Publications

Submitted
Lewarch CL, Hoekstra HE. The evolution of thermoregulatory nesting behaviour in Peromyscus mice. Biorxiv Submitted;Abstract

Structures built by animals, such as nests, are often extended phenotypes that can facilitate the study of animal behaviour. For rodents, nest building is both an important form of behavioural thermoregulation and a critical component of parental care. Changes in nest structure or the prioritization of nesting behaviour are therefore likely to have consequences for survival and reproduction, and both biotic and abiotic environmental factors are likely to influence the adaptive value of such differences. Here we use a novel assay to investigate interspecific variation in the thermoregulatory nesting behaviour of deer mice (genus Peromyscus). We find that, while there is some variation in the complexity of the nests built by Peromyscus mice, differences in the latency to begin nest construction are more striking. Four of the seven taxa examined here build nests within an hour of being given nesting material, but this latency to nest is not related to ultimate differences in nest structure, suggesting that the ability to nest is relatively conserved within the genus, but species differ in their prioritization of nesting behaviour. Latency to nest is not correlated with body size, climate, or the construction of burrows that create microclimates. However, the four taxa with short nesting latencies all have monogamous mating systems, suggesting that evolved differences in nesting latency may be related to social environment. This detailed characterization of nesting behaviour within the genus provides an important foundation for future studies of the genetic and neurobiological mechanisms that contribute to the evolution of behaviour.

Lewarch_biorxiv.pdf
Metz HC, Bedford NL, Pan L, Hoekstra HE. Evolution and genetics of precocious burrowing behavior in Peromyscus mice. Biorxiv Submitted;Abstract
A central challenge in biology is to understand how innate behaviors evolve between closely related species. One way to elucidate how differences arise is to compare the development of behavior in species with distinct adult traits. Here, we report that Peromyscus polionotus is strikingly precocious with regard to burrowing behavior, but not other behaviors, compared to its sister species P. maniculatus. In P. polionotus, burrows were excavated as early as 17 days of age, while P. maniculatus did not build burrows until 10 days later. Moreover, the well-known differences in burrow architecture between adults of these species -- P. polionotus adults excavate long burrows with an escape tunnel, while P. maniculatus dig short, single-tunnel burrows -- were intact in juvenile burrowers. To test whether this juvenile behavior is influenced by early-life environment, pups of both species were reciprocally cross-fostered. Fostering did not alter the characteristic burrowing behavior of either species, suggesting these differences are genetic. In backcross F2 hybrids, we show that precocious burrowing and adult tunnel length are genetically correlated, and that a single P. polionotus allele in a genomic region linked to adult tunnel length is predictive of precocious burrow construction. The co-inheritance of developmental and adult traits indicates the same genetic region -- either a single gene with pleiotropic effects, or closely linked genes -- acts on distinct aspects of the same behavior across life stages. Such genetic variants likely affect behavioral drive (i.e. motivation) to burrow, and thereby affect both the development and adult expression of burrowing behavior.
Metz_biorxiv.pdf
Pfeifer SP, Laurent S, Sousa VC, Linnen CR, Foll M, Excoffier L, Hoekstra HE, Jensen JD. The evolutionary history of Nebraska deer mice: local adaptation in the face of strong gene flow. Biorxiv Submitted;Abstract
The interplay of gene flow, genetic drift, and local selective pressure is a dynamic process that has been well studied from a theoretical perspective over the last century. Wright and Haldane laid the foundation for expectations under an island-continent model, demonstrating that an island specific beneficial allele may be maintained locally if the selection coefficient is larger than the rate of migration of the ancestral allele from the continent. Subsequent extensions of this model have provided considerably more insight into the conditions under which such a beneficial allele may be maintained, lost, or fixed. Yet, connecting theoretical results with empirical data has proven challenging, owing to a lack of information on the relationship between genotype, phenotype, and fitness. Here, we examine the demographic and selective history of deer mice in and around the Nebraska Sand Hills, a system in which variation at the Agouti locus affects cryptic coloration that in turn affects the survival of mice in their local habitat. We first genotyped 250 individuals from eleven sites along a transect spanning the Sand Hills at 670,000 SNPs across the genome. Using these genomic data, we found that deer mice first colonized the Sand Hills following the last glacial period. Subsequent high rates of gene flow have served to homogenize the majority of the genome between populations on and off the Sand Hills, with the exception of the Agouti pigmentation locus. Furthermore, we observe strong haplotype structure around putatively beneficial mutations within the Agouti locus, and these mutations are strongly associated with the pigment traits that are strongly correlated with local soil coloration and thus responsible for cryptic coloration. We discuss these empirical results in light of theoretical expectations, thereby providing a complete example of the dynamics between ancestral gene flow and local adaptation in a classic mammalian system.
Pfeifer_biorxiv.pdf
Delaney EK, Hoekstra HE. Sexual imprinting and speciation in two Peromyscus species. Biorxiv Submitted;Abstract
Sexual isolation, a reproductive barrier, can prevent interbreeding between diverging populations or species. Sexual isolation can have a clear genetic basis; however, it may also result from learned mate preferences that form via sexual imprinting. Here, we demonstrate that two sympatric sister species of mice -- the white-footed mouse (Peromyscus leucopus) and its closest relative, the cotton mouse (P. gossypinus) -- hybridize only rarely in the wild despite co-occurring in the same habitat and lack of any measurable intrinsic postzygotic barriers in laboratory crosses. We present evidence that strong conspecific mate preferences in each species form significant sexual isolation. We find that these mating preferences are learned in one species but may be genetic in the other: P. gossypinus sexually imprints on its parents, but innate biases or social learning affects mating preferences in P. leucopus. Our study demonstrates that sexually imprinting contributes to reproductive isolation that reduces hybridization between otherwise inter-fertile species, supporting a previously underappreciated role for learning in mammalian speciation.
Delaney_biorxiv.pdf
2017
Kingsley EP, Kozak KM, Pfeifer SP, Yang D-S, Hoekstra HE. The ultimate and proximate mechanisms driving the evolution of long tails in forest deer mice. Evolution 2017;71(2):261-273.Abstract

Understanding both the role of selection in driving phenotypic change and its underlying genetic basis remain major challenges in evolutionary biology. Here, we use modern tools to revisit a classic system of local adaptation in the North American deer mouse, Peromyscus maniculatus, which occupies two main habitat types: prairie and forest. Using historical collections, we find that forest-dwelling mice have longer tails than those from nonforested habitat, even when we account for individual and population relatedness. Using genome-wide SNP data, we show that mice from forested habitats in the eastern and western parts of their range form separate clades, suggesting that increased tail length evolved independently. We find that forest mice in the east and west have both more and longer caudal vertebrae, but not trunk vertebrae, than nearby prairie forms. By intercrossing prairie and forest mice, we show that the number and length of caudal vertebrae are not correlated in this recombinant population, indicating that variation in these traits is controlled by separate genetic loci. Together, these results demonstrate convergent evolution of the long-tailed forest phenotype through two distinct genetic mechanisms, affecting number and length of vertebrae, and suggest that these morphological changes — either independently or together — are adaptive.

 

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Bendesky A, Kwon Y-M, Lassance J-M, Lewarch CL, Yao S, Peterson BK, He MX, Dulac C, Hoekstra HE. The genetic basis of parental care evolution in monogamous mice. Nature 2017;554:434-439.Abstract

 

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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Hu CK, Hoekstra HE. Peromyscus burrowing: A model system for behavioral evolution. Seminars in Cell and Developmental Biology 2017;61:107-114.Abstract

A major challenge to understanding the genetic basis of complex behavioral evolution is the quantification of complex behaviors themselves. Deer mice of the genus Peromyscusvary in their burrowing behavior, which leaves behind a physical trace that is easily preserved and measured. Moreover, natural burrowing behaviors are recapitulated in the lab, and there is a strong heritable component. Here we discuss potential mechanisms driving variation in burrows with an emphasis on two sister species: P. maniculatus, which digs a simple, short burrow, and P. polionotus, which digs a long burrow with a complex architecture. A forward-genetic cross between these two species identified several genomic regions associated with burrow traits, suggesting this complex behavior has evolved in a modular fashion. Because burrow differences are most likely due to differences in behavior circuits, Peromyscus burrowing offers an exciting opportunity to link genetic variation between natural populations to evolutionary changes in neural circuits.

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Mallarino R, Linden TA, Linnen CR, Hoekstra HE. The role of isoforms in the evolution of cryptic coloration in Peromyscus mice. Molecular Ecology 2017;26:245-258.Abstract

A central goal of evolutionary biology is to understand the molecular mechanisms underlying phenotypic adaptation. While the contribution of protein-coding and cis-regulatory mutations to adaptive traits have been well documented, additional sources of variation—such as the production of alternative RNA transcripts from a single gene, or isoforms—have been understudied. Here, we focus on the pigmentation gene Agouti, known to express multiple alternative transcripts, to investigate the role of isoform usage in the evolution of cryptic color phenotypes in deer mice (genus Peromyscus). We first characterize the Agouti isoforms expressed in the Peromyscus skin and find two novel isoforms not previously identified in Mus. Next, we show that a locally adapted light-colored population of P. maniculatus living on the Nebraska Sand Hills shows an up-regulation of a single Agouti isoform, termed 1C, compared to their ancestral dark-colored conspecifics. Using in vitro assays, we show that this preference for isoform 1C may be driven by isoform-specific differences in translation. In addition, using an admixed population of wild-caught mice, we find that variation in overall Agouti expression maps to a region near exon 1C, which also has patterns of nucleotide variation consistent with strong positive selection. Finally, we show that the independent evolution of cryptic light pigmentation in a different species, P. polionotus, has been driven by a preference for the same Agouti isoform. Together, these findings present an example of the role of alternative transcript processing in adaptation and demonstrate molecular convergence at the level of isoform regulation.

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2016
Mallarino R, Hoekstra HE, Manceau M. Developmental genetics in emerging rodent models: Case studies and perspectives. Current Opinion in Genetics & Development 2016;39:182-186.Abstract

 

For decades, mammalian developmental genetic studies have focused almost entirely on two laboratory models: Mus and Rattus, species that breed readily in the laboratory and for which a wealth of molecular and genetic resources exist. These species alone, however, do not capture the remarkable diversity of morphological, behavioural and physiological traits seen across rodents, a group that represents >40% of all mammal species. Due to new advances in molecular tools and genomic technologies, studying the developmental events underlying natural variation in a wide range of species for a wide range of traits has become increasingly feasible. Here we review several recent studies and discuss how they not only provided technical resources for newly emerging rodent models in developmental genetics but also are instrumental in further encouraging scientists, from a wide range of research fields, to capitalize on the great diversity in development that has evolved among rodents. 

 

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Mallarino R, Henegar C, Mirasierra M, Manceau MC, Shradin C, Vallejo M, Beronja S, Barsh GS, Hoekstra HE. Developmental mechanisms of stripe patterns in rodents. Nature 2016;539:518-523.Abstract

 

Mammalian colour patterns are among the most recognizable characteristics found in nature and can have a profound impact on fitness. However, little is known about the mechanisms underlying the formation and subsequent evolution of these patterns. Here we show that, in the African striped mouse (Rhabdomys pumilio), periodic dorsal stripes result from underlying differences in melanocyte maturation, which give rise to spatial variation in hair colour. We identify the transcription factor ALX3 as a regulator of this process. In embryonic dorsal skin, patterned expression of Alx3 precedes pigment stripes and acts to directly repress Mitf, a master regulator of melanocyte differentiation, thereby giving rise to light-coloured hair. Moreover, Alx3 is upregulated in the light stripes of chipmunks, which have independently evolved a similar dorsal pattern. Our results show a previously undescribed mechanism for modulating spatial variation in hair colour and provide insights into how phenotypic novelty evolves.

 

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Mallet J, Hoekstra HE. Ecological genetics: A key gene for mimicry and melanism. Current Biology 2016;26:R802-804.Abstract

 

 Mimicry and melanism in Lepidoptera provided the first convincing examples of natural selection in action. Genetic analysis has now shown that, surprisingly, mimicry in Heliconius butterflies and melanism in peppered moths are switched at precisely the same gene: cortex .

 

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Bear DM, Lassance JM, Hoekstra HE, Datta SR. The evolving neural and genetic architecture of vertebrate olfaction. Current Biology 2016;26:R1039-R1049.Abstract

 

Evolution sculpts the olfactory nervous system in response to the unique sensory challenges facing each species. In vertebrates, dramatic and diverse adaptations to the chemical environment are possible because of the hierarchical structure of the olfactory receptor (OR) gene superfamily: expansion or contraction of OR subfamilies accompanies major changes in habitat and lifestyle; independent selection on OR subfamilies can permit local adaptation or conserved chemical communication; and genetic variation in single OR genes can alter odor percepts and behaviors driven by precise chemical cues. However, this genetic flexibility con- trasts with the relatively fixed neural architecture of the vertebrate olfactory system, which requires that new olfactory receptors integrate into segregated and functionally distinct neural pathways. This organization allows evolution to couple critical chemical signals with selectively advantageous responses, but also con- strains relationships between olfactory receptors and behavior. The coevolution of the OR repertoire and the olfactory system therefore reveals general principles of how the brain solves specific sensory problems and how it adapts to new ones.

 

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Fisher HS, Jacobs-Palmer E, Lassance JM, Hoekstra HE. The genetic basis and fitness consequences of sperm midpiece size in deer mice. Nature Communications 2016;7:13652.Abstract

 

An extensive array of reproductive traits varies among species, yet the genetic mechanisms that enable divergence, often over short evolutionary timescales, remain elusive. Here we examine two sister-species of Peromyscus mice with divergent mating systems. We find that the promiscuous species produces sperm with longer midpiece than the monogamous species, and midpiece size correlates positively with competitive ability and swimming performance. Using forward genetics, we identify a gene associated with midpiece length: Prkar1a, which encodes the R1a regulatory subunit of PKA. R1a localizes to midpiece in Peromyscus and is differentially expressed in mature sperm of the two species yet is similarly abundant in the testis. We also show that genetic variation at this locus accurately predicts male reproductive success. Our findings suggest that rapid evolution of reproductive traits can occur through cell type-specific changes to ubiquitously expressed genes and have an important effect on fitness.

 

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Copes LE, Lucas LM, Thostenson JO, Hoekstra HE, Boyer DM. A collection of non-human primate computed tomography scans housed in MorphoSource, a repository for 3D data. Scientific Data 2016;3Abstract

A dataset of high-resolution microCT scans of primate skulls (crania and mandibles) and certain postcranial elements was collected to address questions about primate skull morphology. The sample consists of 489 scans taken from 431 specimens, representing 59 species of most Primate families. These data have transformative reuse potential as such datasets are necessary for conducting high power research into primate evolution, but require significant time and funding to collect. Similar datasets were previously only available to select research groups across the world. The physical specimens are vouchered at Harvard’s Museum of Comparative Zoology. The data collection took place at the Center for Nanoscale Systems at Harvard. The dataset is archived on MorphoSource.org. Though this is the largest high fidelity comparative dataset yet available, its provisioning on a web archive that allows unlimited researcher contributions promises a future with vastly increased digital collections available at researchers’ finger tips.

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Greer PL, Bear DM, Lassance JM, Bloom ML, Tsukahara T, Masada FK, Nolan AC, Hoekstra HE, Datta SR. A family of non-GPCR chemosensors defines an alternative logic for mammalian olfaction. Cell 2016;165(7):1734-1748.Abstract

Odor perception in mammals is mediated by parallel sensory pathways that convey distinct information about the olfactory world. Multiple olfactory subsystems express characteristic seven-transmembrane G-protein-coupled receptors (GPCRs) in a one-receptor-per-neuron pattern that facilitates odor discrimination. Sensory neurons of the “necklace” subsystem are nestled within the recesses of the olfactory epithelium and detect diverse odorants; however, they do not express known GPCR odor receptors. Here, we report that members of the four-pass transmembrane MS4A protein family are chemosensors expressed within necklace sensory neurons. These receptors localize to sensory endings and confer responses to ethologically relevant ligands, including pheromones and fatty acids, in vitro and in vivo. Individual necklace neurons co-express many MS4A proteins and are activated by multiple MS4A ligands; this pooling of information suggests that the necklace is organized more like subsystems for taste than for smell. The MS4As therefore define a distinct mechanism and functional logic for mammalian olfaction.


 

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2015
Bedford NL, Hoekstra HE. Peromyscus mice as a model for studying natural variation. eLIFE 2015;4:eO6813Abstract

The deer mouse (genus Peromyscus) is the most abundant mammal in North America, and it occupies almost every type of terrestrial habitat. It is not surprising therefore that the natural history of Peromyscus is among the best studied of any small mammal. For decades, the deer mouse has contributed to our understanding of population genetics, disease ecology, longevity, endocrinology and behavior. Over a century’s worth of detailed descriptive studies of Peromyscus in the wild,
coupled with emerging genetic and genomic techniques, have now positioned these mice as model organisms for the study of natural variation and adaptation. Recent work, combining field observations and laboratory experiments, has lead to exciting advances in a number of fields—from evolution and genetics, to physiology and neurobiology.

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Corbett-Detig R, Jacobs-Palmer E, Hartl DL, Hoekstra HE. Direct gamete sequencing reveals no evidence for segregation distorters in house mouse hybrids. PLoS One 2015;10(6):e0131933.Abstract

Understanding the molecular basis of species formation is an important goal in evolutionary genetics, and Dobzhansky-Muller incompatibilities are thought to be a common source of postzygotic reproductive isolation between closely related lineages. However, the evolutionary forces that lead to the accumulation of such incompatibilities between diverging taxa are poorly understood. Segregation distorters are believed to be an important source of Dobzhansky-Muller incompatibilities between Drosophila species and crop plants, but it remains unclear if these selfish genetic elements contribute to reproductive isolation in other species. Here, we collected viable sperm from first-generation hybrid male progeny of Mus musculus castaneus and M. m. domesticus, two subspecies of rodent in the earliest stages of speciation. We then genotyped millions of single nucleotide polymorphisms in these gamete pools and tested for a skew in the frequency of parental alleles across the genome. We show that segregation distorters are not measurable contributors to observed infertility in these hybrid males, despite sufficient statistical power to detect even weak segregation distortion with our novel method. Thus, reduced hybrid male fertility in crosses between these nascent species is attributable to other evolutionary forces.

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2014
Wray GA, Futuyma DA, Lenski RE, MacKay TFC, Schluter D, Strassman JE, Hoekstra HE. Does evolutionary biology need a rethink? Counterpoint: No, all is well. Nature 2014;514:161-4.Abstract

Theory accommodates evidence through relentless synthesis, say Gregory A. Wray, Hopi E. Hoekstra and colleagues.

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Fisher HS, Giomi L, Hoekstra HE, Mahadevan L. The dynamics of sperm cooperation in a competitive environment. Proceedings of the Royal Society B 2014;281:20140296.Abstract

Sperm cooperation has evolved in a variety of taxa and is often considered a response to sperm competition, yet the benefit of this form of collective movement remains unclear. Here, we use fine-scale imaging and a minimal mathematical model to study sperm aggregation in the rodent genus Peromyscus. We demonstrate that as the number of sperm cells in an aggregate increase, the group moves with more persistent linearity but without increasing speed. This benefit, however, is offset in larger aggregates as the geometry of the group forces sperm to swim against one another. The result is a non-monotonic relationship between aggregate size and average velocity with both a theoretically predicted and empirically observed optimum of six to seven sperm per aggregate. To understand the role of sexual selection in driving these sperm group dynamics, we compared two sister-species with divergent mating systems. We find that sperm of Peromyscus maniculatus (highly promiscuous), which have evolved under intense competition, form optimal-sized aggregates more often than sperm of Peromyscus polionotus (strictly monogamous), which lack competition. Our combined mathematical and experimental study of coordinated sperm movement reveals the importance of geometry, motion and group size on sperm velocity and suggests how these physical variables interact with evolutionary selective pressures to regulate cooperation in competitive environments.

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Poh YP, Domingues VS, Hoekstra HE, Jensen JD. On the prospect of identifying adaptive loci in recently bottlenecked populations. PLoS One 2014;9:e110579.Abstract

Identifying adaptively important loci in recently bottlenecked populations - be it natural selection acting on a population following the colonization of novel habitats in the wild, or artificial selection during the domestication of a breed - remains a major challenge. Here we report the results of a simulation study examining the performance of available population-genetic tools for identifying genomic regions under selection. To illustrate our findings, we examined the interplay between selection and demography in two species of Peromyscus mice, for which we have independent evidence of selection acting on phenotype as well as functional evidence identifying the underlying genotype. With this unusual information, we tested whether population-genetic-based approaches could have been utilized to identify the adaptive locus. Contrary to published claims, we conclude that the use of the background site frequency spectrum as a null model is largely ineffective in bottlenecked populations. Results are quantified both for site frequency spectrum and linkage disequilibrium-based predictions, and are found to hold true across a large parameter space that encompasses many species and populations currently under study. These results suggest that the genomic footprint left by selection on both new and standing variation in strongly bottlenecked populations will be difficult, if not impossible, to find using current approaches.

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