Publications

2016
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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2013
Linnen CR, Poh YP, Peterson BK, Barrett RD, Larson JG, Jensen JD, Hoekstra HE. Adaptive evolution of multiple traits through multiple mutations at a single gene. Science 2013;339:1312-6.Abstract

The identification of precise mutations is required for a complete understanding of the underlying molecular and evolutionary mechanisms driving adaptive phenotypic change. Using plasticine models in the field, we show that the light coat color of deer mice that recently colonized the light-colored soil of the Nebraska Sand Hills provides a strong selective advantage against visually hunting predators. Color variation in an admixed population suggests that this light Sand Hills phenotype is composed of multiple traits. We identified distinct regions within the Agouti locus associated with each color trait and found that only haplotypes associated with light trait values have evidence of selection. Thus, local adaptation is the result of independent selection on many mutations within a single locus, each with a specific effect on an adaptive phenotype, thereby minimizing pleiotropic consequences.

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Weber JN, Peterson BK, Hoekstra HE. Discrete genetic modules are responsible for complex burrow evolution in Peromyscus mice. Nature 2013;493:402-5.Abstract

Relative to morphological traits, we know little about how genetics influence the evolution of complex behavioural differences in nature. It is unclear how the environment influences natural variation in heritable behaviour, and whether complex behavioural differences evolve through few genetic changes, each affecting many aspects of behaviour, or through the accumulation of several genetic changes that, when combined, give rise to behavioural complexity. Here we show that in nature, oldfield mice (Peromyscus polionotus) build complex burrows with long entrance and escape tunnels, and that burrow length is consistent across populations, although burrow depth varies with soil composition. This burrow architecture is in contrast with the small, simple burrows of its sister species, deer mice (P. maniculatus). When investigated under laboratory conditions, both species recapitulate their natural burrowing behaviour. Genetic crosses between the two species reveal that the derived burrows of oldfield mice are dominant and evolved through the addition of multiple genetic changes. In burrows built by first-generation backcross mice, entrance-tunnel length and the presence of an escape tunnel can be uncoupled, suggesting that these traits are modular. Quantitative trait locus analysis also indicates that tunnel length segregates as a complex trait, affected by at least three independent genetic regions, whereas the presence of an escape tunnel is associated with only a single locus. Together, these results suggest that complex behaviours--in this case, a classic 'extended phenotype'--can evolve through multiple genetic changes each affecting distinct behaviour modules.

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Kocher SD, Li C, Yang W, Tan H, Yi SV, Yang X, Hoekstra HE, Zhang G, Pierce NE, Yu DW. The draft genome of a socially polymorphic halictid bee, Lasioglossum albipes. Genome Biology 2013;14:R142.Abstract

BACKGROUND: Taxa that harbor natural phenotypic variation are ideal for ecological genomic approaches aimed at understanding how the interplay between genetic and environmental factors can lead to the evolution of complex traits. Lasioglossum albipes is a polymorphic halictid bee that expresses variation in social behavior among populations, and common-garden experiments have suggested that this variation is likely to have a genetic component. RESULTS: We present the L. albipes genome assembly to characterize the genetic and ecological factors associated with the evolution of social behavior. The de novo assembly is comparable to other published social insect genomes, with an N50 scaffold length of 602 kb. Gene families unique to L. albipes are associated with integrin-mediated signaling and DNA-binding domains, and several appear to be expanded in this species, including the glutathione-s-transferases and the inositol monophosphatases. L. albipes has an intact DNA methylation system, and in silico analyses suggest that methylation occurs primarily in exons. Comparisons to other insect genomes indicate that genes associated with metabolism and nucleotide binding undergo accelerated evolution in the halictid lineage. Whole-genome resequencing data from one solitary and one social L. albipes female identify six genes that appear to be rapidly diverging between social forms, including a putative odorant receptor and a cuticular protein. CONCLUSIONS: L. albipes represents a novel genetic model system for understanding the evolution of social behavior. It represents the first published genome sequence of a primitively social insect, thereby facilitating comparative genomic studies across the Hymenoptera as a whole.

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Losos JB, Arnold SJ, Bejerano G, Brodie ED, Hibbett D, Hoekstra HE, Mindell DP, Monteiro A, Moritz C, Orr HA, Petrov DA, Renner SS, Ricklefs RE, Soltis PS, Turner TL. Evolutionary biology for the 21st century. PLoS Biology 2013;11:e1001466 PDF
Kowalko JE, Rohner N, Rompani SB, Peterson BK, Linden TA, Yoshizawa M, Kay EH, Weber J, Hoekstra HE, Jeffery WR, Borowsky R, Tabin CJ. Loss of schooling behavior in cavefish through sight-dependent and sight-independent mechanisms. Current Biology 2013;23:1874-83.Abstract

BACKGROUND: Surface populations of Astyanax mexicanus, living in rivers like their common ancestors, school, while several, independently derived cave populations of the same species have lost schooling behavior. RESULTS: We quantify schooling behavior in individual A. mexicanus and identify quantitative trait loci (QTL) for this trait. We find that the evolutionary modulation of schooling has both vision-dependent and -independent components. We also quantify differences in the lateral line and vision between cavefish and surface fish and relate these differences to the evolutionary loss of schooling behavior. We provide evidence that a monoamine neurotransmitter may have played a role in the evolution of schooling behavior. CONCLUSIONS: We find that vision is essential for schooling tendency in A. mexicanus, while the lateral line has a small effect on this behavior. Schooling behavior in A. mexicanus has evolved both through changes in sensory systems and through changes in genetic loci that likely act downstream of sensory inputs.

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2012
Tong W, Hoekstra HE. Mus spicilegus. Current Biology 2012;20(2):858-859.Abstract

What or who is Mus spicilegus? Mus spicilegus, aka ‘the mound-building mouse’, is a rather nondescript, brown mouse that looks just like its close relative, the commensal house mouse (Mus musculus). In fact, they look so much like house mice that the first individuals described in 1840 from a garden in Odessa probably were house mice. Its epithet ‘spicilegus’ is derived from the Latin, spica meaning a spike of grain, and legere, to collect, which makes sense, since these mice do in fact gather grains.

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Peterson BK, Weber JN, Kay EH, Fisher HS, Hoekstra HE. Double digest RADseq: An inexpensive method for de novo SNP discovery and genotyping in model and non-model species. PLoS One 2012;7:e37135.Abstract

The ability to efficiently and accurately determine genotypes is a keystone technology in modern genetics, crucial to studies ranging from clinical diagnostics, to genotype-phenotype association, to reconstruction of ancestry and the detection of selection. To date, high capacity, low cost genotyping has been largely achieved via "SNP chip" microarray-based platforms which require substantial prior knowledge of both genome sequence and variability, and once designed are suitable only for those targeted variable nucleotide sites. This method introduces substantial ascertainment bias and inherently precludes detection of rare or population-specific variants, a major source of information for both population history and genotype-phenotype association. Recent developments in reduced-representation genome sequencing experiments on massively parallel sequencers (commonly referred to as RAD-tag or RADseq) have brought direct sequencing to the problem of population genotyping, but increased cost and procedural and analytical complexity have limited their widespread adoption. Here, we describe a complete laboratory protocol, including a custom combinatorial indexing method, and accompanying software tools to facilitate genotyping across large numbers (hundreds or more) of individuals for a range of markers (hundreds to hundreds of thousands). Our method requires no prior genomic knowledge and achieves per-site and per-individual costs below that of current SNP chip technology, while requiring similar hands-on time investment, comparable amounts of input DNA, and downstream analysis times on the order of hours. Finally, we provide empirical results from the application of this method to both genotyping in a laboratory cross and in wild populations. Because of its flexibility, this modified RADseq approach promises to be applicable to a diversity of biological questions in a wide range of organisms.

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Domingues VS, Poh YP, Peterson BK, Pennings PS, Jensen JD, Hoekstra HE. Evidence of adaptation from ancestral variation in young populations of beach mice. Evolution 2012;66:3209-23.Abstract

To understand how organisms adapt to novel habitats, which involves both demographic and selective events, we require knowledge of the evolutionary history of populations and also selected alleles. There are still few cases in which the precise mutations (and hence, defined alleles) that contribute to adaptive change have been identified in nature; one exception is the genetic basis of camouflaging pigmentation of oldfield mice (Peromyscus polionotus) that have colonized the sandy dunes of Florida's Gulf Coast. To quantify the genomic impact of colonization as well as the signature of selection, we resequenced 5000 1.5-kb noncoding loci as well as a 160-kb genomic region surrounding the melanocortin-1 receptor (Mc1r), a gene that contributes to pigmentation differences, in beach and mainland populations. Using a genome-wide phylogenetic approach, we recovered a single monophyletic group comprised of beach mice, consistent with a single colonization event of the Gulf Coast. We also found evidence of a severe founder event, estimated to have occurred less than 3000 years ago. In this demographic context, we show that all beach subspecies share a single derived light Mc1r allele, which was likely selected from standing genetic variation that originated in the mainland. Surprisingly, we were unable to identify a clear signature of selection in the Mc1r region, despite independent evidence that this locus contributes to adaptive coloration. Nonetheless, these data allow us to reconstruct and compare the evolutionary history of populations and alleles to better understand how adaptive evolution, following the colonization of a novel habitat, proceeds in nature.

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Hoekstra HE. Genomics: Stickleback is the catch of the day. Nature 2012;484:46-7. PDF
Kronforst MR, Barsh GS, Kopp A, Mallet J, Monteiro A, Mullen SP, Protas M, Rosenblum EB, Schneider CJ, Hoekstra HE. Unraveling the thread of nature's tapestry: The genetics of diversity and convergence in animal pigmentation. Pigment Cell & Melanoma Research 2012;25:411-33.Abstract

Animals display incredibly diverse color patterns yet little is known about the underlying genetic basis of these phenotypes. However, emerging results are reshaping our view of how the process of phenotypic evolution occurs. Here, we outline recent research from three particularly active areas of investigation: melanin pigmentation in Drosophila, wing patterning in butterflies, and pigment variation in lizards. For each system, we highlight (i) the function and evolution of color variation, (ii) various approaches that have been used to explore the genetic basis of pigment variation, and (iii) conclusions regarding the genetic basis of convergent evolution which have emerged from comparative analyses. Results from these studies indicate that natural variation in pigmentation is a particularly powerful tool to examine the molecular basis of evolution, especially with regard to convergent or parallel evolution. Comparison of these systems also reveals that the molecular basis of convergent evolution is heterogeneous, sometimes involving conserved mechanisms and sometimes not. In the near future, additional work in other emerging systems will substantially expand the scope of available comparisons.

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2011
Goncalves G, Hoekstra HE, de Freitas. TRO. Striking coat colour variation in tuco-tucos (Rodentia: Ctenomyidae): A role for the melanocortin-1 receptor?. Biological Journal of the Linnean Society 2011;105:665-80.Abstract

South American tuco-tucos (Ctenomys) are characterized by striking variation in coat colour. A range of phenotypes, from pale blonde to dark black, is observed across species, with some of them matching their local substrate colour. Moreover, phenotypic convergence is evident in some taxa that occupy similar habitats. The present study investigated a role for the melanocortin-1 receptor (Mc1r) in determining coat-colour variation in a wide range of Ctenomys species. We sequenced 1250 bp, including the entire Mc1r coding region and a portion of the adjacent 5 and 3untranslated regions, in 21 species. In total, 20 amino acid replacements were identified in Mc1r. However, our findings suggest that these changes have not contributed to coat-colour differences among tuco-tucos because no amino acid replacement was associated with pigmentation phenotype in a simple way. Levels of Mc1r expression were measured in skin samples from dorsal, flank, and ventral body regions in pale, brown, and melanic individuals. We did not observe any significant difference in transcript abundance among phenotypes, although we identified a significant reduction of expression level from the dorsal to ventral region in both pale and brown morphs but not in the completely melanic form. Thus, a role for Mc1r regulation in tuco-tucos colour pattern cannot be completely ruled out, although further functional assays are needed. Finally, selection analysis suggests that Mc1r, in a majority of lineages, has evolved under purifying selection but with relaxation in functional constraint in some regions, especially in the fourth transmembrane domain. In summary, the results obtained in the present study suggest that this trait may have a complex basis, and that other pigmentation genes are involved in generating the dramatic diversity in coat-colour phenotypes observed among Ctenomys species. © 2012 The Linnean Society of London, Biological Journal of the Linnean Society, 2012, 105, 665–680.

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Manceau M, Domingues VS, Mallarino R, Hoekstra HE. The developmental role of Agouti in color pattern evolution. Science 2011;331:1062-5.Abstract

Animal color patterns can affect fitness in the wild; however, little is known about the mechanisms that control their formation and subsequent evolution. We took advantage of two locally camouflaged populations of Peromyscus mice to show that the negative regulator of adult pigmentation, Agouti, also plays a key developmental role in color pattern evolution. Genetic and functional analyses showed that ventral-specific embryonic expression of Agouti establishes a prepattern by delaying the terminal differentiation of ventral melanocytes. Moreover, a skin-specific increase in both the level and spatial domain of Agouti expression prevents melanocyte maturation in a regionalized manner, resulting in a novel and adaptive color pattern. Thus, natural selection favors late-acting, tissue-specific changes in embryonic Agouti expression to produce large changes in adult color pattern.

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