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The genetic basis of parental care evolution in monogamous mice


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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Figure 1: Parental behaviours of monogamous and promiscuous Peromyscus mice.
Figure 2: Effect of cross-fostering on parental behaviour.
Figure 3: Distribution of parental behaviours in each species and their interspecific hybrids.
Figure 4: The genetic architecture of parental behaviour.
Figure 5: Role for vasopressin in parental nest building.

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E. Kingsley shared unpublished data.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.

Author information

Authors and Affiliations



A.B. and H.E.H. conceived and designed the study. A.B. and Y.-M.K. collected and analysed behavioural data. A.B., Y.-M.K., and C.L.L. generated ddRAD-seq libraries. B.K.P. wrote code to map ddRAD-seq data. B.K.P. and A.B. wrote code to track animal behaviour from videos. A.B. and M.X.H. made a chromosome-level map of the Peromyscus genome. A.B. performed genetic mapping, pharmacology, and chemogenetics experiments. A.B. and J.-M.L. collected and analysed the RNA sequencing data. C.L.L. blind-scored behavioural assays. S.Y. made the Avp-Cre transgenic mice. A.B., Y.-M.K., J.-M.L., C.D., and H.E.H. analysed and interpreted results. A.B. and H.E.H. wrote the paper with input from all authors.

Corresponding author

Correspondence to Hopi E. Hoekstra.

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The authors declare no competing financial interests.

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Reviewer Information Nature thanks S. Phelps and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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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.

Source data

Extended Data Figure 2 Parental behaviours towards own pups and heterospecific pups.

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).

Source data

Extended Data Figure 3 QTL mapping of parental behaviours.

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). ac, Dashed lines denote the P = 0.05 genome-wide significance level determined by 1,000 permutations.

Extended Data Figure 4 QTL effect plots.

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).

Extended Data Figure 5 Behaviour of sexually naive and parental animals.

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.

Source data

Extended Data Figure 6 RNA-seq analysis of P. maniculatus and P. polionotus hypothalamus.

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.

Extended Data Figure 7 Expression analysis of genes in the chromosome 4 nest-building QTL.

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.

Source data

Extended Data Figure 8 Allele-specific expression of Avp in different brain regions.

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.

Source data

Extended Data Figure 9 Relationship between anxiety and nest building.

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).

Source data

Extended Data Figure 10 Chemogenetic experiments on vasopressin neurons of M. musculus.

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.

Source data

Supplementary information

Supplementary Information

This file contains a Supplementary Discussion and Supplementary References. (PDF 113 kb)

Supplementary Data 1

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)

Supplementary Data 2

This file contains a chromosome-level map of Peromyscus maniculatus bairdii (BW). (XLSX 116 kb)

Parental behaviour of a Peromyscus polionotus father

This video represents the typical behaviour of P. polionotus fathers. (MP4 10963 kb)

Parental behaviour of a Peromyscus maniculatus father

This video represents the typical behaviour of P. maniculatus fathers. (MP4 11254 kb)

Parental behaviour of a Peromyscus polionotus mother

This video represents the typical behaviour of P. polionotus mothers. (MP4 15956 kb)

Parental behaviour of a Peromyscus maniculatus mother

This video represents the typical behaviour of P. maniculatus mothers. (MP4 16469 kb)

P. polionotus mother approaching a pup

This video shows a short clip from Video 3. (MP4 1509 kb)

P. polionotus father handling and licking a pup

This video shows a short clip from Video 1. (MP4 5979 kb)

P. maniculatus mother huddling a pup.

This video shows a short clip from Video 4. (MP4 1934 kb)

P. polionotus mother retrieving a pup

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).

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