Biology subjects

Abbot, P.

Publications and source records attributed to Abbot, P..

6 recordsLinked to original sources

bioRxiv2019

Accounting for diverse evolutionary forces reveals the mosaic nature of selection on genomic regions associated with human preterm birth

Human pregnancy requires the coordinated function of multiple tissues in both mother and fetus and has evolved in concert with major human adaptations. As a result, pregnancy-associated phenotypes and related disorders are genetically complex and have likely been sculpted by diverse evolutionary forces. However, there is no framework to comprehensively evaluate how these traits evolved or to explore the relationship of evolutionary signatures on trait-associated genetic variants to molecular function. Here we develop an approach to test for signatures of diverse evolutionary forces, including multiple types of selection, and apply it to genomic regions associated with spontaneous preterm birth (sPTB), a complex disorder of global health concern. We find that sPTB-associated regions harbor diverse evolutionary signatures including evolutionary sequence conservation (consistent with the action of negative selection), excess population differentiation (local adaptation), accelerated evolution (positive selection), and balanced polymorphism (balancing selection). Furthermore, these genomic regions show diverse functional characteristics which enables us to use evolutionary and molecular lines of evidence to develop hypotheses about how these genomic regions contribute to sPTB risk. In summary, we introduce an approach for inferring the spectrum of evolutionary forces acting on genomic regions associated with complex disorders. When applied to sPTB-associated genomic regions, this approach both improves our understanding of the potential roles of these regions in pathology and illuminates the mosaic nature of evolutionary forces acting on genomic regions associated with sPTB.

evolutionary biology↗

bioRxiv2019

Trans-generational transcriptomic response to natural variation in host plant toxicity and insecticides in a specialist insect.

Insects have been challenged by plant secondary metabolites throughout their evolutionary history. An important mechanism thought to promote insecticide resistance is the ability of insects to use preexisting detoxification systems originally evolved for tolerance of plant defenses. However, it remains unclear what level of convergence exists in metabolic mechanisms employed against various natural and xenobiotic chemicals? How do transcriptomic responses to these stressors change in response to novel and long-term exposure? We employ an experimental evolution approach in a milkweed- specialist aphid (Aphis nerii) model to test the effects of a more toxic host plant species and two insecticides commonly used in rotation in agriculture (a neonicotinoid, Imidacloprid, and a general homopteran blocker, Pymetrozine) on aphid gene expression and fitness over multiple generations of selection. Aphids were selected on three stress treatments: a toxic host plant species and two pesticides (Imidacloprid and Pymetrozine) for five generations. Whole transcriptome gene expression changes and changes in development time and fecundity were compared at generations one and five. While there were no consistent fitness costs or benefits to long-term exposure, exposure to stress is associated with increased transcriptional plasticity and changes in genes associated with the metabolism of secondary metabolites as well as genes important in transcription, translation, and post-translation processes.

genomics↗

bioRxiv2019

Signatures of recent positive selection in enhancers across 41 human tissues

Evolutionary changes in enhancers are widely associated with variation in human traits and diseases. However, studies comprehensively quantifying levels of selection on enhancers at multiple evolutionary time points during recent human evolution and how enhancer evolution varies across human tissues are lacking. To address these questions, we integrated a dataset of 41,561 transcribed enhancers active in 41 different human tissues (FANTOM Consortium) with whole genome sequences of 1,668 individuals from the African, Asian, and European populations (1000 Genomes Project). Our analyses based on four different metrics (Tajimas D, FST, H12, nSL) showed that ~5.90% of enhancers considered showed evidence of recent positive selection and that genes associated with enhancers under positive selection are enriched for diverse immune-related functions. The distributions of these metrics for brain and testis enhancers were often statistically significantly different compared to those of other tissues; the same was true for brain and testis enhancers that are tissue-specific compared to those that are tissue-broad and for testis enhancers associated with tissue-enriched and non-tissue-enriched genes. These differences varied considerably across metrics and tissues and were generally due to changes in distributions shapes rather than shifts in their values. These results suggest that many human enhancers experienced recent positive selection throughout multiple time periods in human evolutionary history, that this selection occurred in a tissue-dependent and immune-related functional context, and that much like the evolution of their coding counterparts, the evolution of brain and testis enhancers has been markedly different from that of enhancers in other tissues.

evolutionary biology↗

bioRxiv2018

integRATE: a desirability-based data integration framework for the prioritization of candidate genes across heterogeneous omics and its application to preterm birth

BackgroundThe integration of high-quality, genome-wide analyses offers a robust approach to elucidating genetic factors involved in complex human diseases. Even though several methods exist to integrate heterogeneous omics data, most biologists still manually select candidate genes by examining the intersection of lists of candidates stemming from analyses of different types of omics data that have been generated by imposing hard (strict) thresholds on quantitative variables, such as P-values and fold changes, increasing the chance of missing potentially important candidates.\n\nMethodsTo better facilitate the unbiased integration of heterogeneous omics data collected from diverse platforms and samples, we propose a desirability function framework for identifying candidate genes with strong evidence across data types as targets for follow-up functional analysis. Our approach is targeted towards disease systems with sparse, heterogeneous omics data, so we tested it on one such pathology: spontaneous preterm birth (sPTB).\n\nResultsWe developed the software integRATE, which uses desirability functions to rank genes both within and across studies, identifying well-supported candidate genes according to the cumulative weight of biological evidence rather than based on imposition of hard thresholds of key variables. Integrating 10 sPTB omics studies identified both genes in pathways previously suspected to be involved in sPTB as well as novel genes never before linked to this syndrome. integRATE is available as an R package on GitHub (https://github.com/haleyeidem/integRATE).\n\nConclusionsDesirability-based data integration is a solution most applicable in biological research areas where omics data is especially heterogeneous and sparse, allowing for the prioritization of candidate genes that can be used to inform more targeted downstream functional analyses.

genomics↗

bioRxiv2018

Genome wide association analysis identifies genetic variants associated with reproductive variation across domestic dog breeds and uncovers links to domestication

The diversity of eutherian reproductive strategies has led to variation in many traits, such as number of offspring, age of reproductive maturity, and gestation length. While reproductive trait variation has been extensively investigated and is well established in mammals, the genetic loci contributing to this variation remain largely unknown. The domestic dog, Canis lupus familiaris is a powerful model for studies of the genetics of inherited disease due to its unique history of domestication. To gain insight into the genetic basis of reproductive traits across domestic dog breeds, we collected phenotypic data for four traits - cesarean section rate (n = 97 breeds), litter size (n = 60), stillbirth rate (n = 57), and gestation length (n = 23) - from primary literature and breeders handbooks. By matching our phenotypic data to genomic data from the Cornell Veterinary Biobank, we performed genome wide association analyses for these four reproductive traits, using body mass and kinship among breeds as co-variates. We identified 14 genome-wide significant associations between these traits and genetic loci, including variants near CACNA2D3 with gestation length, MSRB3 with litter size, SMOC2 with cesarean section rate, MITF with litter size and still birth rate, KRT71 with cesarean section rate, litter size, and stillbirth rate, and HTR2C with stillbirth rate. Some of these loci, such as CACNA2D3 and MSRB3, have been previously implicated in human reproductive pathologies. Many of the variants that we identified have been previously associated with domestication-related traits, including brachycephaly (SMOC2), coat color (MITF), coat curl (KRT71), and tameness (HTR2C). These results raise the hypothesis that the artificial selection that gave rise to dog breeds also shaped the observed variation in their reproductive traits. Overall, our work establishes the domestic dog as a system for studying the genetics of reproductive biology and disease.

evolutionary biology↗

bioRxiv2017

Genes Involved In Human Sialic Acid Biology Do Not Harbor Signatures Of Recent Positive Selection

AbstractSialic acids are nine carbon sugars ubiquitously found on the surfaces of vertebrate cells and are involved in various immune response-related processes. In humans, at least 58 genes spanning diverse functions, from biosynthesis and activation to recycling and degradation, are involved in sialic acid biology. Because of their role in immunity, sialic acid biology genes have been hypothesized to exhibit elevated rates of evolutionary change. Consistent with this hypothesis, several genes involved in sialic acid biology have experienced higher rates of non-synonymous substitutions in the human lineage than their counterparts in other great apes, perhaps in response to ancient pathogens that infected hominins millions of years ago (paleopathogens). To test whether sialic acid biology genes have also experienced more recent positive selection during the evolution of the modern human lineage, reflecting adaptation to contemporary cosmopolitan or geographically-restricted pathogens, we examined whether their protein-coding regions showed evidence of recent hard and soft selective sweeps. This examination involved the calculation of four measures that quantify changes in allele frequency spectra, extent of population differentiation, and haplotype homozygosity caused by recent hard and soft selective sweeps for 55 sialic acid biology genes using publicly available whole genome sequencing data from 1,668 humans from three ethnic groups. To disentangle evidence for selection from confounding demographic effects, we compared the observed patterns in sialic acid biology genes to simulated sequences of the same length under a model of neutral evolution that takes into account human demographic history. We found that the patterns of genetic variation of most sialic acid biology genes did not significantly deviate from neutral expectations and were not significantly different among genes belonging to different functional categories. Those few sialic acid biology genes that significantly deviated from neutrality either experienced soft sweeps or population-specific hard sweeps. Interestingly, while most hard sweeps occurred on genes involved in sialic acid recognition, most soft sweeps involved genes associated with recycling, degradation and activation, transport, and transfer functions. We propose that the lack of signatures of recent positive selection for the majority of the sialic acid biology genes is consistent with the view that these genes regulate immune responses against ancient rather than contemporary cosmopolitan or geographically restricted pathogens.

evolutionary biology↗