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Single cell functional genomics reveals the importance of mitochondria in cell-to-cell phenotypic variation.

ABSTRACT: Mutations frequently have outcomes that differ across individuals, even when these individuals are genetically identical and share a common environment. Moreover, individual microbial and mammalian cells can vary substantially in their proliferation rates, stress tolerance, and drug resistance, with important implications for the treatment of infections and cancer. To investigate the causes of cell-to-cell variation in proliferation, we used a high-throughput automated microscopy assay to quantify the impact of deleting >1500 genes in yeast. Mutations affecting mitochondria were particularly variable in their outcome. In both mutant and wild-type cells mitochondrial membrane potential - but not amount - varied substantially across individual cells and predicted cell-to-cell variation in proliferation, mutation outcome, stress tolerance, and resistance to a clinically used anti-fungal drug. These results suggest an important role for cell-to-cell variation in the state of an organelle in single cell phenotypic variation.

SUBMITTER: Dhar R

PROVIDER: S-EPMC6366901 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Single cell functional genomics reveals the importance of mitochondria in cell-to-cell phenotypic variation.

Dhar Riddhiman R Missarova Alsu M AM Lehner Ben B Carey Lucas B LB

eLife 20190114

Mutations frequently have outcomes that differ across individuals, even when these individuals are genetically identical and share a common environment. Moreover, individual microbial and mammalian cells can vary substantially in their proliferation rates, stress tolerance, and drug resistance, with important implications for the treatment of infections and cancer. To investigate the causes of cell-to-cell variation in proliferation, we used a high-throughput automated microscopy assay to quanti ...[more]

PMID: 30638445

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Project description:Climate change is a threat to sustainable livestock production and livelihoods in the tropics. It has adverse impacts on feed and water availability, disease prevalence, production, environmental temperature, and biodiversity. Unravelling the drivers of local adaptation and understanding the underlying genetic variation in random mating indigenous livestock populations informs the design of genetic improvement programmes that aim to increase productivity and resilience. In the present study, we combined environmental, genomic, and phenotypic information of Ethiopian indigenous chickens to investigate their environmental adaptability. Through a hybrid sampling strategy, we captured wide biological and ecological variabilities across the country. Our environmental dataset comprised mean values of 34 climatic, vegetation and soil variables collected over a thirty-year period for 260 geolocations. Our biological dataset included whole genome sequences and quantitative measurements (on eight traits) from 513 individuals, representing 26 chicken populations spread along 4 elevational gradients (6-7 populations per gradient). We performed signatures of selection analyses ([Formula: see text] and XP-EHH) to detect footprints of natural selection, and redundancy analyses (RDA) to determine genotype-environment and genotype-phenotype-associations. RDA identified 1909 outlier SNPs linked with six environmental predictors, which have the highest contributions as ecological drivers of adaptive phenotypic variation. The same method detected 2430 outlier SNPs that are associated with five traits. A large overlap has been observed between signatures of selection identified by[Formula: see text]and XP-EHH showing that both methods target similar selective sweep regions. Average genetic differences measured by [Formula: see text] are low between gradients, but XP-EHH signals are the strongest between agroecologies. Genes in the calcium signalling pathway, those associated with the hypoxia-inducible factor (HIF) transcription factors, and sports performance (GALNTL6) are under selection in high-altitude populations. Our study underscores the relevance of landscape genomics as a powerful interdisciplinary approach to dissect adaptive phenotypic and genetic variation in random mating indigenous livestock populations.

Dataset Information

Single cell functional genomics reveals the importance of mitochondria in cell-to-cell phenotypic variation.

Publications

Single cell functional genomics reveals the importance of mitochondria in cell-to-cell phenotypic variation.

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