Extent and context dependence of pleiotropy revealed by high-throughput single-cell phenotyping

AbstractPleiotropy – when a single mutation affects multiple traits – is a controversial topic with far-reaching implications. Pleiotropy plays a central role in debates about how complex traits evolve and whether biological systems are modular or are organized such that every gene has the potential to affect many traits. Pleiotropy is also critical to initiatives in evolutionary medicine that seek to trap infectious microbes or tumors by selecting for mutations that encourage growth in some conditions at the expense of others. Research in these fields, and others, would benefit from understanding the extent to which pleiotropy reflects inherent relationships among phenotypes that correlate no matter the perturbation (vertical pleiotropy). Alternatively, pleiotropy may result from genetic changes that impose correlations between otherwise independent traits (horizontal pleiotropy). We distinguish these possibilities by using clonal populations of yeast cells to quantify the inherent relationships between single-cell morphological features. Then, we demonstrate how often these relationships underlie vertical pleiotropy and how often these relationships are modified by genetic variants (QTL) acting via horizontal pleiotropy. Our comprehensive screen measures thousands of pairwise trait correlations across hundreds of thousands of yeast cells and reveals ample evidence of both vertical and horizontal pleiotropy. Additionally, we observe that the correlations between traits can change with the environment, genetic background and cell-cycle position. These changing dependencies suggest a nuanced view of pleiotropy: biological systems demonstrate limited pleiotropy in any given context, but across contexts (e.g., across diverse environments and genetic backgrounds) each genetic change has the potential to influence a larger number of traits. Our method suggests that exploiting pleiotropy for applications in evolutionary medicine would benefit from focusing on traits with correlations that are less dependent on context.

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Characterizing the genetic basis of trait evolution in the Mexican cavefish

10.1101/2021.12.16.472318 ◽

2021 ◽

Author(s):

Camila Oliva ◽

Nicole K Hinz ◽

Wayne Robinson ◽

Alexys M Barrett Thompson ◽

Julianna Booth ◽

...

Keyword(s):

Complex Traits ◽

Morphological Traits ◽

Prey Capture ◽

Molecular Genetic ◽

Startle Reflex ◽

Fish Population ◽

Multiple Traits ◽

Genetic Changes ◽

Behavioral Traits ◽

Critical Gap

Evolution in response to a change in ecology often coincides with various morphological, physiological, and behavioral traits. For most organisms little is known about the genetic and functional relationship between evolutionarily derived traits, representing a critical gap in our understanding of adaptation The Mexican tetra, Astyanax mexicanus, consists of largely independent populations of fish that inhabit at least 30 caves in Northeast Mexico, and a surface fish population, that inhabits the rivers of Mexico and Southern Texas. The recent application of molecular genetic approaches combined with behavioral phenotyping have established A. mexicanus as a model for studying the evolution of complex traits. Cave populations of A. mexicanus are interfertile with surface populations and have evolved numerous traits including eye degeneration, insomnia, albinism and enhanced mechanosensory function. The infertility of different populations from the same species provides a unique opportunity to define the genetic relationship between evolved traits and assess the co-evolution of behavioral and morphological traits with one another. To define the relationships between morphological and behavioral traits, we developed a pipeline to test individual fish for multiple traits. This pipeline confirmed differences in locomotor activity, prey capture, and startle reflex between surface and cavefish populations. To measure the relationship between traits, individual F2 hybrid fish were characterized for locomotor behavior, prey-capture behavior, startle reflex and morphological attributes. Analysis revealed an association between body length and slower escape reflex, suggesting a trade-off between increased size and predator avoidance in cavefish. Overall, there were few associations between individual behavioral traits, or behavioral and morphological traits, suggesting independent genetic changes underlie the evolution of behavioral and morphological traits. Taken together, this approach provides a novel system to identify genes that underlie naturally occurring genetic variation in morphological and behavioral traits.

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A Gap in Brain Gain for Emerging Countries: Evidence of International Immigration on Non-Resident Patents

Journal of Risk and Financial Management ◽

10.3390/jrfm14010007 ◽

2020 ◽

Vol 14 (1) ◽

pp. 7

Author(s):

Bolortuya Enkhtaivan ◽

Jorge Brusa ◽

Zagdbazar Davaadorj

Keyword(s):

Developed Countries ◽

Emerging Countries ◽

Culture Learning ◽

Host Countries ◽

Creative People ◽

Brain Gain ◽

Ample Evidence ◽

The World ◽

Controversial Topic ◽

Global Data

Immigration is a controversial topic that draws much debate. From a human sustainability perspective, immigration is disadvantageous for home countries causing brain drains. Ample evidence suggests the developed host countries benefit from immigration in terms of diversification, culture, learning, and brain gains, yet less is understood for emerging countries. The purpose of this paper is to examine the presence of brain gains due to immigration for emerging countries, and explore any gaps as compared to developed countries. Using global data from 88 host and 109 home countries over the period from 1995 to 2015, we find significant brain gains due to immigration for emerging countries. However, our results show that there is still a significant brain gain gap between emerging and developed countries. A brain gain to the developed host countries is about 5.5 times greater than that of the emerging countries. The results hold after addressing endogeneity, self-selection, and large sample biases. Furthermore, brain gain is heterogenous by immigrant types. Skilled or creative immigrants tend to benefit the host countries about three times greater than the other immigrants. In addition, the Top 10 destination countries seem to attract the most creative people, thus harvest the most out of the talented immigrants. In contrast, we find countries of origin other than the Top 10 seem to send these creative people to the rest of the world.

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Single-cell analysis for drug development using convex lens-induced confinement imaging

BioTechniques ◽

10.2144/btn-2019-0067 ◽

2019 ◽

Vol 67 (5) ◽

pp. 210-217 ◽

Cited By ~ 1

Author(s):

Ndeye Khady Thiombane ◽

Nicolas Coutin ◽

Daniel Berard ◽

Radin Tahvildari ◽

Sabrina Leslie ◽

...

Keyword(s):

Single Cell ◽

Drug Response ◽

Drug Exposure ◽

Cellular Proliferation ◽

New Technologies ◽

Detection Sensitivity ◽

Yeast Cells ◽

Sample Population ◽

Phenotypic Analysis ◽

Convex Lens

New technologies have powered rapid advances in cellular imaging, genomics and phenotypic analysis in life sciences. However, most of these methods operate at sample population levels and provide statistical averages of aggregated data that fail to capture single-cell heterogeneity, complicating drug discovery and development. Here we demonstrate a new single-cell approach based on convex lens-induced confinement (CLiC) microscopy. We validated CLiC on yeast cells, demonstrating subcellular localization with an enhanced signal-to-noise and fluorescent signal detection sensitivity compared with traditional imaging. In the live-cell CLiC assay, cellular proliferation times were consistent with flask culture. Using methotrexate, we provide drug response data showing a fivefold cell size increase following drug exposure. Taken together, CLiC enables high-quality imaging of single-cell drug response and proliferation for extended observation periods.

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Receding meniscus induced docking of yeast cells inside microfluidic channels at single cell level

2006 International Conference on Microtechnologies in Medicine and Biology ◽

10.1109/mmb.2006.251540 ◽

2006 ◽

Author(s):

Min Cheol Park ◽

Jae Young Hur ◽

Keon Woo Kwon ◽

Jee Won Park ◽

Sang-Hyun park ◽

...

Keyword(s):

Single Cell ◽

Yeast Cells ◽

Microfluidic Channels ◽

Single Cell Level ◽

Cell Level

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Transformative opportunities for single-cell proteomics

10.7287/peerj.preprints.26821v2 ◽

2018 ◽

Cited By ~ 1

Author(s):

Harrison Specht ◽

Nikolai Slavov

Keyword(s):

Mass Spectrometry ◽

Stem Cell ◽

Cell Differentiation ◽

Single Cell ◽

Single Cells ◽

Biological Systems ◽

Stem Cell Differentiation ◽

New Age ◽

Technological Developments

Many pressing medical challenges - such as diagnosing disease, enhancing directed stem cell differentiation, and classifying cancers - have long been hindered by limitations in our ability to quantify proteins in single cells. Mass-spectrometry (MS) is poised to transcend these limitations by developing powerful methods to routinely quantify thousands of proteins and proteoforms across many thousands of single cells. We outline specific technological developments and ideas that can increase the sensitivity and throughput of single cell MS by orders of magnitude and usher in this new age. These advances will transform medicine and ultimately contribute to understanding biological systems on an entirely new level.

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Extensive Regulation of Metabolism and Growth during the Cell Division Cycle

10.1101/005629 ◽

2014 ◽

Author(s):

Nikolai Slavov ◽

David Botstein ◽

Amy Caudy

Keyword(s):

Gene Expression ◽

Oxygen Consumption ◽

Cell Division ◽

Single Cell ◽

Single Cells ◽

Emergent Behavior ◽

Yeast Cells ◽

Physiological Data ◽

Synchronized Cultures ◽

Metabolic Cycle

Yeast cells grown in culture can spontaneously synchronize their respiration, metabolism, gene expression and cell division. Such metabolic oscillations in synchronized cultures reflect single-cell oscillations, but the relationship between the oscillations in single cells and synchronized cultures is poorly understood. To understand this relationship and the coordination between metabolism and cell division, we collected and analyzed DNA-content, gene-expression and physiological data, at hundreds of time-points, from cultures metabolically-synchronized at different growth rates, carbon sources and biomass densities. The data enabled us to extend and generalize our mechanistic model, based on ensemble average over phases (EAP), connecting the population-average gene-expression of asynchronous cultures to the gene-expression dynamics in the single-cells comprising the cultures. The extended model explains the carbon-source specific growth-rate responses of hundreds of genes. Our physiological data demonstrate that the frequency of metabolic cycling in synchronized cultures increases with the biomass density, suggesting that this cycling is an emergent behavior, resulting from the entraining of the single-cell metabolic cycle by a quorum-sensing mechanism, and thus underscoring the difference between metabolic cycling in single cells and in synchronized cultures. Measurements of constant levels of residual glucose across metabolically synchronized cultures indicate that storage carbohydrates are required to fuel not only the G1/S transition of the division cycle but also the metabolic cycle. Despite the large variation in profiled conditions and in the scale of their dynamics, most genes preserve invariant dynamics of coordination with each other and with the rate of oxygen consumption. Similarly, the G1/S transition always occurs at the beginning, middle or end of the high oxygen consumption phases, analogous to observations in human and drosophila cells. These results highlight evolutionary conserved coordination among metabolism, cell growth and division.

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Expansion microscopy: enabling single cell analysis in intact biological systems

FEBS Journal ◽

10.1111/febs.14597 ◽

2018 ◽

Vol 286 (8) ◽

pp. 1482-1494 ◽

Cited By ~ 14

Author(s):

Shahar Alon ◽

Grace H. Huynh ◽

Edward S. Boyden

Keyword(s):

Single Cell ◽

Single Cell Analysis ◽

Biological Systems ◽

Cell Analysis

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Receding meniscus induced docking of yeast cells inside microfluidic channels at single-cell level

World Congress on Medical Physics and Biomedical Engineering 2006 - IFMBE Proceedings ◽

10.1007/978-3-540-36841-0_70 ◽

2007 ◽

pp. 246-249

Author(s):

Min Cheol Park ◽

Jae Young Hur ◽

Keon Woo Kwon ◽

Jee Won Park ◽

Sang-Hyun Park ◽

...

Keyword(s):

Single Cell ◽

Yeast Cells ◽

Microfluidic Channels ◽

Single Cell Level ◽

Cell Level

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Complex Traits in Natural Populations

A Primer of Population Genetics and Genomics ◽

10.1093/oso/9780198862291.003.0009 ◽

2020 ◽

pp. 263-290

Author(s):

Daniel L. Hartl

Keyword(s):

Complex Traits ◽

Population Genomics ◽

Association Studies ◽

Natural Populations ◽

Complex Diseases ◽

Stabilizing Selection ◽

Phenotypic Evolution ◽

Genetic Changes ◽

Number Of Genes ◽

Almost All

This chapter could as well be titled “Population Genomics,” although many aspects of population genomics are integrated throughout the other chapters. It includes estimates of mutational variance and standing variance, phenotypic evolution under directional selection as measured by the linear selection gradient, and phenotypic evolution under stabilizing selection. It explores the strengths and limitations of genome-wide association studies of quantitative trait loci (QTLs) and expression (eQTLs) to detect genetic influencing complex traits in natural populations and genetic risk factors for complex diseases such as heart disease or diabetes. The number of genes affecting complex traits is considered, as well as evidence bearing on the issue of whether complex diseases are primarily affected by a very large number of genes, almost all of small effect, and how this bears on direct-to-consumer and over-the-counter genetic testing. The population genomics of adaptation is considered, including drug resistance, domestication, and local selection versus gene flow. The chapter concludes with the population genomics of speciation as illustrated by reinforcement of mating barriers, the reproducibility of phenotypic and genetic changes, and the accumulation of genetic incompatibilities.

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