Molly Schumer is an Assistant Professor in Biology. She is interested in the genetic and evolutionary consequences of hybridization. After receiving her PhD at Princeton, she did her postdoctoral work at Columbia and was a Junior Fellow in the Harvard Society of Fellows and Hanna H. Gray Fellow at Harvard Medical School. Current research in the lab focuses on understanding genetic interactions that occur in hybrids and how these impact genome evolution.
Honors & Awards
Doctoral Dissertation Improvement Grant, National Science Foundation (2014-2016)
Milton Award, Harvard University (2017)
Fellow, L'Oréal USA for Women in Science (2017)
Theodosius Dobzhansky Prize, Society for the Study of Evolution (2017)
Rosalind Franklin Young Investigator Award, Genetics Society of America (2019)
BIO 85 (Win)
- bioBUDS (Building Up Developing Scientists): Science In & Beyond the Lab
BIO 114 (Win, Spr)
Independent Studies (1)
- Graduate Research
BIO 300 (Aut, Win)
- Graduate Research
The Genetic Architecture of Variation in the Sexually Selected Sword Ornament and Its Evolution in Hybrid Populations.
Current biology : CB
Biologists since Darwin have been fascinated by the evolution of sexually selected ornaments, particularly those that reduce viability. Uncovering the genetic architecture of these traits is key to understanding how they evolve and are maintained. Here, we investigate the genetic architecture and evolutionary loss of a sexually selected ornament, the "sword" fin extension that characterizes many species of swordtail fish (Xiphophorus). Using sworded and swordless sister species of Xiphophorus, we generated a mapping population and show that the sword ornament is polygenic-with ancestry across the genome explaining substantial variation in the trait. After accounting for the impacts of genome-wide ancestry, we identify one major-effect quantitative trait locus (QTL) that explains ~5% of the overall variation in the trait. Using a series of approaches, we narrow this large QTL interval to several likely candidate genes, including genes involved in fin regeneration and growth. Furthermore, we find evidence of selection on ancestry at one of these candidates in four natural hybrid populations, consistent with selection against the sword in these populations.
View details for DOI 10.1016/j.cub.2020.12.049
View details for PubMedID 33513352
Immune genomic response associated with preference behavior: an examination in a freshwater fish
AMER ASSOC IMMUNOLOGISTS. 2020
View details for Web of Science ID 000589972401040
Versatile simulations of admixture and accurate local ancestry inference with mixnmatch and ancestryinfer.
Molecular ecology resources
It has become clear that hybridization between species is much more common than previously recognized. As a result, we now know that the genomes of many modern species, including our own, are a patchwork of regions derived from past hybridization events. Increasingly researchers are interested in disentangling which regions of the genome originated from each parental species using local ancestry inference methods. Due to the diverse effects of admixture, this interest is shared across disparate fields, from human genetics to research in ecology and evolutionary biology. However, local ancestry inference methods are sensitive to a range of biological and technical parameters which can impact accuracy. Here we present paired simulation and ancestry inference pipelines, mixnmatch and ancestryinfer, to help researchers plan and execute local ancestry inference studies. mixnmatch can simulate arbitrarily complex demographic histories in the parental and hybrid populations, selection on hybrids, and technical variables such as coverage and contamination. ancestryinfer takes as input sequencing reads from simulated or real individuals, and implements an efficient local ancestry inference pipeline. We perform a series of simulations with mixnmatch to pinpoint factors that influence accuracy in local ancestry inference and highlight useful features of the two pipelines. mixnmatch is a powerful tool for simulations of hybridization while ancestryinfer facilitates local ancestry inference on real or simulated data.
View details for DOI 10.1111/1755-0998.13175
View details for PubMedID 32324964
Natural hybridization reveals incompatible alleles that cause melanoma in swordtail fish.
Science (New York, N.Y.)
2020; 368 (6492): 731–36
The establishment of reproductive barriers between populations can fuel the evolution of new species. A genetic framework for this process posits that "incompatible" interactions between genes can evolve that result in reduced survival or reproduction in hybrids. However, progress has been slow in identifying individual genes that underlie hybrid incompatibilities. We used a combination of approaches to map the genes that drive the development of an incompatibility that causes melanoma in swordtail fish hybrids. One of the genes involved in this incompatibility also causes melanoma in hybrids between distantly related species. Moreover, this melanoma reduces survival in the wild, likely because of progressive degradation of the fin. This work identifies genes underlying a vertebrate hybrid incompatibility and provides a glimpse into the action of these genes in natural hybrid populations.
View details for DOI 10.1126/science.aba5216
View details for PubMedID 32409469
- Draft Genome Assembly and Annotation of the Gila Topminnow Poeciliopsis occidentalis FRONTIERS IN ECOLOGY AND EVOLUTION 2019; 7
Natural selection interacts with recombination to shape the evolution of hybrid genomes
2018; 360 (6389): 656–59
To investigate the consequences of hybridization between species, we studied three replicate hybrid populations that formed naturally between two swordtail fish species, estimating their fine-scale genetic map and inferring ancestry along the genomes of 690 individuals. In all three populations, ancestry from the "minor" parental species is more common in regions of high recombination and where there is linkage to fewer putative targets of selection. The same patterns are apparent in a reanalysis of human and archaic admixture. These results support models in which ancestry from the minor parental species is more likely to persist when rapidly uncoupled from alleles that are deleterious in hybrids. Our analyses further indicate that selection on swordtail hybrids stems predominantly from deleterious combinations of epistatically interacting alleles.
View details for DOI 10.1126/science.aar3684
View details for Web of Science ID 000431790900046
View details for PubMedID 29674434
View details for PubMedCentralID PMC6069607
- How the manakin got its crown: A novel trait that is unlikely to cause speciation PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2018; 115 (18): E4144–E4145
- What do we mean when we talk about hybrid speciation? HEREDITY 2018; 120 (4): 379–82
Assortative mating and persistent reproductive isolation in hybrids
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
2017; 114 (41): 10936–41
The emergence of new species is driven by the establishment of mechanisms that limit gene flow between populations. A major challenge is reconciling the theoretical and empirical importance of assortative mating in speciation with the ease with which it can fail. Swordtail fish have an evolutionary history of hybridization and fragile prezygotic isolating mechanisms. Hybridization between two swordtail species likely arose via pollution-mediated breakdown of assortative mating in the 1990s. Here we track unusual genetic patterns in one hybrid population over the past decade using whole-genome sequencing. Hybrids in this population formed separate genetic clusters by 2003, and maintained near-perfect isolation over 25 generations through strong ancestry-assortative mating. However, we also find that assortative mating was plastic, varying in strength over time and disappearing under manipulated conditions. In addition, a nearby population did not show evidence of assortative mating. Thus, our findings suggest that assortative mating may constitute an intermittent and unpredictable barrier to gene flow, but that variation in its strength can have a major effect on how hybrid populations evolve. Understanding how reproductive isolation varies across populations and through time is critical to understanding speciation and hybridization, as well as their dependence on disturbance.
View details for DOI 10.1073/pnas.1711238114
View details for Web of Science ID 000412653900060
View details for PubMedID 28973863
View details for PubMedCentralID PMC5642718
Repeated losses of PRDM9-directed recombination despite the conservation of PRDM9 across vertebrates
Studies of highly diverged species have revealed two mechanisms by which meiotic recombination is directed to the genome-through PRDM9 binding or by targeting promoter-like features-that lead to dramatically different evolutionary dynamics of hotspots. Here, we identify PRDM9 orthologs from genome and transcriptome data in 225 species. We find the complete PRDM9 ortholog across distantly related vertebrates but, despite this broad conservation, infer a minimum of six partial and three complete losses. Strikingly, taxa carrying the complete ortholog of PRDM9 are precisely those with rapid evolution of its predicted binding affinity, suggesting that all domains are necessary for directing recombination. Indeed, as we show, swordtail fish carrying only a partial but conserved ortholog share recombination properties with PRDM9 knock-outs.
View details for DOI 10.7554/eLife.24133
View details for Web of Science ID 000405904400001
View details for PubMedID 28590247
View details for PubMedCentralID PMC5519329
Early social learning triggers neurogenomic expression changes in a swordtail fish
PROCEEDINGS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES
2017; 284 (1854)
Mate choice can play a pivotal role in the nature and extent of reproductive isolation between species. Mating preferences are often dependent on an individual's social experience with adult phenotypes throughout development. We show that olfactory preference in a swordtail fish (Xiphophorus malinche) is affected by previous experience with adult olfactory signals. We compare transcriptome-wide gene expression levels of pooled sensory and brain tissues between three treatment groups that differ by social experience: females with no adult exposure, females exposed to conspecifics and females exposed to heterospecifics. We identify potential functionally relevant genes and biological pathways differentially expressed not only between control and exposure groups, but also between groups exposed to conspecifics and heterospecifics. Based on our results, we speculate that vomeronasal receptor type 2 paralogs may detect species-specific pheromone components and thus play an important role in reproductive isolation between species.
View details for DOI 10.1098/rspb.2017.0701
View details for Web of Science ID 000404425100001
View details for PubMedID 28515207
View details for PubMedCentralID PMC5443958
Determining epistatic selection in admixed populations
2016; 25 (11): 2577–91
When two diverging species begin hybridizing, selection against hybridization is likely driven not by single substitutions, but by interactions between incompatible mutations. To identify these incompatibilities in natural populations, researchers examine the extent of nonrandom associations between ancestry at physically unlinked loci in admixed populations. In this approach, which we call 'AD scans', locus pairs with significantly positive 'ancestry disequilibrium' (AD, i.e. locus pairs that positively covary by ancestry) represent incompatible alleles. Past research has uniformly revealed an excess of locus pairs with significantly positive AD, suggesting that dozens to hundreds of incompatibilities separate species. With forward simulations, we show that many realistic demographic scenarios, including recent and/or ongoing hybridization, generate a bias towards positive ancestry disequilibrium. We suggest steps that researchers can take to avoid pitfalls in interpreting AD scans, and present a novel measure of AD, which minimizes but does not fully eliminate bias in the AD distribution. We also show, by simulation, that the tail of the AD distribution is enriched for true incompatibilities. To illustrate the potential power and appropriate caution in interpretation of AD scans, we reanalyse previously published data from two admixed populations of Xiphophorus fishes. Our results imply that the prevalence of positive LD in admixed populations does not in itself support the idea that two-locus incompatibilities are widespread, but the co-enrichment of top AD hits across the two Xiphophorus populations supports the idea that AD scans can identify candidate interspecific incompatibilities.
View details for DOI 10.1111/mec.13641
View details for Web of Science ID 000378941100019
View details for PubMedID 27061282
Ancient hybridization and genomic stabilization in a swordtail fish
2016; 25 (11): 2661–79
A rapidly increasing body of work is revealing that the genomes of distinct species often exhibit hybrid ancestry, presumably due to postspeciation hybridization between closely related species. Despite the growing number of documented cases, we still know relatively little about how genomes evolve and stabilize following hybridization, and to what extent hybridization is functionally relevant. Here, we examine the case of Xiphophorus nezahualcoyotl, a teleost fish whose genome exhibits significant hybrid ancestry. We show that hybridization was relatively ancient and is unlikely to be ongoing. Strikingly, the genome of X. nezahualcoyotl has largely stabilized following hybridization, distinguishing it from examples such as human-Neanderthal hybridization. Hybridization-derived regions are remarkably distinct from other regions of the genome, tending to be enriched in genomic regions with reduced constraint. These results suggest that selection has played a role in removing hybrid ancestry from certain functionally important regions. Combined with findings in other systems, our results raise many questions about the process of genomic stabilization and the role of selection in shaping patterns of hybrid ancestry in the genome.
View details for DOI 10.1111/mec.13602
View details for Web of Science ID 000378941100025
View details for PubMedID 26937625
Admix'em: a flexible framework for forward-time simulations of hybrid populations with selection and mate choice
2016; 32 (7): 1103–5
We introduce a new forward-time simulator, Admix'em, that allows for rapid and realistic simulations of admixed populations with selection. Complex selection can be achieved through user-defined fitness and mating-preference probability functions. Users can specify realistic genomic landscapes and model neutral SNPs in addition to sites under selection. Admix'em is designed to simulate selection in admixed populations but can also be used as a general population simulator. Usage and examples are in the supplement.C ++ and OpenMP, supports 64-bit Linux/Unix-like platforms. https://email@example.comSupplementary data are available at Bioinformatics online.
View details for DOI 10.1093/bioinformatics/btv700
View details for Web of Science ID 000374236400024
View details for PubMedID 26615212
simMSG: an experimental design tool for high-throughput genotyping of hybrids
MOLECULAR ECOLOGY RESOURCES
2016; 16 (1): 183–92
Hybridization between closely related species, whether naturally occurring or laboratory generated, is a useful tool for mapping the genetic basis of the phenotypic traits that distinguish species. The development of next-generation sequencing techniques has greatly improved our ability to assign ancestry to hybrid genomes. One such next-generation sequencing technique, multiplexed shotgun genotyping (or MSG), can be a powerful tool for genotyping hybrids. However, it is difficult a priori to predict the accuracy of MSG in natural hybrids because accuracy depends on ancestry tract length and number of ancestry informative markers. Here, we present a simulator, 'simMSG', that will allow researchers to design MSG experiments and show that in many cases MSG can accurately assign ancestry to hundreds of thousands of sites in the genomes of natural hybrids. The simMSG tool can be used to design experiments for diverse applications including QTL mapping, genotyping introgressed lines or admixture mapping.
View details for DOI 10.1111/1755-0998.12434
View details for Web of Science ID 000369141000019
View details for PubMedID 26032857
Genetics of Intraspecies Variation in Avoidance Behavior Induced by a Thermal Stimulus in Caenorhabditis elegans
2015; 200 (4): 1327-+
Individuals within a species vary in their responses to a wide range of stimuli, partly as a result of differences in their genetic makeup. Relatively little is known about the genetic and neuronal mechanisms contributing to diversity of behavior in natural populations. By studying intraspecies variation in innate avoidance behavior to thermal stimuli in the nematode Caenorhabditis elegans, we uncovered genetic principles of how different components of a behavioral response can be altered in nature to generate behavioral diversity. Using a thermal pulse assay, we uncovered heritable variation in responses to a transient temperature increase. Quantitative trait locus mapping revealed that separate components of this response were controlled by distinct genomic loci. The loci we identified contributed to variation in components of thermal pulse avoidance behavior in an additive fashion. Our results show that the escape behavior induced by thermal stimuli is composed of simpler behavioral components that are influenced by at least six distinct genetic loci. The loci that decouple components of the escape behavior reveal a genetic system that allows independent modification of behavioral parameters. Our work sets the foundation for future studies of evolution of innate behaviors at the molecular and neuronal level.
View details for DOI 10.1534/genetics.115.178491
View details for Web of Science ID 000359917000027
View details for PubMedID 26092720
View details for PubMedCentralID PMC4574258
Reproductive Isolation of Hybrid Populations Driven by Genetic Incompatibilities
2015; 11 (3): e1005041
Despite its role in homogenizing populations, hybridization has also been proposed as a means to generate new species. The conceptual basis for this idea is that hybridization can result in novel phenotypes through recombination between the parental genomes, allowing a hybrid population to occupy ecological niches unavailable to parental species. Here we present an alternative model of the evolution of reproductive isolation in hybrid populations that occurs as a simple consequence of selection against genetic incompatibilities. Unlike previous models of hybrid speciation, our model does not incorporate inbreeding, or assume that hybrids have an ecological or reproductive fitness advantage relative to parental populations. We show that reproductive isolation between hybrids and parental species can evolve frequently and rapidly under this model, even in the presence of substantial ongoing immigration from parental species and strong selection against hybrids. An interesting prediction of our model is that replicate hybrid populations formed from the same pair of parental species can evolve reproductive isolation from each other. This non-adaptive process can therefore generate patterns of species diversity and relatedness that resemble an adaptive radiation. Intriguingly, several known hybrid species exhibit patterns of reproductive isolation consistent with the predictions of our model.
View details for DOI 10.1371/journal.pgen.1005041
View details for Web of Science ID 000352197100031
View details for PubMedID 25768654
View details for PubMedCentralID PMC4359097
Environmental heterogeneity generates opposite gene-by-environment interactions for two fitness-related traits within a population
2015; 69 (2): 541–50
Theory predicts that environmental heterogeneity offers a potential solution to the maintenance of genetic variation within populations, but empirical evidence remains sparse. The live-bearing fish Xiphophorus variatus exhibits polymorphism at a single locus, with different alleles resulting in up to five distinct melanistic "tailspot" patterns within populations. We investigated the effects of heterogeneity in two ubiquitous environmental variables (temperature and food availability) on two fitness-related traits (upper thermal limits and body condition) in two different tailspot types (wild-type and upper cut crescent). We found gene-by-environment (G × E) interactions between tailspot type and food level affecting upper thermal limits (UTL), as well as between tailspot type and thermal environment affecting body condition. Exploring mechanistic bases underlying these G × E patterns, we found no differences between tailspot types in hsp70 gene expression despite significant overall increases in expression under both thermal and food stress. Similarly, there was no difference in routine metabolic rates between the tailspot types. The reversal of relative performance of the two tailspot types under different environmental conditions revealed a mechanism by which environmental heterogeneity can balance polymorphism within populations through selection on different fitness-related traits.
View details for DOI 10.1111/evo.12574
View details for Web of Science ID 000348916200020
View details for PubMedID 25496554
High-resolution Mapping Reveals Hundreds of Genetic Incompatibilities in Hybridizing Fish Species
Hybridization is increasingly being recognized as a common process in both animal and plant species. Negative epistatic interactions between genes from different parental genomes decrease the fitness of hybrids and can limit gene flow between species. However, little is known about the number and genome-wide distribution of genetic incompatibilities separating species. To detect interacting genes, we perform a high-resolution genome scan for linkage disequilibrium between unlinked genomic regions in naturally occurring hybrid populations of swordtail fish. We estimate that hundreds of pairs of genomic regions contribute to reproductive isolation between these species, despite them being recently diverged. Many of these incompatibilities are likely the result of natural or sexual selection on hybrids, since intrinsic isolation is known to be weak. Patterns of genomic divergence at these regions imply that genetic incompatibilities play a significant role in limiting gene flow even in young species.
View details for DOI 10.7554/eLife.02535
View details for Web of Science ID 000336837300003
View details for PubMedID 24898754
View details for PubMedCentralID PMC4080447
HOW COMMON IS HOMOPLOID HYBRID SPECIATION?
2014; 68 (6): 1553–60
Hybridization has long been considered a process that prevents divergence between species. In contrast to this historical view, an increasing number of empirical studies claim to show evidence for hybrid speciation without a ploidy change. However, the importance of hybridization as a route to speciation is poorly understood, and many claims have been made with insufficient evidence that hybridization played a role in the speciation process. We propose criteria to determine the strength of evidence for homoploid hybrid speciation. Based on an evaluation of the literature using this framework, we conclude that although hybridization appears to be common, evidence for an important role of hybridization in homoploid speciation is more circumscribed.
View details for DOI 10.1111/evo.12399
View details for Web of Science ID 000337558900001
View details for PubMedID 24620775
PHYLOGENOMICS REVEALS EXTENSIVE RETICULATE EVOLUTION IN XIPHOPHORUS FISHES
2013; 67 (8): 2166–79
Hybridization is increasingly being recognized as a widespread process, even between ecologically and behaviorally divergent animal species. Determining phylogenetic relationships in the presence of hybridization remains a major challenge for evolutionary biologists, but advances in sequencing technology and phylogenetic techniques are beginning to address these challenges. Here we reconstruct evolutionary relationships among swordtails and platyfishes (Xiphophorus: Poeciliidae), a group of species characterized by remarkable morphological diversity and behavioral barriers to interspecific mating. Past attempts to reconstruct phylogenetic relationships within Xiphophorus have produced conflicting results. Because many of the 26 species in the genus are interfertile, these conflicts are likely due to hybridization. Using genomic data, we resolve a high-confidence species tree of Xiphophorus that accounts for both incomplete lineage sorting and hybridization. Our results allow us to reexamine a long-standing controversy about the evolution of the sexually selected sword in Xiphophorus, and demonstrate that hybridization has been strikingly widespread in the evolutionary history of this genus.
View details for DOI 10.1111/evo.12099
View details for Web of Science ID 000322329500002
View details for PubMedID 23888843
- Infestation by a Common Parasite is Correlated with Ant Symbiont Identity in a Plant-Ant Mutualism BIOTROPICA 2013; 45 (3): 276–79
- Genetic accommodation and behavioural evolution: insights from genomic studies ANIMAL BEHAVIOUR 2013; 85 (5): 1012–22
AN EVALUATION OF THE HYBRID SPECIATION HYPOTHESIS FOR XIPHOPHORUS CLEMENCIAE BASED ON WHOLE GENOME SEQUENCES
2013; 67 (4): 1155–68
Once thought rare in animal taxa, hybridization has been increasingly recognized as an important and common force in animal evolution. In the past decade, a number of studies have suggested that hybridization has driven speciation in some animal groups. We investigate the signature of hybridization in the genome of a putative hybrid species, Xiphophorus clemenciae, through whole genome sequencing of this species and its hypothesized progenitors. Based on analysis of this data, we find that X. clemenciae is unlikely to have been derived from admixture between its proposed parental species. However, we find significant evidence for recent gene flow between Xiphophorus species. Although we detect genetic exchange in two pairs of species analyzed, the proportion of genomic regions that can be attributed to hybrid origin is small, suggesting that strong behavioral premating isolation prevents frequent hybridization in Xiphophorus. The direction of gene flow between species is potentially consistent with a role for sexual selection in mediating hybridization.
View details for DOI 10.1111/evo.12009
View details for Web of Science ID 000317133800019
View details for PubMedID 23550763
View details for PubMedCentralID PMC3621027
Parallel Molecular Evolution in an Herbivore Community
2012; 337 (6102): 1634–37
Numerous insects have independently evolved the ability to feed on plants that produce toxic secondary compounds called cardenolides and can sequester these compounds for use in their defense. We surveyed the protein target for cardenolides, the alpha subunit of the sodium pump, Na(+),K(+)-ATPase (ATPα), in 14 species that feed on cardenolide-producing plants and 15 outgroups spanning three insect orders. Despite the large number of potential targets for modulating cardenolide sensitivity, amino acid substitutions associated with host-plant specialization are highly clustered, with many parallel substitutions. Additionally, we document four independent duplications of ATPα with convergent tissue-specific expression patterns. We find that unique substitutions are disproportionately associated with recent duplications relative to parallel substitutions. Together, these findings support the hypothesis that adaptation tends to take evolutionary paths that minimize negative pleiotropy.
View details for DOI 10.1126/science.1226630
View details for Web of Science ID 000309215400039
View details for PubMedID 23019645
View details for PubMedCentralID PMC3770729
Comparative gene expression profiles for highly similar aggressive phenotypes in male and female cichlid fishes (Julidochromis)
JOURNAL OF EXPERIMENTAL BIOLOGY
2011; 214 (19): 3269–78
Julidochromis marlieri and Julidochromis transcriptus are two closely related Tanganyikan cichlids that have evolved different behavior and mating strategies since they diverged from their common ancestor. While J. transcriptus follows the ancestral pattern of male dominance, male-biased sexual size dimorphism and territoriality, the pattern is reversed in J. marlieri. In J. marlieri, females show all of these behavioral and morphological characteristics. This raises the question of whether female J. marlieri achieve the dominant phenotype by expressing the same genes as J. transcriptus males or whether novel brain gene expression patterns have evolved to produce a similar behavioral phenotype in the females of J. marlieri. This study used cDNA microarrays to investigate whether female J. marlieri and male J. transcriptus show conserved or divergent patterns of brain gene expression. Analysis of microarray data in both species showed certain gene expression patterns associated with sex role independent of gonadal sex and, to a lesser extent, gene expression patterns associated with sex independent of sex role. In general, these data suggest that while there has been substantial divergence in gene expression patterns between J. transcriptus and J. marlieri, we can detect a highly significant overlap for a core set of genes related to aggression in both species. These results suggest that the proximate mechanisms regulating aggressive behavior in J. transcriptus and J. marlieri may be shared.
View details for DOI 10.1242/jeb.055467
View details for Web of Science ID 000294663300020
View details for PubMedID 21900474
View details for PubMedCentralID PMC3168378
A serine cluster mediates BMAL1-dependent CLOCK phosphorylation and degradation
2009; 8 (24): 4138–46
The circadian clock regulates biological processes from gene expression to organism behavior in a precise, sustained rhythm that is generated at the unicellular level by coordinated function of interlocked transcriptional feedback loops and post-translational modifications of core clock proteins. CLOCK phosphorylation regulates transcriptional activity, cellular localization and stability; however little is known about the specific residues and enzymes involved. We have identified a conserved cluster of serines that include, Ser431, which is a prerequisite phosphorylation site for the generation of BMAL dependent phospho-primed CLOCK and for the potential GSK-3 phosphorylation at Ser427. Mutational analysis and protein stability assays indicate that this serine cluster functions as a phospho-degron. Through the use of GSK-3 activators/inhibitors and kinase assays, we demonstrate that GSK-3beta regulates the degron site by increasing CLOCK phosphorylation/degradation, which correlates with an increase in the expression of CLOCK responsive promoters. Stabilization of phospho-deficient CLOCK delays the phase of oscillation in synchronized fibroblasts. This investigation begins the characterization of a complex phospho-regulatory site that controls the activity and degradation of CLOCK, a core transcription factor that is essential for circadian behavior.
View details for DOI 10.4161/cc.8.24.10273
View details for Web of Science ID 000273232300032
View details for PubMedID 19946213
View details for PubMedCentralID PMC4073639