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Article ; Online: Patterns of Genomic Diversity in a Fig-Associated Close Relative of Caenorhabditis elegans.

Woodruff, Gavin C / Willis, John H / Phillips, Patrick C

2024 Volume 16, Issue 2

Abstract: ... the sister species of C. elegans, is a gonochoristic nematode that thrives in figs and obligately disperses ... on fig wasps. Here, we describe patterns of genomic diversity in C. inopinata. We performed RAD-seq ... on individual worms isolated from the field across three Okinawan island populations. C. inopinata is about five ...

Abstract	The evolution of reproductive mode is expected to have profound impacts on the genetic composition of populations. At the same time, ecological interactions can generate close associations among species, which can in turn generate a high degree of overlap in their spatial distributions. Caenorhabditis elegans is a hermaphroditic nematode that has enabled extensive advances in developmental genetics. Caenorhabditis inopinata, the sister species of C. elegans, is a gonochoristic nematode that thrives in figs and obligately disperses on fig wasps. Here, we describe patterns of genomic diversity in C. inopinata. We performed RAD-seq on individual worms isolated from the field across three Okinawan island populations. C. inopinata is about five times more diverse than C. elegans. Additionally, C. inopinata harbors greater differences in diversity among functional genomic regions (such as between genic and intergenic sequences) than C. elegans. Conversely, C. elegans harbors greater differences in diversity between high-recombining chromosome arms and low-recombining chromosome centers than C. inopinata. FST is low among island population pairs, and clear population structure could not be easily detected among islands, suggesting frequent migration of wasps between islands. These patterns of population differentiation appear comparable with those previously reported in its fig wasp vector. These results confirm many theoretical population genetic predictions regarding the evolution of reproductive mode and suggest C. inopinata population dynamics may be driven by wasp dispersal. This work sets the stage for future evolutionary genomic studies aimed at understanding the evolution of sex as well as the evolution of ecological interactions.
MeSH term(s)	Animals ; Caenorhabditis elegans/genetics ; Ficus/genetics ; Caenorhabditis/genetics ; Genetics, Population ; Genomics
Language	English
Publishing date	2024-01-30
Publishing country	England
Document type	Journal Article
ZDB-ID	2495328-3
ISSN	1759-6653 ; 1759-6653
ISSN (online)	1759-6653
ISSN	1759-6653
DOI	10.1093/gbe/evae020
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Heritable epigenetic variation facilitates long-term maintenance of epigenetic and genetic variation.

Webster, Amy K / Phillips, Patrick C

G3 (Bethesda, Md.)

2023 Volume 14, Issue 2

Abstract: How genetic and phenotypic variation are maintained has long been one of the fundamental questions in population and quantitative genetics. A variety of factors have been implicated to explain the maintenance of genetic variation in some contexts (e.g. ... ...

Abstract	How genetic and phenotypic variation are maintained has long been one of the fundamental questions in population and quantitative genetics. A variety of factors have been implicated to explain the maintenance of genetic variation in some contexts (e.g. balancing selection), but the potential role of epigenetic regulation to influence population dynamics has been understudied. It is well recognized that epigenetic regulation, including histone methylation, small RNA expression, and DNA methylation, helps to define differences between cell types and facilitate phenotypic plasticity. In recent years, empirical studies have shown the potential for epigenetic regulation to also be heritable for at least a few generations without selection, raising the possibility that differences in epigenetic regulation can act alongside genetic variation to shape evolutionary trajectories. Heritable differences in epigenetic regulation that arise spontaneously are termed "epimutations." Epimutations differ from genetic mutations in 2 key ways-they occur at a higher rate and the loci at which they occur often revert back to their original state within a few generations. Here, we present an extension of the standard population genetic model with selection to incorporate epigenetic variation arising via epimutation. Our model assumes a diploid, sexually reproducing population with random mating. In addition to spontaneous genetic mutation, we included parameters for spontaneous epimutation and back-epimutation, allowing for 4 potential epialleles at a single locus (2 genetic alleles, each with 2 epigenetic states), each of which affect fitness. We then analyzed the conditions under which stable epialleles were maintained. Our results show that highly reversible epialleles can be maintained in long-term equilibrium under neutral conditions in a manner that depends on the epimutation and back-epimutation rates, which we term epimutation-back-epimutation equilibrium. On the other hand, epialleles that compensate for deleterious mutations cause deviations from the expectations of mutation-selection balance by a simple factor that depends on the epimutation and back-epimutation rates. We also numerically analyze several sets of fitness parameters for which large deviations from mutation-selection balance occur. Together, these results demonstrate that transient epigenetic regulation may be an important factor in the maintenance of both epigenetic and genetic variation in populations.
MeSH term(s)	Epigenesis, Genetic ; DNA Methylation ; Mutation ; Alleles ; Genetic Variation
Language	English
Publishing date	2023-12-19
Publishing country	England
Document type	Journal Article
ZDB-ID	2629978-1
ISSN	2160-1836 ; 2160-1836
ISSN (online)	2160-1836
ISSN	2160-1836
DOI	10.1093/g3journal/jkad287
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Expansion of the split hygromycin toolkit for transgene insertion in

Moerdyk-Schauwecker, Megan J / Jahahn, Erin K / Muñoz, Zachariah I / Robinson, Kristin J / Phillips, Patrick C

microPublication biology

2024 Volume 2024

Abstract: Engineered sites for genetic transformation have simplified transgene insertion ... ...

Abstract	Engineered sites for genetic transformation have simplified transgene insertion in
Language	English
Publishing date	2024-01-29
Publishing country	United States
Document type	Journal Article
ISSN	2578-9430
ISSN (online)	2578-9430
DOI	10.17912/micropub.biology.001091
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Article: Widespread changes in gene expression accompany body size evolution in nematodes.

Woodruff, Gavin C / Willis, John H / Johnson, Erik / Phillips, Patrick C

bioRxiv : the preprint server for biology

2023

Abstract: Body size is a fundamental trait that drives multiple evolutionary and ecological patterns. ...

Abstract	Body size is a fundamental trait that drives multiple evolutionary and ecological patterns.
Language	English
Publishing date	2023-11-02
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.10.30.564729
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Article: Post-insemination sexual selection in males indirectly masculinizes the female transcriptome.

Kasimatis, Katja R / Willis, John H / Phillips, Patrick C

bioRxiv : the preprint server for biology

2023

Abstract: Sex-specific regulation of gene expression is the most plausible way for generating sexually differentiated phenotypes from an essentially shared genome. However, since genetic material is shared, sex-specific selection in one sex can have an indirect ... ...

Abstract	Sex-specific regulation of gene expression is the most plausible way for generating sexually differentiated phenotypes from an essentially shared genome. However, since genetic material is shared, sex-specific selection in one sex can have an indirect response in the other sex. From a gene expression perspective, this tethered response can move one sex away from their wildtype expression state and impact potentially many gene regulatory networks. Here, using experimental evolution in the model nematode Lay summary: Sexual selection drives the evolution of some of the most dramatic phenotypic differences between the sexes. Such sexual dimorphism is so common across multicellular organisms that we often overlook how remarkable it is for shared genetic material to create numerous and complex sex differences. At an evolutionary level, sexual dimorphism furthers the opportunity for sex-specific selection to optimize the fitness of a given sex. As a consequence, sex-specific selection, such as sexual selection, can have an indirect evolutionary response in the other sex due to genetic associations created by the sexes sharing the same genome. This correlated evolutionary response can create sexual conflict by shifting a sex away from their fitness optimum. At the functional level, sexual dimorphism is generated is through sex-specific regulation of gene expression. Bridging the evolutionary response to sexual selection with the evolution of sex-specific gene regulation during post-mating interactions has proved challenging. We previously used experimental evolution to increase male fertility by directly selecting for increased sperm competitive ability. In this study, we examined the effect of this direct selection on males on gene expression patterns in females. Differential gene expression was determined by whether a female was ancestral or evolved generation, indicating that gene expression changes were an evolved response due to indirect selection on females. Significantly differentially expressed genes were downregulated in evolved females. These genes tended to be female-biased in wildtype individuals and located on the X chromosome. The downregulation of X-linked genes suggests expression levels in females equal to or lower than that in males. Together these results indicate a less female-like transcriptome after experimental evolution. This supports a sexual conflict scenario by which direct sexual selection on males indirectly masculinizes the female transcriptome over short evolutionary timescales.
Language	English
Publishing date	2023-08-13
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.08.09.552689
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Article: Keeping phase III tuberculosis trials relevant: Adapting to a rapidly changing landscape

Phillips, Patrick / Mitnick, Carole / Nahid, Payam

PLoS medicine, 16(3):e1002767

2019

Abstract: SUMMARY POINTS: (*) The landscape of tuberculosis (TB) treatment has evolved considerably over the last 10 years, necessitating careful consideration of various trial design aspects to ensure that TB phase III trials are still impactful at trial ... ...

Abstract	SUMMARY POINTS: () The landscape of tuberculosis (TB) treatment has evolved considerably over the last 10 years, necessitating careful consideration of various trial design aspects to ensure that TB phase III trials are still impactful at trial completion, often more than 4–5 years after initial design. () The choice of control is guided by the specific trial objectives, weighing the relative merits of internal validity and external generalizability alongside randomization in making the correct inference. A particular challenge occurs when international or national guidelines change during the trial. () Improved execution and relevance of noninferiority trials for TB require greater emphasis on study quality, especially maximizing treatment adherence and minimizing missing outcome data; preferred use of intention-to-treat rather than per-protocol analyses; more careful justification of the margin of noninferiority; and consideration of recent innovations such as a Bayesian approach to noninferiority. () Many adaptive trial designs are well suited to optimization of TB treatment. A thorough understanding of type I error rates and biases in treatment effect estimates is critical for regulatory approval and consideration in establishing World Health Organization (WHO) guidelines. () Treatment stratification is an area of limited experience for TB trials, and trialists must learn from well-established methodology in other disease areas. () Explanatory trials are important for evaluating the efficacy of an intervention under close to ideal conditions. However, no single trial can address all relevant questions about a given therapeutic intervention at one time, and pragmatic trials will be essential for public health and policy decision-making purposes. (*) TB treatment trials today should favor bold and creative approaches that can produce high-quality evidence for effective, patient-centered care made accessible to all 10 million new TB patients, including the half-million with drug-resistant TB (DR-TB), each year.
Keywords	Clinical trials ; Drug therapy ; Extensively drug-resistant tuberculosis ; Multi-drug-resistant tuberculosis ; Phase III clinical investigation ; Treatment guidelines ; Tuberculosis ; Tuberculosis diagnosis and management
Language	English
Document type	Article
Database	Repository for Life Sciences

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Article ; Online: Evolution: Five Heads Are Better Than One.

Phillips, Patrick C

Current biology : CB

2016 Volume 26, Issue 7, Page(s) R283–5

Abstract: Three newly discovered species of fig-living nematodes display remarkable diversity in head morphology depending on their local environment. This shows that a great deal of ecological diversity can be maintained in the absence of substantial genetic ... ...

Abstract	Three newly discovered species of fig-living nematodes display remarkable diversity in head morphology depending on their local environment. This shows that a great deal of ecological diversity can be maintained in the absence of substantial genetic variation.
MeSH term(s)	Animals ; Biological Evolution ; Ecology ; Genetic Variation ; Head ; Phylogeny
Language	English
Publishing date	2016-04-04
Publishing country	England
Document type	Comment ; Journal Article
ZDB-ID	1071731-6
ISSN	1879-0445 ; 0960-9822
ISSN (online)	1879-0445
ISSN	0960-9822
DOI	10.1016/j.cub.2016.02.048
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Article: Epigenetic context predicts gene expression variation and reproductive traits across genetically identical individuals.

Webster, Amy K / Willis, John H / Johnson, Erik / Sarkies, Peter / Phillips, Patrick C

bioRxiv : the preprint server for biology

2023

Abstract: In recent decades, genome-wide association studies (GWAS) have been the major approach to understand the biological basis of individual differences in traits and diseases. However, GWAS approaches have proven to have limited predictive power to explain ... ...

Abstract	In recent decades, genome-wide association studies (GWAS) have been the major approach to understand the biological basis of individual differences in traits and diseases. However, GWAS approaches have proven to have limited predictive power to explain individual differences, particularly for complex traits and diseases in which environmental factors play a substantial role in their etiology. Indeed, individual differences persist even in genetically identical individuals, although fully separating genetic and environmental causation is difficult or impossible in most organisms. To understand the basis of individual differences in the absence of genetic differences, we measured two quantitative reproductive traits in 180 genetically identical young adult
Language	English
Publishing date	2023-10-13
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.10.13.562270
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Article ; Online: Genomic diversity landscapes in outcrossing and selfing Caenorhabditis nematodes.

Teterina, Anastasia A / Willis, John H / Lukac, Matt / Jovelin, Richard / Cutter, Asher D / Phillips, Patrick C

PLoS genetics

2023 Volume 19, Issue 8, Page(s) e1010879

Abstract: ... genetic map, for the outcrossing nematode C. remanei. We demonstrate that the genomic distribution ... of recombination in C. remanei, like the model nematode C. elegans, shows high recombination rates on chromosome ... similar between these species, but differ dramatically in scale, being tenfold greater for C. remanei ...

Abstract	Caenorhabditis nematodes form an excellent model for studying how the mode of reproduction affects genetic diversity, as some species reproduce via outcrossing whereas others can self-fertilize. Currently, chromosome-level patterns of diversity and recombination are only available for self-reproducing Caenorhabditis, making the generality of genomic patterns across the genus unclear given the profound potential influence of reproductive mode. Here we present a whole-genome diversity landscape, coupled with a new genetic map, for the outcrossing nematode C. remanei. We demonstrate that the genomic distribution of recombination in C. remanei, like the model nematode C. elegans, shows high recombination rates on chromosome arms and low rates toward the central regions. Patterns of genetic variation across the genome are also similar between these species, but differ dramatically in scale, being tenfold greater for C. remanei. Historical reconstructions of variation in effective population size over the past million generations echo this difference in polymorphism. Evolutionary simulations demonstrate how selection, recombination, mutation, and selfing shape variation along the genome, and that multiple drivers can produce patterns similar to those observed in natural populations. The results illustrate how genome organization and selection play a crucial role in shaping the genomic pattern of diversity whereas demographic processes scale the level of diversity across the genome as a whole.
MeSH term(s)	Animals ; Caenorhabditis/genetics ; Caenorhabditis elegans/genetics ; Polymorphism, Genetic ; Biological Evolution ; Genomics ; Genetic Variation
Language	English
Publishing date	2023-08-16
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2186725-2
ISSN	1553-7404 ; 1553-7390
ISSN (online)	1553-7404
ISSN	1553-7390
DOI	10.1371/journal.pgen.1010879
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Article: The Egg-Counter: A novel microfluidic platform for characterization of

Banse, Stephen A / Jarrett, Cody M / Robinson, Kristin J / Blue, Benjamin W / Shaw, Emily L / Phillips, Patrick C

bioRxiv : the preprint server for biology

2023

Abstract: Reproduction is a fundamental process that shapes the demography of every living organism yet is often difficult to assess with high precision in animals that produce large numbers of offspring. Here, we present a novel microfluidic research platform for ...

Abstract	Reproduction is a fundamental process that shapes the demography of every living organism yet is often difficult to assess with high precision in animals that produce large numbers of offspring. Here, we present a novel microfluidic research platform for studying
Language	English
Publishing date	2023-09-04
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.09.01.555781
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