012)
Choi, Y., Sims, G. E., Murphy, S., Miller, J. R. & Chan, A. P. Predicting the functional effect of amino acid substitutions and indels. PLoS ONE 7, e46688 (2012)
Lagoutte, E. et al. Oxidation of hydrogen sulfide remains a priority in mammalian cells and causes reverse electron transfer in colonocytes. Biochim. Biophys. Acta Bioenerg. 1797, 1500–1511 (2010)
Seth, R. B., Sun, L., Ea, C.-K. & Chen, Z. J. Identification and characterization of MAVS, a mitochondrial antiviral signaling protein that activates NF-κB and IRF 3. Cell 122, 669–682 (2005)
Renella, R. et al. Codanin-1 mutations in congenital dyserythropoietic anemia type 1 affect HP1α localization in erythroblasts. Blood 117, 6928–6938 (2011)
Lindfors, P. H., Lindahl, M., Rossi, J., Saarma, M. & Airaksinen, M. S. Ablation of persephin receptor glial cell line-derived neurotrophic factor family receptor α4 impairs thyroid calcitonin production in young mice. Endocrinology 147, 2237–2244 (2006)
Numan, M. Medial preoptic area and maternal behavior in the female rat. J. Comp. Physiol. Psychol. 87, 746–759 (1974)
Insel, T. R. & Harbaugh, C. R. Lesions of the hypothalamic paraventricular nucleus disrupt the initiation of maternal behavior. Physiol. Behav. 45, 1033–1041 (1989)
Insel, T. R. The challenge of translation in social neuroscience: a review of oxytocin, vasopressin, and affiliative behavior. Neuron 65, 768–779 (2010)
Kramer, K. M., Yamamoto, Y., Hoffman, G. E. & Cushing, B. S. Estrogen receptor α and vasopressin in the paraventricular nucleus of the hypothalamus in Peromyscus. Brain Res. 1032, 154–161 (2005)
Neumann, I. D. & Landgraf, R. Balance of brain oxytocin and vasopressin: implications for anxiety, depression, and social behaviors. Trends Neurosci. 35, 649–659 (2012)
Bult, A., van der Zee, E. A., Compaan, J. C. & Lynch, C. B. Differences in the number of arginine-vasopressin-immunoreactive neurons exist in the suprachiasmatic nuclei of house mice selected for differences in nest-building behavior. Brain Res. 578, 335–338 (1992)
Bendesky, A. & Bargmann, C. I. Genetic contributions to behavioural diversity at the gene–environment interface. Nat. Rev. Genet. 12, 809–820 (2011)
De Vries, G. J. Sex differences in adult and developing brains: compensation, compensation, compensation. Endocrinology 145, 1063–1068 (2004)
Tinbergen, N. The hierarchical organization of nervous mechanisms underlying instinctive behaviour. Symp. Soc. Exp. Biol. 4, 305–312 (1950)
Kennedy, A. et al. Internal states and behavioral decision-making: toward an integration of emotion and cognition. Cold Spring Harb. Symp. Quant. Biol. 79, 199–210 (2014)
Devidze, N., Lee, A. W., Zhou, J. & Pfaff, D. W. CNS arousal mechanisms bearing on sex and other biologically regulated behaviors. Physiol. Behav. 88, 283–293 (2006)
Wu, Z., Autry, A. E., Bergan, J. F., Watabe-Uchida, M. & Dulac, C. G. Galanin neurons in the medial preoptic area govern parental behaviour. Nature 509, 325–330 (2014)
Insel, T. R., Gelhard, R. & Shapiro, L. E. The comparative distribution of forebrain receptors for neurohypophyseal peptides in monogamous and polygamous mice. Neuroscience 43, 623–630 (1991)
Donaldson, Z. R. & Young, L. J. Oxytocin, vasopressin, and the neurogenetics of sociality. Science 322, 900–904 (2008)
Dawson, W. D. Fertility and size inheritance in a Peromyscus species cross. Evolution 19, 44–55 (1965)
Li, H. & Durbin, R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 25, 1754–1760 (2009)
Lunter, G. & Goodson, M. Stampy: a statistical algorithm for sensitive and fast mapping of Illumina sequence reads. Genome Res. 21, 936–939 (2011)
Van der Auwera, G. A. et al. From FastQ data to high confidence variant calls: the Genome Analysis Toolkit best practices pipeline. Curr. Protoc. Bioinformatics 11, 11.10.1–11.10.33 (2013)
Painter, T. S. A comparative study of the chromosomes of mammals. Am. Nat. 59, 385–409 (1925)
Greenbaum, I. F. et al. Cytogenetic nomenclature of deer mice, Peromyscus (Rodentia): revision and review of the standardized karyotype. Report of the Committee for the Standardization of Chromosomes of Peromyscus. Cytogenet. Cell Genet. 66, 181–195 (1994)
Fraley, C . & Raftery, A. mclust version 4 for R: normal mixture modeling for model-based clustering, classification, and density estimation (Department of Statistics, University of Washington, 2012)
Broman, K. W. R/qtlcharts: interactive graphics for quantitative trait locus mapping. Genetics 199, 359–361 (2015)
Kenney-Hunt, J. et al. A genetic map of Peromyscus with chromosomal assignment of linkage groups (a Peromyscus genetic map). Mamm. Genome 25, 160–179 (2014)
Li, H. et al. The Sequence Alignment/Map format and SAMtools. Bioinformatics 25, 2078–2079 (2009)
Cande, J., Andolfatto, P., Prud’homme, B., Stern, D. L. & Gompel, N. Evolution of multiple additive loci caused divergence between Drosophila yakuba and D. santomea in wing rowing during male courtship. PLoS ONE 7, e43888 (2012)
Lynch, M & Walsh, B. Genetics and Analysis of Quantitative Traits 469–476 (Sinauer, 1998)
Broman, K. W., Wu, H., Sen, S. & Churchill, G. A. R/qtl: QTL mapping in experimental crosses. Bioinformatics 19, 889–890 (2003)
Zapala, M. A. et al. Adult mouse brain gene expression patterns bear an embryologic imprint. Proc. Natl Acad. Sci. USA 102, 10357–10362 (2005)
Dobin, A. et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics 29, 15–21 (2013)
Rozowsky, J. et al. AlleleSeq: analysis of allele-specific expression and binding in a network framework. Mol. Syst. Biol. 7, 522 (2011)
Li, B. & Dewey, C. N. RSEM: accurate transcript quantification from RNA-Seq data with or without a reference genome. BMC Bioinformatics 12, 323 (2011)
Ritchie, M. E. et al. limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 43, e47 (2015)
Law, C. W., Chen, Y., Shi, W. & Smyth, G. K. voom: precision weights unlock linear model analysis tools for RNA-seq read counts. Genome Biol. 15, R29 (2014)
Robinson, M. D. & Oshlack, A. A scaling normalization method for differential expression analysis of RNA-seq data. Genome Biol. 11, R25 (2010)
Benjamini, Y. & Hochberg, Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J. R. Stat. Soc. B 57, 289–300 (1995)
Cingolani, P. et al. A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff. Fly 6, 80–92 (2012)
Clark, R. G., Jones, P. M. & Robinson, I. C. A. F. Clearance of vasopressin from cerebrospinal fluid to blood in chronically cannulated Brattleboro rats. Neuroendocrinology 37, 242–247 (1983)
Diamant, M. & De Wied, D. Differential effects of centrally injected AVP on heart rate, core temperature, and behavior in rats. Am. J. Physiol. 264, R51–R61 (1993)
Pedersen, C. A., Ascher, J. A., Monroe, Y. L. & Prange, A. J., Jr. Oxytocin induces maternal behavior in virgin female rats. Science 216, 648–650 (1982)
Fahrbach, S. E., Morrell, J. I. & Pfaff, D. W. Oxytocin induction of short-latency maternal behavior in nulliparous, estrogen-primed female rats. Horm. Behav. 18, 267–286 (1984)
Winslow, J. T., Hastings, N., Carter, C. S., Harbaugh, C. R. & Insel, T. R. A role for central vasopressin in pair bonding in monogamous prairie voles. Nature 365, 545–548 (1993)
Kessler, M. S., Bosch, O. J., Bunck, M., Landgraf, R. & Neumann, I. D. Maternal care differs in mice bred for high vs. low trait anxiety: impact of brain vasopressin and cross-fostering. Soc. Neurosci. 6, 156–168 (2011)
Bosch, O. J. & Neumann, I. D. Brain vasopressin is an important regulator of maternal behavior independent of dams’ trait anxiety. Proc. Natl Acad. Sci. USA 105, 17139–17144 (2008)
Kuroda, K. O., Tachikawa, K., Yoshida, S., Tsuneoka, Y. & Numan, M. Neuromolecular basis of parental behavior in laboratory mice and rats: with special emphasis on technical issues of using mouse genetics. Prog. Neuropsychopharmacol. Biol. Psychiatry 35, 1205–1231 (2011)
Xu, X. et al. Modular genetic control of sexually dimorphic behaviors. Cell 148, 596–607 (2012)
E. Kingsley shared unpublished data. D. Stern, P. Andolfatto, and A. Kitzmiller helped implement MSG; V. Bajic helped with anchoring genomic scaffolds; M. Khadraoui with allele-specific expression analysis; K. Turner with ddRAD library construction. Computations were run on the Odyssey cluster supported by the Harvard FAS Research Computing Group. R. Hellmiss provided advice on figures. C. Bargmann and P. McGrath provided comments on the manuscript. This work was supported by a Helen Hay Whitney Foundation Postdoctoral Fellowship and a National Institutes of Health (NIH) K99 award HD084732 to A.B., Harvard Museum of Comparative Zoology Grants in Aid and Harvard Undergraduate Research Fellowships to Y.-M.K., a European Molecular Biology Organization (ALTF 379-2011), Human Frontier Science Program, and Belgian American Educational Foundation fellowships to J.-M.L., NIH training grant GM008313 (to M.X.H.), National Philanthropic Trust grant RFP-12-03 (to A.B. and H.E.H.), and a Harvard Mind Brain Behavior Award and Harvard Brain Science Initiative Grant to H.E.H. C.D. and H.E.H. are investigators of the Howard Hughes Medical Institute.
The authors declare no competing financial interests.
Reviewer Information Nature thanks S. Phelps and the other anonymous reviewer(s) for their contribution to the peer review of this work.
Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Extended data figures and tables
Extended Data Figure 1 Parental behaviours in undisturbed home cages for 3 days after the birth of a litter.
The fraction of time an animal was engaged in each behaviour averaged across 5-min samples for each hour, for the 16 h of light and 8 h of dark parts of the day separately. Horizontal lines denote the mean. *P < 0.05; NS, not significant by Mann–Whitney U-test.
The behaviour of parents was measured across 4 consecutive days, alternating the pup species each day (randomizing the pup that was given on day 1). Grey lines connect an individual’s behaviour. Blue and red lines denote the median for fathers and mothers, respectively. *P < 0.05; **P < 0.01; NS, not significant by paired t-test or Wilcoxon signed-rank test (nest quality).
Non-parametric interval mapping of (a) six parental behaviours in males (n = 419) and females (n = 350), and (b) the subset of F2 animals that performed a behaviour (that is, excluding the animals that did not huddle or lick their pups for the duration of all three trials). Sample sizes for huddling were as follows: males, 259; females, 300; for licking: males, 319; females, 313. c, Haley–Knott regression on nqrank normalized values of all F2 individuals, using sex as a covariate. Plots show the difference in lod scores for the scan with sex as an interactive and as an additive covariate minus the scan with sex as an additive covariate alone. The artificial narrow peaks at the ends of chromosomes result from lack of genotype imputation by MSG at chromosome ends (nest quality, chromosome 22; latency to approach, chromosome 9; latency to handle, chromosome 14). a–c, Dashed lines denote the P = 0.05 genome-wide significance level determined by 1,000 permutations.
Phenotype means (±s.e.m.) against genotypes at peak QTL markers reported in Fig. 4 and Extended Data Fig. 3. Above each graph is the chromosomal position of the QTL peak. *Significant QTL-by-sex interaction. The per cent variance explained is given for each QTL and is underlined if the QTL was significant in a QTL analysis of that sex (Extended Data Fig. 3a, b).
a, Sexually naive animals were tested with 4- to 6-day-old conspecific pups, and parents with their own 4- to 6-day-old pups. Box plots indicate median, interquartile range, and 10th–90th percentiles. P. maniculatus (man, magenta) and P. polionotus (pol, green). *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.001; NS, not significant by Mann–Whitney U-test or Fisher’s exact test (retrieving and infanticide). b, Nest quality (mean ± s.e.m., and each pair in magenta circles for P. maniculatus and green squares for P. polionotus) in the 2 weeks after the birth of a litter. Existing nests were removed from the parents’ cage at the time of weaning and 5 g of new cotton nesting material (Nestlet) was provided. Litters were born 1–4 days after weaning the previous litter, and nest quality was evaluated once a day in the home cage, where both mother and father were present. ****P < 0.0001 effect of species in a two-way ANOVA including species and time as factors. There was no significant effect of time or species-by-time interaction.
a, Clustering dendogram of RNA-seq samples by Euclidian distances of transcript expression levels. Samples cluster by species but not by sex. b, Strength of differential expression between species. Each circle represents a gene and is colour-coded in magenta or green if its differential expression was significant at a 5% FDR. c, Relationship between average gene expression level and differential expression between species. In both b and c, genes that have been associated with parental care in previous studies (by physiological/pharmacological studies or induced mutations)64,65,66 are labelled; the gene is also boxed if located inside parental behaviour QTLs identified in this study.
a, Twenty-three genes that are differentially expressed in the hypothalamus at 5% FDR between P. maniculatus and P. polionotus, sorted by FDR-adjusted P value. There were no significant differences between sexes for any gene. For each gene, its average expression level in each species and sex is shown on the left, the fold-difference in expression between the species in the middle, and the FDR-adjusted P value on the right. b, Allele-specific expression of the 15 genes from a for which interspecific genetic variation allows this analysis. Mean fraction of reads (±s.e.m.) matching the P. maniculatus allele from RNA-seq of the hypothalamus of 12 male and 12 female P. maniculatus × P. polionotus F1 hybrids. There were no significant differences between males and females, so the sexes were combined for the plot. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001 by a linear model measuring allelic bias for each gene: ln(allelic bias) = α + β × sex + ε.
a, Immunofluorescence staining of vasopressin in a coronal section of a P. maniculatus male brain, showing the main vasopressin-producing nuclei. Red circles illustrate the 1 mm diameter (1.5 mm thick) circular punches used to microdissect these nuclei. b, c, Number of Avp transcripts (b) and allele-specific expression of Avp (c) in each of the microdissected regions in P. maniculatus × P. polionotus F1 hybrid animals, measured by droplet-digital PCR; horizontal line at the mean. **P < 0.01; ***P < 0.001 by ANOVA with Bonferroni correction. SCN, suprachiasmatic nucleus; SON, supraoptic nucleus; PVN, paraventricular nucleus of the hypothalamus; BNST, bed nucleus of the stria terminalis.
a, Fraction of time in the open arms of an elevated plus maze. Line at the mean. ****P < 0.0001 for difference between species by two-way ANOVA with sex and species as factors. No significant effect of sex or sex-by-species interaction. b, Spearman’s correlation coefficients among F2 mice between fraction of time in the open arms and parental behaviours. Handling and approach are promptness to perform those behaviours. c, Linkage (lod score) to chromosome 4 of nest-building behaviour and fraction of time in open arms. Males and females combined since there are no major differences in the lod scores between sexes. Red line denotes the location of Avp. Dashed lines denote the P = 0.05 genome-wide significance level determined by 1,000 permutations of each trait (n = 769).
a, Generation of Avp-Cre BAC-transgenic M. musculus. Top: schematic diagram illustrating the targeting of the IRES-Cre cassette immediately after the Avp stop codon. Bottom: immunofluorescence histology of vasopressin (AVP) and Cre in the paraventricular nuclei (PVN) of the hypothalamus of an Avp-Cre BAC-transgenic M. musculus. Scale bar, 100 μm. b, A recombinant adeno-associated virus (rAAV) containing a Cre-dependent DREADD was injected into the PVN of Avp-Cre transgenic M. musculus. c, d, Nest-building behaviour for 1 h after intraperitoneal injection with 0.9% NaCl or with the DREADD agonist clozapine-N-oxide (CNO) at 10 mg per kg. In c, animals expressed the inhibitory Gi-DREADD and in d, the excitatory Gq-DREADD. Males (with blue symbols at the mean ± s.e.m.) are on the left and females (red) are on the right in each panel. Statistical significance determined by repeated-measures ANOVA for quadratic trend.
This file contains a Supplementary Discussion and Supplementary References. (PDF 113 kb)
This file contains genes within and up to 100 kb outside parental behaviour QTLs. Genes expressed at different levels in the hypothalamus of P. maniculatus and P. polionotus at a False Discovery Rate of 5% are shown. See Methods for details on the linear model. This file also indicates which genes in the QTLs have interspecific differences in protein sequence. (XLSX 227 kb)
This file contains a chromosome-level map of Peromyscus maniculatus bairdii (BW). (XLSX 116 kb)
This video represents the typical behaviour of P. polionotus fathers. (MP4 10963 kb)
This video represents the typical behaviour of P. maniculatus fathers. (MP4 11254 kb)
This video represents the typical behaviour of P. polionotus mothers. (MP4 15956 kb)
This video represents the typical behaviour of P. maniculatus mothers. (MP4 16469 kb)
This video shows a short clip from Video 3. (MP4 1509 kb)
This video shows a short clip from Video 1. (MP4 5979 kb)
This video shows a short clip from Video 4. (MP4 1934 kb)
This video shows a short clip from Video 3. (MP4 1949 kb)
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Bendesky, A., Kwon, YM., Lassance, JM. et al. The genetic basis of parental care evolution in monogamous mice. Nature 544, 434–439 (2017). https://doi.org/10.1038/nature22074
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