Biology subjects

Willis, J. H.

Publications and source records attributed to Willis, J. H..

16 recordsLinked to original sources

bioRxiv2024

Computer prediction and genetic analysis identifies retinoic acid modulation as a driver of conserved longevity pathways in genetically-diverse Caenorhabditis nematodes

Aging is a pan-metazoan process with significant consequences for human health and society--discovery of new compounds that ameliorate the negative health impacts of aging promise to be of tremendous benefit across a number of age-based comorbidities. One method to prioritize a testable subset of the nearly infinite universe of potential compounds is to use computational prediction of their likely anti-aging capacity. Here we present a survey of longevity effects for 16 compounds suggested by a previously published computational prediction set, capitalizing upon the comprehensive, multi-species approach utilized by the Caenorhabditis Intervention Testing Program (CITP). While eleven compounds (aldosterone, arecoline, bortezomib, dasatinib, decitabine, dexamethasone, erlotinib, everolimus, gefitinib, temsirolimus, and thalidomide) either had no effect on median lifespan or were toxic, five compounds (all-trans retinoic acid, berberine, fisetin, propranolol, and ritonavir) extended lifespan in Caenorhabditis elegans. These computer predictions yield a remarkable positive hit rate of 30%. Deeper genetic characterization of the longevity effects of one of the most efficacious compounds, the endogenous signaling ligand all-trans retinoic acid (atRA, designated tretinoin in medical products), which is widely prescribed for treatment of acne, skin photoaging and acute promyelocytic leukemia, demonstrated a requirement for the regulatory kinases AKT-1 and AKT-2. While the canonical Akt-target FOXO/DAF-16 was largely dispensable, other conserved Akt-targets (Nrf2/SKN-1 and HSF1/HSF-1), as well as the conserved catalytic subunit of AMPK AAK-2, were all necessary for longevity extension by atRA. Evolutionary conservation of retinoic acid as a signaling ligand and the structure of the downstream effector network of retinoic acid combine to suggest that the all-trans retinoic acid pathway is an ancient metabolic regulatory system that can modulate lifespan. Our results highlight the potential of combining computational prediction of longevity interventions with the power of nematode functional genetics and underscore that the manipulation of a conserved metabolic regulatory circuit by co-opting endogenous signaling molecules is a powerful approach for discovering aging interventions.

genetics↗

bioRxiv2024

Pervasive conservation of intron number and other genetic elements revealed by a chromosome-level genomic assembly of the hyper-polymorphic nematode Caenorhabditis brenneri

With within-species genetic diversity estimates that span the gambit of that seen across the entirety of animals, the Caenorhabditis genus of nematodes holds unique potential to provide insights into how population size and reproductive strategies influence gene and genome organization and evolution. Our study focuses on Caenorhabditis brenneri, currently known as one of the most genetically diverse nematodes within its genus and metazoan phyla. Here, we present a high-quality gapless genome assembly and annotation for C. brenneri, revealing a common nematode chromosome arrangement characterized by gene-dense central regions and repeat rich peripheral parts. Comparison of C. brenneri with other nematodes from the Elegans group revealed conserved macrosynteny but a lack of microsynteny, characterized by frequent rearrangements and low correlation iof orthogroup sizes, indicative of high rates of gene turnover. We also assessed genome organization within corresponding syntenic blocks in selfing and outcrossing species, affirming that selfing species predominantly experience loss of both genes and intergenic DNA. Comparison of gene structures revealed strikingly small number of shared introns across species, yet consistent distributions of intron number and length, regardless of population size or reproductive mode, suggesting that their evolutionary dynamics are primarily reflective of functional constraints. Our study provides valuable insights into genome evolution and expands the nematode genome resources with the highly genetically diverse C. brenneri, facilitating research into various aspects of nematode biology and evolutionary processes.

genomics↗

bioRxiv2023

Widespread changes in gene expression accompany body size evolution in nematodes

Body size is a fundamental trait that drives multiple evolutionary and ecological patterns. Caenorhabditis inopinata is a fig-associated nematode that is exceptionally large relative to other members of the genus, including C. elegans. We previously showed that C. inopinata is large primarily due to postembryonic cell size expansion that occurs during the larval-to-adult transition. Here, we describe gene expression patterns in C. elegans and C. inopinata throughout this developmental period to understand the transcriptional basis of body size change. We performed RNA-seq in both species across the L3, L4, and adult stages. Most genes are differentially expressed across all developmental stages, consistent with C. inopinatas divergent ecology and morphology. We also used a model comparison approach to identify orthologs with divergent dynamics across this developmental period between the two species. This included genes connected to neurons, behavior, stress response, developmental timing, and small RNA/chromatin regulation. Multiple hypodermal collagens were also observed to harbor divergent developmental dynamics across this period, and genes important for molting and body morphology were also detected. Genes associated with TGF-{beta} signaling revealed idiosyncratic and unexpected transcriptional patterns given their role in body size regulation in C. elegans. Widespread transcriptional divergence between these species is unexpected and may be a signature of the ecological and morphological divergence of C. inopinata. Alternatively, transcriptional turnover may be the rule in the Caenorhabditis genus, indicative of widespread developmental system drift among species. This work lays the foundation for future functional genetic studies interrogating the bases of body size evolution in this group.

genomics↗

bioRxiv2023

Epigenetic context predicts gene expression variation and reproductive traits across genetically identical individuals

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 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 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 Caenorhabditis elegans roundworms in a shared environment and performed single-individual transcriptomics on each worm. We identified hundreds of genes for which expression variation was strongly associated with reproductive traits, some of which depended on individuals historical environments and some of which was random. Multiple small sets of genes together were highly predictive of reproductive traits, explaining on average over half and over a quarter of variation in the two traits. We manipulated mRNA levels of predictive genes to identify a set of causal genes, demonstrating the utility of this approach for both prediction and understanding underlying biology. Finally, we found that the chromatin environment of predictive genes was enriched for H3K27 trimethylation, suggesting that gene expression variation may be driven in part by chromatin structure. Together, this work shows that individual, non-genetic differences in gene expression are both highly predictive and causal in shaping reproductive traits.

genomics↗

bioRxiv2023

Post-insemination sexual selection in males indirectly masculinizes the female transcriptome

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 Caenorhabditis elegans, we explore the coupling of direct sexual selection on males with the transcriptomic response in males and females over microevolutionary timescales to uncover the extent to which post-insemination reproductive traits share a genetic basis between the sexes. We find that differential gene expression evolved in a sex-specific manner in males, while in females indirect selection causes an evolved response. Almost all differentially expressed genes were downregulated in both evolved males and females. Moreover, 97% of significantly differentially expressed genes in males and 69% of significantly differentially expressed genes in females have wildtype female-biased expression profile. Changes in gene expression profiles were likely driven through trans-acting pathways that are shared between the sexes. We found no evidence that the core dosage compensation machinery was impacted by experimental evolution. Together these data suggest a de-feminization of the male transcriptome and masculinization of the female transcriptome driven by direct selection on male sperm competitive ability. Our results indicate that on short evolutionary timescales sexual selection can generate putative sexual conflict in expression space.

evolutionary biology↗

bioRxiv2022

Genetic diversity landscapes in outcrossing and selfing Caenorhabditis nematodes

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 10-fold 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. Convolutional neural networks demonstrate the potential for classifying distinct evolutionary scenarios in simulated populations. Distinguishing these forces confidently with the empirical data, however, will benefit from larger population genomic samples from multiple populations and consideration of an even more extensive training set of simulations.

evolutionary biology↗

bioRxiv2022

The genetic basis of traits associated with the evolution of serpentine endemism in monkeyflowers

The floras on chemically and physically challenging soils, such as gypsum, shale, and serpentine, are characterized by narrowly endemic species. These edaphic endemics often have widespread close relatives that are not restricted to specific soil types. The evolution of edaphic endemics may be facilitated or constrained by genetic correlations among traits contributing to adaptation and reproductive isolation across soil boundaries. The yellow monkeyflowers in the Mimulus guttatus species complex are an ideal system in which to examine these evolutionary patterns. To determine the genetic basis of adaptive and prezygotic isolating traits, we performed genetic mapping experiments with F2 hybrids derived from a cross between a serpentine endemic, M. nudatus, and its close relative M. guttatus. Plants occurring on serpentine soils have repeatedly evolved short statures and small leaves, suggesting that these traits are adaptive, and M. nudatus shows all these characteristics compared to M. guttatus. Previous research demonstrated that flower size and life history differences between these species contribute to prezygotic reproductive isolation between them. Few large effect and many small effect loci contribute to interspecific divergence in life history, floral and leaf traits, and a history of directional selection contributed to trait divergence. Loci contributing to adaptive traits and prezygotic reproductive isolation overlap, and their allelic effects are largely in the direction of species divergence. These loci contain promising candidate genes regulating flowering time and plant organ size. Together our results suggest that genetic correlations among traits facilitated the evolution of edaphic adaptation and speciation in this species pair.

evolutionary biology↗

bioRxiv2021

Alignment of genetic differentiation across trophic levels in a fig community

Ecological interactions can generate close associations among species, which can in turn generate a high degree of overlap in their spatial distributions. Co-occurrence is likely to be particularly intense when species exhibit obligate comigration, in which they not only overlap in spatial distributions but also travel together from patch to patch. In theory, this pattern of ecological co-occurrence should leave a distinct signature in the pattern of genetic differentiation within and among species. Perhaps the most famous mutual co-isolation partners are fig trees and their co-evolved wasp pollinators. Here, we add another tropic level to this system by examining patterns of genomic diversity in the nematode Caenorhabditis inopinata, a close relative of the C. elegans model system that thrives in figs and obligately disperses on fig wasps. We performed RADseq on individual worms isolated from the field across three Okinawan island populations. The male/female C. inopinata is about five times more diverse than the hermaphroditic C. elegans, and polymorphism is enriched on chromosome arms relative to chromosome centers. FST is low among island population pairs, and clear population structure could not be easily detected among figs, trees, and islands, suggesting frequent migration of wasps between islands. Moreover, inbreeding coefficients are elevated in C. inopinata, consistent with field observations suggesting small C. inopinata founding populations in individual figs. These genetic patterns in C. inopinata overlap with those previously reported in its specific fig wasp vector and are consistent with C. inopinata population dynamics being driven by wasp dispersal. Thus, interspecific interactions can align patterns of genetic diversity across species separated by hundreds of millions of years of evolutionary divergence. HighlightsO_LIThe fig-dwelling female/male nematode Caenorhabditis inopinata is five times more diverse than its closest relative, the self-fertilizing nematode C. elegans. C_LIO_LIC. inopinata migrates frequently among three Okinawan islands despite high levels of inbreeding within individual figs. C_LIO_LIC. inopinata has patterns of genetic diversity that mirror its fig wasp vector. C_LIO_LIEcological specialization aligns patterns of genetic differentiation in closely interacting species. C_LI

evolutionary biology↗

bioRxiv2021

Post-Insemination Selection Dominates Pre-Insemination Selection in Driving Rapid Evolution of Male Competitive Ability

Sexual reproduction is a complex process that contributes to differences between the sexes and divergence between species. From a males perspective, sexual selection can optimize reproductive success by acting on the variance in mating success (pre-insemination selection) as well as the variance in fertilization success (post-insemination selection). The balance between pre- and post-insemination selection has not yet been investigated using a strong hypothesis-testing framework that directly quantifies the effects of post-insemination selection on the evolution of reproductive success. Here we use experimental evolution of a uniquely engineered genetic system that allows sperm production to be turned off and on in obligate male-female populations of Caenorhabditis elegans. We show that enhanced post-insemination competition increases the efficacy of selection and surpasses pre-insemination sexual selection in driving a polygenic response in male reproductive success. We find that after 30 generations post-insemination selection increased male reproductive success by an average of 5- to 7-fold. Contrary to expectation, enhanced pre-insemination competition hindered selection and slowed the rate of evolution. Furthermore, we found that post-insemination selection resulted in a strong polygenic response at the whole-genome level. Our results demonstrate that post-insemination sexual selection plays a critical role in the rapid optimization of male reproductive fitness. Therefore, explicit consideration should be given to post-insemination dynamics when considering the population effects of sexual selection.

evolutionary biology↗

bioRxiv2020

The genetic architecture and evolution of life history divergence among perennials in the Mimulus guttatus species complex

Ecological divergence is a main source of trait divergence between closely related species. Despite its importance in generating phenotypic diversity, the genetic architecture of most ecologically relevant traits is poorly understood. Differences in elevation can impose substantial selection for phenotypic divergence of both complex, correlated suites of traits (such as life history), as well as novel adaptations. Here, we use the Mimulus guttatus species complex to assess if divergence in elevation is accompanied by trait divergence in a group of closely related perennial species, and determine the genetic architecture of this divergence. We find that divergence in elevation is associated with differences in multivariate quantitative life history traits, as well as a unique trait; the production of rhizomes, which may play an important role in overwintering survival. However, the extent of phenotypic divergence among species depended on ontogeny, suggesting that species also diverged in investment strategies across development. Lastly, we show that the genetic architecture of life history divergence between two species is simple, involving few mid to large effect Quantitative Trait Loci (QTLs), and that the genetic architecture of the ability to produce rhizomes changes through development, which has potential implications for hybrid fitness in the wild.

evolutionary biology↗

bioRxiv2020

Chromosome-level assembly of the Caenorhabditis remanei genome reveals conserved patterns of nematode genome organization

The nematode Caenorhabditis elegans is one of the key model systems in biology, including possessing the first fully assembled animal genome. Whereas C. elegans is a self-reproducing hermaphrodite with fairly limited within-population variation, its relative C. remanei is an outcrossing species with much more extensive genetic variation, making it an ideal parallel model system for evolutionary genetic investigations. Here, we greatly improve on previous assemblies by generating a chromosome-level assembly of the entire C. remanei genome (124.8 Mb of total size) using long-read sequencing and chromatin conformation capture data. Like other fully assembled genomes in the genus, we find that the C. remanei genome displays a high degree of synteny with C. elegans despite multiple within-chromosome rearrangements. Both genomes have high gene density in central regions of chromosomes relative to chromosome ends and the opposite pattern for the accumulation of repetitive elements. C. elegans and C. remanei also show similar patterns of inter-chromosome interactions, with the central regions of chromosomes appearing to interact with one another more than the distal ends. The new C. remanei genome presented here greatly augments the use of the Caenorhabditis as a platform for comparative genomics and serves as a basis for molecular population genetics within this highly diverse species.

genomics↗

bioRxiv2019

Slow recovery from inbreeding depression generated by the complex genetic architecture of segregating deleterious mutations

The deleterious effects of inbreeding have been of extreme importance to evolutionary biology, but it has been difficult to characterize the complex interactions between genetic constraints and selection that lead to fitness loss and recovery after inbreeding. Viruses, bacteria, and the selfing nematode Caenorhabditis elegans have been shown to be capable of rapid recovery from the fixation of novel deleterious mutation, however the potential for fitness recovery from fixation of segregating variation under inbreeding in outcrossing organisms is poorly understood. C. remanei is an outcrossing relative of C. elegans with high polymorphic variation and extreme inbreeding depression. Here we sought to characterize changes C. remanei in patterns of genomic diversity after [~]30 generations of inbreeding via brother-sister mating followed by several hundred generations of recovery at large population size. As expected, inbreeding led to a large decline in reproductive fitness, but unlike results from mutation accumulation experiments, recovery from inbreeding at large populations sizes generated only very moderate recovery in fitness after 300 generations. At the genomic level, we found that while 66% of ancestral segregating SNPs were fixed in the inbred population, this was far fewer than expected under neutral processes. Under recovery, 36 SNPs across 30 genes involved in alimentary, muscular, nervous and reproductive systems changed reproducibly across all replicates, indicating that strong selection for fitness recovery does exist but is likely mutationally limited due to the large number of potential targets. Our results indicate that recovery from inbreeding depression via new compensatory mutations is likely to be constrained by the large number of segregating deleterious variants present in natural populations, limiting the capacity for rapid evolutionary rescue of small populations. Impact SummaryInbreeding is defined as mating between close relatives and can have a large effect on the genetic diversity and fitness of populations. This has been recognized for over 100 years of study in evolutionary biology, but the specific genomic changes that accompany inbreeding and the loss of fitness are still not known. Evolutionary theory predicts that inbred populations lose fitness through the fixation of many deleterious alleles and it is not known if populations can recover fitness after prolonged periods of inbreeding and deleterious fixations, or how long recovery may take. These questions are particularly important for wild populations experiencing declines. In this study we use laboratory populations of the nematode worm Caenorhabditis remanei to analyze the loss of fitness and genomic changes that accompany inbreeding via brother-sister mating, and to track the populations as they recover from inbreeding at large population size over 300 generations. We find that: O_LITotal progeny decreased by 65% after inbreeding C_LIO_LIThere were many nucleotides in the genome that remained heterozygous after inbreeding C_LIO_LIThere was an excess of inbreeding-resistant nucleotides on the X chromosome C_LIO_LIThe number of progeny remained low after 300 generations of recovery from inbreeding C_LIO_LI30 genes changed significant in allele frequency during recovery, including genes involved in the alimentary, muscular, nervous and reproductive systems C_LI Together, our results demonstrate that recovery from inbreeding is difficult, likely due to the fixation of numerous deleterious alleles throughout the genome.

evolutionary biology↗

bioRxiv2018

Patterns of hybrid seed inviability in perennials of the Mimulus guttatus sp. complex reveal a potential role of parental conflict in reproductive isolation

Genomic conflicts may play a central role in the evolution of reproductive barriers. Theory predicts that early-onset hybrid inviability may stem from conflict between parents for resource allocation to offspring. Here we describe M. decorus; a group of cryptic species within the M. guttatus species complex that are largely reproductively isolated by hybrid seed inviability (HSI). HSI between M. guttatus and M. decorus is common and strong, but populations of M. decorus vary in the magnitude and directionality of HSI with M. guttatus. Patterns of HSI between M. guttatus and M. decorus, as well as within M. decorus conform to the predictions of parental conflict: (1) reciprocal F1s exhibit size differences and parent-of-origin specific endosperm defects, (2) the extent of asymmetry between reciprocal F1 seed size is correlated with asymmetry in HSI, and (3) inferred differences in the extent of conflict predict the extent of HSI between populations. We also find that HSI is rapidly evolving, as populations that exhibit the most HSI are each others closest relative. Lastly, while all populations are largely outcrossing, we find that the differences in the inferred strength of conflict scale positively with {pi}, suggesting that demographic or life history factors other than mating system may also influence the rate of parental conflict driven evolution. Overall, these patterns suggest the rapid evolution of parent-of-origin specific resource allocation alleles coincident with HSI within and between M. guttatus and M. decorus. Parental conflict may therefore be an important evolutionary driver of reproductive isolation.

evolutionary biology↗

bioRxiv2018

Parallel patterns of development between independent cases of hybrid seed inviability in Mimulus

RationaleHybrid seed inviability (HSI) is a common reproductive barrier in angiosperms, yet the evolutionary and developmental drivers of HSI remain largely unknown. We test whether conflict between maternal and paternal interests in resource allocation to developing offspring (i.e. parental conflict) are associated with HSI and determine the degree of developmental parallelism between independent incidences of HSI in Mimulus.\n\nMethodsWe quantified HSI between M. guttatus and two clades of M. decorus with oppositely asymmetric incompatibilities and surveyed development of hybrid and parental seeds.\n\nKey ResultsCrosses between M. guttatus and both clades of M. decorus show parent-of-origin effects on reciprocal F1 seed development, but in opposing directions. Inviable hybrid seeds exhibit paternal excess phenotypes, wherein endosperm is large and chaotic while viable hybrid seeds produce endosperm cells that are smaller and less prolific (i.e. maternal-excess phenotypes).\n\nMain ConclusionsWe find strong parent-of-origin effects on development in reciprocal F1s in multiple incidences of HSI in Mimulus. These patterns suggest that parental conflict may be an important force generating HSI in this group, and mismatches between maternal and paternal contributions to developing seeds result in repeatable developmental defects in hybrids.

evolutionary biology↗

bioRxiv2018

Major QTL controls adaptation to serpentine soils in Mimulus guttatus

Spatially varying selection is a critical driver of adaptive differentiation. Yet, there are few examples where the fitness effects of naturally segregating variants that contribute to local adaptation have been measured in the field. This project investigates the genetic basis of adaption to serpentine soils in Mimulus guttatus. Reciprocal transplant studies show that serpentine and non-serpentine populations of M. guttatus are genetically differentiated in their ability to survive on serpentine soils. We mapped serpentine tolerance by performing a bulk segregant analysis on F2 survivors from a field transplant study and identify a single QTL where individuals that are homozygous for the non-serpentine allele do not survive on serpentine soils. This same QTL controls serpentine tolerance in a second, geographically distant population. A common garden study where the two serpentine populations were grown on each other's soil finds that one of the populations has significantly lower survival on this \"foreign\" serpentine soil compared to its home soil. So, while these two populations share a major QTL they either differ at other loci involved in serpentine adaptation or have different causal alleles at this QTL. This raises the possibility that serpentine populations may not be broadly tolerant to serpentine soils but may instead be locally adapted to their particular patch. Nevertheless, despite the myriad chemical and physical challenges that plants face in serpentine habitats, adaptation to these soils in M. guttatus has a simple genetic basis.

evolutionary biology↗

bioRxiv2016

The Phenotypic, Genotypic, & Environmental Drivers of Local Adaptation to a Harsh Granite Outcrop Environment in Mimulus

A primary goal in evolutionary biology is to understand which environmental variables and traits drive adaptation to harsh environments. This is difficult since many traits evolve simultaneously as populations or species diverge. Here we investigate the ecological variables and traits that underlie Mimulus laciniatus adaptation to granite outcrops compared to its sympatric, mesic-adapted progenitor M. guttatus. We use fine scale measurements of soil moisture and herbivory to examine differences in selective forces between the species habitats, and measure selection on flowering time, flower size, plant height, and leaf shape in a reciprocal transplant using M. laciniatus x M. guttatus F4 hybrids. We find that differences in drought & herbivory drive survival differences between habitats, that M. laciniatus and M. guttatus are each better adapted to their native habitat, and differential habitat selection on flowering time, plant stature, and leaf shape. We conclude that while early flowering time, small stature, and lobed leaf shape underlie plant fitness in M. laciniatus seasonally dry environment, increased plant size is advantageous in a competitive mesic environment replete with herbivores like M. guttatus.

evolutionary biology↗