Genetic Redundancy Enhances Problems of Beneficial Mutations

Abstract If multiple linked polymorphisms are under natural selection, then conflicts arise and the efficiency of natural selection is hindered relative to the case of no linkage. This simple interaction between linkage and natural selection creates an opportunity for mutations that raise the level of recombination to increase in frequency and have an enhanced chance of fixation. This important finding by S. Otto and N. Barton means that mutations that raise the recombination rate, but are otherwise neutral, will be selectively favored under fairly general circumstances of multilocus selection and linkage. The effect described by Otto and Barton, which was limited to neutral modifiers, can also be extended to include all modifiers of recombination, both beneficial and deleterious. Computer simulations show that beneficial mutations that also increase recombination have an increased chance of fixation. Similarly, deleterious mutations that also decrease recombination have an increased chance of fixation. The results suggest that a simple model of recombination modifiers, including both neutral and pleiotropic modifiers, is a necessary explanation for the evolutionary origin of recombination.

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Combinatorial CRISPR screen identifies fitness effects of gene paralogues

Nature Communications ◽

10.1038/s41467-021-21478-9 ◽

2021 ◽

Vol 12 (1) ◽

Cited By ~ 1

Author(s):

Nicola A. Thompson ◽

Marco Ranzani ◽

Louise van der Weyden ◽

Vivek Iyer ◽

Victoria Offord ◽

...

Keyword(s):

Cancer Cells ◽

Cell Lines ◽

Unknown Function ◽

Single Copy ◽

Genetic Redundancy ◽

Synthetic Lethal ◽

Fitness Effects ◽

Synthetic Lethal Interactions ◽

Crispr Screen ◽

Multiple Cell

AbstractGenetic redundancy has evolved as a way for human cells to survive the loss of genes that are single copy and essential in other organisms, but also allows tumours to survive despite having highly rearranged genomes. In this study we CRISPR screen 1191 gene pairs, including paralogues and known and predicted synthetic lethal interactions to identify 105 gene combinations whose co-disruption results in a loss of cellular fitness. 27 pairs influence fitness across multiple cell lines including the paralogues FAM50A/FAM50B, two genes of unknown function. Silencing of FAM50B occurs across a range of tumour types and in this context disruption of FAM50A reduces cellular fitness whilst promoting micronucleus formation and extensive perturbation of transcriptional programmes. Our studies reveal the fitness effects of FAM50A/FAM50B in cancer cells.

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The Probability of Fixation in Populations of Changing Size

Genetics ◽

10.1093/genetics/146.2.723 ◽

1997 ◽

Vol 146 (2) ◽

pp. 723-733 ◽

Cited By ~ 33

Author(s):

Sarah P Otto ◽

Michael C Whitlock

Keyword(s):

Diffusion Equation ◽

Adaptive Evolution ◽

Process Model ◽

Branching Process ◽

Approximate Solutions ◽

Logistic Growth ◽

Beneficial Mutations ◽

Demographic Models ◽

Deleterious Alleles ◽

Probability Of Fixation

The rate of adaptive evolution of a population ultimately depends on the rate of incorporation of beneficial mutations. Even beneficial mutations may, however, be lost from a population since mutant individuals may, by chance, fail to reproduce. In this paper, we calculate the probability of fixation of beneficial mutations that occur in populations of changing size. We examine a number of demographic models, including a population whose size changes once, a population experiencing exponential growth or decline, one that is experiencing logistic growth or decline, and a population that fluctuates in size. The results are based on a branching process model but are shown to be approximate solutions to the diffusion equation describing changes in the probability of fixation over time. Using the diffusion equation, the probability of fixation of deleterious alleles can also be determined for populations that are changing in size. The results developed in this paper can be used to estimate the fixation flux, defined as the rate at which beneficial alleles fix within a population. The fixation flux measures the rate of adaptive evolution of a population and, as we shall see, depends strongly on changes that occur in population size.

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The Advantages of Segregation and the Evolution of Sex

Genetics ◽

10.1093/genetics/164.3.1099 ◽

2003 ◽

Vol 164 (3) ◽

pp. 1099-1118 ◽

Cited By ~ 12

Author(s):

Sarah P Otto

Keyword(s):

Sexual Reproduction ◽

Asexual Reproduction ◽

Deleterious Mutations ◽

Evolution Of Sex ◽

Beneficial Mutations ◽

Selection Regime ◽

Strong Selection ◽

Genome Wide ◽

Low Levels

AbstractIn diploids, sexual reproduction promotes both the segregation of alleles at the same locus and the recombination of alleles at different loci. This article is the first to investigate the possibility that sex might have evolved and been maintained to promote segregation, using a model that incorporates both a general selection regime and modifier alleles that alter an individual’s allocation to sexual vs. asexual reproduction. The fate of different modifier alleles was found to depend strongly on the strength of selection at fitness loci and on the presence of inbreeding among individuals undergoing sexual reproduction. When selection is weak and mating occurs randomly among sexually produced gametes, reductions in the occurrence of sex are favored, but the genome-wide strength of selection is extremely small. In contrast, when selection is weak and some inbreeding occurs among gametes, increased allocation to sexual reproduction is expected as long as deleterious mutations are partially recessive and/or beneficial mutations are partially dominant. Under strong selection, the conditions under which increased allocation to sex evolves are reversed. Because deleterious mutations are typically considered to be partially recessive and weakly selected and because most populations exhibit some degree of inbreeding, this model predicts that higher frequencies of sex would evolve and be maintained as a consequence of the effects of segregation. Even with low levels of inbreeding, selection is stronger on a modifier that promotes segregation than on a modifier that promotes recombination, suggesting that the benefits of segregation are more likely than the benefits of recombination to have driven the evolution of sexual reproduction in diploids.

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Two Putative RNA-Binding Proteins Function with Unequal Genetic Redundancy in the MOS4-Associated Complex

PLANT PHYSIOLOGY ◽

10.1104/pp.110.158931 ◽

2010 ◽

Vol 154 (4) ◽

pp. 1783-1793 ◽

Cited By ~ 24

Author(s):

Jacqueline Monaghan ◽

Fang Xu ◽

Shaohua Xu ◽

Yuelin Zhang ◽

Xin Li

Keyword(s):

Binding Proteins ◽

Rna Binding ◽

Rna Binding Proteins ◽

Genetic Redundancy

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PLEIOTROPIC REGULATORY LOCUS 2 exhibits unequal genetic redundancy with its homolog PRL1

Plant and Cell Physiology ◽

10.1093/pcp/pcs103 ◽

2012 ◽

Vol 53 (9) ◽

pp. 1617-1626 ◽

Cited By ~ 4

Author(s):

Tabea Weihmann ◽

Kristoffer Palma ◽

Yukino Nitta ◽

Xin Li

Keyword(s):

Genetic Redundancy ◽

Regulatory Locus

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Depletion of Undecaprenyl Pyrophosphate Phosphatases Disrupts Cell Envelope Biogenesis in Bacillus subtilis

Journal of Bacteriology ◽

10.1128/jb.00507-16 ◽

2016 ◽

Vol 198 (21) ◽

pp. 2925-2935 ◽

Cited By ~ 33

Author(s):

Heng Zhao ◽

Yingjie Sun ◽

Jason M. Peters ◽

Carol A. Gross ◽

Ethan C. Garner ◽

...

Keyword(s):

Bacillus Subtilis ◽

Transcriptional Repression ◽

Cell Envelope ◽

Turgor Pressure ◽

Teichoic Acid ◽

Lethal Gene ◽

Genetic Redundancy ◽

Wall Teichoic Acid ◽

Content Type ◽

Lipid Ii

ABSTRACTThe integrity of the bacterial cell envelope is essential to sustain life by countering the high turgor pressure of the cell and providing a barrier against chemical insults. InBacillus subtilis, synthesis of both peptidoglycan and wall teichoic acids requires a common C55lipid carrier, undecaprenyl-pyrophosphate (UPP), to ferry precursors across the cytoplasmic membrane. The synthesis and recycling of UPP requires a phosphatase to generate the monophosphate form Und-P, which is the substrate for peptidoglycan and wall teichoic acid synthases. Using an optimizedclusteredregularlyinterspacedshortpalindromicrepeat (CRISPR) system with catalytically inactive (“dead”)CRISPR-associated protein9(dCas9)-based transcriptional repression system (CRISPR interference [CRISPRi]), we demonstrate thatB. subtilisrequires either of two UPP phosphatases, UppP or BcrC, for viability. We show that a third predicted lipid phosphatase (YodM), with homology to diacylglycerol pyrophosphatases, can also support growth when overexpressed. Depletion of UPP phosphatase activity leads to morphological defects consistent with a failure of cell envelope synthesis and strongly activates the σM-dependent cell envelope stress response, includingbcrC, which encodes one of the two UPP phosphatases. These results highlight the utility of an optimized CRISPRi system for the investigation of synthetic lethal gene pairs, clarify the nature of theB. subtilisUPP-Pase enzymes, and provide further evidence linking the σMregulon to cell envelope homeostasis pathways.IMPORTANCEThe emergence of antibiotic resistance among bacterial pathogens is of critical concern and motivates efforts to develop new therapeutics and increase the utility of those already in use. The lipid II cycle is one of the most frequently targeted processes for antibiotics and has been intensively studied. Despite these efforts, some steps have remained poorly defined, partly due to genetic redundancy. CRISPRi provides a powerful tool to investigate the functions of essential genes and sets of genes. Here, we used an optimized CRISPRi system to demonstrate functional redundancy of two UPP phosphatases that are required for the conversion of the initially synthesized UPP lipid carrier to Und-P, the substrate for the synthesis of the initial lipid-linked precursors in peptidoglycan and wall teichoic acid synthesis.

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