Experimental evolution reveals a general role for the methyltransferase Hmt1 in noise buffering

You, Shu-Ting; Jhou, Yu-Ting; Kao, Cheng-Fu; Leu, Jun‐Yi

doi:10.1101/714949

Cited by 5 publications

(3 citation statements)

References 86 publications

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“…Notably, many biological mechanisms can buffer stochastic gene expression and reduce the phenotypic impact of the differences observed at the mRNA level [42][43][44][45]. Indeed, the half-life of proteins being significantly longer could buffer the variability observed at the mRNA level [46].…”

Section: Discussionmentioning

confidence: 99%

Hematopoietic differentiation is characterized by a transient peak of entropy at a single-cell level

et al. 2022

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Background Mature blood cells arise from hematopoietic stem cells in the bone marrow by a process of differentiation along one of several different lineage trajectories. This is often represented as a series of discrete steps of increasing progenitor cell commitment to a given lineage, but as for differentiation in general, whether the process is instructive or stochastic remains controversial. Here, we examine this question by analyzing single-cell transcriptomic data from human bone marrow cells, assessing cell-to-cell variability along the trajectories of hematopoietic differentiation into four different types of mature blood cells. The instructive model predicts that cells will be following the same sequence of instructions and that there will be minimal variability of gene expression between them throughout the process, while the stochastic model predicts a role for cell-to-cell variability when lineage commitments are being made. Results Applying Shannon entropy to measure cell-to-cell variability among human hematopoietic bone marrow cells at the same stage of differentiation, we observed a transient peak of gene expression variability occurring at characteristic points in all hematopoietic differentiation pathways. Strikingly, the genes whose cell-to-cell variation of expression fluctuated the most over the course of a given differentiation trajectory are pathway-specific genes, whereas genes which showed the greatest variation of mean expression are common to all pathways. Finally, we showed that the level of cell-to-cell variation is increased in the most immature compartment of hematopoiesis in myelodysplastic syndromes. Conclusions These data suggest that human hematopoietic differentiation could be better conceptualized as a dynamical stochastic process with a transient stage of cellular indetermination, and strongly support the stochastic view of differentiation. They also highlight the need to consider the role of stochastic gene expression in complex physiological processes and pathologies such as cancers, paving the way for possible noise-based therapies through epigenetic regulation.

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Section: Discussionmentioning

confidence: 99%

Hematopoietic differentiation is characterized by a transient peak of entropy at a single-cell level

et al. 2022

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“…Of note, many biological mechanisms can buffer stochastic gene expression, and reduce the phenotypic impact of the differences observed at the mRNA level( 39–42 ). Notably, the half-life of proteins being significantly longer, it could buffer the variability observed at the mRNA level ( 43 ).…”

Section: Discussionmentioning

confidence: 99%

“…Of note, many biological mechanisms can buffer stochastic gene expression, and reduce the phenotypic impact of the differences observed at the mRNA level (35)(36)(37)(38).…”

Section: Discussionmentioning

confidence: 99%

Hematopoietic differentiation is characterized by a transient peak of entropy at a single cell level

Dussiau

Boussaroque

Gaillard³

et al. 2021

Preprint

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Hematopoietic differentiation has been considered as a multistep process which is metaphorically represented as linear trajectories with discrete steps from hematopoietic stem cells to mature cells. While the transcriptional state of cells at the beginning or at the end of these trajectories are relatively well described from bulk analysis, what happens in the intermediate states has remained elusive until the use of single cell approaches allowed to capture the dynamic changes of transcriptomic states.Applying Shannon entropy to measure cell-to-cell variability among cells at the same stage of differentiation, we observed a transient peak of gene expression variability in all the hematopoietic differentiation pathways. Strikingly, genes with the highest entropy variation in a given differentiation pathway matched genes known as pathway-specific, whereas genes with the highest expression variation were common to all pathways. Finally, we showed that the level of cell-to-cell variation is increased in the most immature compartment of hematopoiesis in myelodysplastic syndromes.These data suggest that differentiation may not be as deterministic and linear as previously thought, but could be better conceptualized as a dynamical stochastic process with a transient stage of cellular indetermination.

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Phenotype switching of the mutation rate as a strategy for crossing fitness valleys

Ram

2021

Preprint

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The mutation rate is an important determinant of evolutionary dynamics. Because the mutation rate determines the rate of appearance of beneficial and deleterious mutations, it is subject to second-order selection. The mutation rate varies between and within species and populations, increases under stress, and is genetically controlled by mutator alleles. The mutation rate may also vary among genetically identical individuals: empirical evidence from bacteria suggests that the mutation rate may be affected by translation errors and expression noise in various proteins (1). Importantly, this non-genetic variation may be heritable via transgenerational epigenetic inheritance. Here we investigate how the inheritance mode of the mutation rate affects the rate of adaptive evolution on rugged fitness landscapes. We model an asexual population with two mutation rate phenotypes, non-mutator and mutator. An offspring may switch from its parental phenotype to the other phenotype. The rate of switching between the mutation rate phenotypes is allowed to span a range of values. Thus, the mutation rate can be interpreted as a genetically inherited trait when the switching rate is low, as an epigenetically inherited trait when the switching rate is intermediate, or as a randomly determined trait when the switching rate is high. We find that epigenetically inherited mutation rates result in the highest rates of adaptation on rugged fitness landscapes for most realistic parameter sets. This is because an intermediate switching rate can maintain the association between a mutator phenotype and pre-existing mutations, which facilitates the crossing of fitness valleys. Our results provide a rationale for the evolution of epigenetic inheritance of the mutation rate, suggesting that it could have been selected because it facilitates adaptive evolution.

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Experimental evolution reveals a general role for the methyltransferase Hmt1 in noise buffering

Cited by 5 publications

References 86 publications

Hematopoietic differentiation is characterized by a transient peak of entropy at a single-cell level

Hematopoietic differentiation is characterized by a transient peak of entropy at a single-cell level

Hematopoietic differentiation is characterized by a transient peak of entropy at a single cell level

Phenotype switching of the mutation rate as a strategy for crossing fitness valleys

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