Rare variants contribute disproportionately to quantitative trait variation in yeast

Bloom, Joshua S.; Boocock, James; Treusch, Sebastian; Sadhu, Meru J.; Day, Laura; Oates-Barker, Holly; Kruglyak, Leonid

doi:10.7554/elife.49212

Cited by 83 publications

(117 citation statements)

References 60 publications

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“…We obtained the additive QTL for each of the 38 phenotypes that were measured in ∼14,000 progeny from 16 parental crosses in Bloom et al ( 16 ). We tested all triplets of these QTL to see whether they were involved in any three-way QTL interactions.…”

Section: Methodsmentioning

confidence: 99%

“…In the course of mapping the genetic basis of variation in growth on multiple carbon sources, we discovered a three-way genetic interaction for growth in galactose ( 16 ). Here, we fine-mapped these three loci to genes in the galactose pathway and identified specific allelic combinations of these genes that are incompatible for growth in galactose.…”

Section: Introductionmentioning

confidence: 99%

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Ancient balancing selection maintains incompatible versions of a conserved metabolic pathway in yeast

Boocock

Sadhu²,

Bloom³

et al. 2019

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20Differences in nutrient availability have led to the evolution of diverse metabolic 21 strategies across species, but within species these strategies are expected to be 22 32 dairy environments, and they grow faster in galactose, but slower in glucose, 33 revealing a tradeoff on which balancing selection may have acted. 34 35 48 49One exceptionally well-studied example of alternative carbon utilization is the 50 Leloir pathway of galactose metabolism (4). This pathway consists of a galactose 51 transporter, encoded by the gene GAL2, enzymes that work together to convert 52 galactose into glucose-1-phosphate, and regulatory components that control their 53 expression. The enzymatic components are encoded by GAL1, GAL10, and 54 GAL7, together known as the structural galactose genes. Phosphoglucomutase, 55 encoded by PGM1 and PGM2, then converts glucose-1-phosphate to glucose-6-56 phosphate-the substrate for glycolysis. The GAL genes are strongly repressed 57 when either glucose or glycerol is present but are induced up to 1000-fold when 58 only galactose is available (5). Induction of the galactose pathway is controlled 59 by the GAL4 transcription factor and its regulators GAL80 and GAL3 (4). 61Although the enzymes involved in galactose metabolism are highly conserved 62 from yeast to humans, the regulation of galactose metabolism varies substantially 63 (6, 7). Within the yeast family Saccharomycetaceae, species show radically 64 different responses to galactose (8). For example, in S. uvarum, a species that is 65 separated from S. cerevisiae by approximately 10-20 million years, GAL genes 66 are not repressed by glucose (9, 10). Some strains of S. kudriavzevii can 67 metabolize galactose, while others have lost this ability through pseudogenization 68 of multiple genes in the pathway, and it has been proposed that the two versions 69 of the pathway have been maintained by multi-locus balancing selection (11). 70 Recent population surveys of S. cerevisae identified substantial sequence 71 diversity in genes involved in galactose metabolism and uncovered some strains 72 that lack glucose repression, a feature thought to be characteristic of galactose 73 regulation in this species (12)(13)(14)(15). 74 75 In the course of mapping the genetic basis of variation in growth on multiple 76 carbon sources, we discovered a three-way genetic interaction for growth in 77 galactose (16). Here, we fine-mapped these three loci to genes in the galactose 78 kna (35, 50). We did not use GAL2 in this analysis because this gene is only found

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Ancient balancing selection maintains incompatible versions of a conserved metabolic pathway in yeast

Boocock

Sadhu²,

Bloom³

et al. 2019

Preprint

Self Cite

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“…Coupled with the observation of transgressive phenotypes in several of our experiments, these data may suggest the presence of many unidentified QTL and undiscovered epistatic interactions. Both larger mapping populations and higher order models that test for multiple (Li and Sillanpää, 2012) and interacting loci (Bloom et al, 2019) may help to detect these elusive QTL in future studies.…”

Section: The Genetic Complexity Of Virulence Phenotypesmentioning

confidence: 99%

Pleiotropy and epistasis within and between signaling pathways defines the genetic architecture of fungal virulence

Roth

Murray

Scott

et al. 2020

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Cryptococcal disease is estimated to affect nearly a quarter of a million people annually. Environmental isolates of Cryptococcus deneoformans, which make up 15 to 30% of clinical infections in temperate climates such as Europe, vary in their pathogenicity, ranging from benign to hyper-virulent. Key traits that contribute to virulence, such as the production of the pigment melanin, an extracellular polysaccharide capsule, and the ability to grow at human body temperature have been identified, yet little is known about the genetic basis of variation in such traits. Here we investigate the genetic basis of melanization, capsule size, thermal tolerance, oxidative stress resistance, and antifungal drug sensitivity using quantitative trait locus (QTL) mapping in progeny derived from a cross between two divergent C. deneoformans strains. Using a "function-valued" QTL analysis framework that exploits both time-series information and growth differences across multiple environments, we identified QTL for each of these virulence traits and drug susceptibility. For three QTL we identified the underlying genes and nucleotide differences that govern variation in virulence traits. One of these genes, RIC8, which encodes a regulator of cAMP-PKA signaling, contributes to variation in four virulence traits: melanization, capsule size, thermal tolerance, and resistance to oxidative stress. Two major effect QTL for amphotericin B resistance map to the genes SSK1 and SSK2, which encode key components of the HOG pathway, a fungal-specific signal transduction network that orchestrates cellular responses to osmotic and other stresses. We also discovered complex epistatic interactions within and between genes in the HOG and cAMP-PKA pathways that regulate antifungal drug resistance and resistance to oxdiative stress. Our findings advance the understanding of virulence traits among diverse lineages of Cryptococcus, and highlight the role of genetic variation in key stress-responsive signaling pathways as a major contributor to phenotypic variation.

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“…GWAS increases resolution of the mapping due to long history of recombination within the gene pool. However, it still suffer from under consideration of rare alleles, which then lead to the phenomenon of “missing heritability” often observed where most of the phenotypic variation could not be explained by the genetic variants considered in the genetic model (Bloom et al, 2019). One partial solution to that was given in plants, where genome scans evolved to the point where large multi-parent populations attempt to bridge the advantages of QTL mapping and GWAS, e.g, nested-association-mapping (McMullen et al, 2009)(Maurer et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

RECAS9: Recombining wild species introgression via mitotic gene editing in barley

Lazar

Prusty

Bishara

et al. 2020

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Genetic loci underlying variation in traits with agronomic importance or genetic risk factors in human diseases have been identified by linkage analysis and genome-wide association studies.However, narrowing down the mapping to the individual causal genes and variations within these is much more challenging, and so is the ability to break linkage drag between beneficial and unfavourable loci in crop breeding. We developed RECAS9 as a transgene-free approach for precisely targeting recombination events by delivering CRISPR/Cas9 ribonucleotide protein (RNP) complex into heterozygous mitotic cells for the barley (Hordeum vulgare) Heat3.1 locus. A wild species (H. spontaneum) introgression in this region carries the agronomical unfavourable tough rachis phenotype (non-brittle) allele linked with a circadian clock accelerating QTL near GIGANTEA gene. We delivered RNP, which was targeted between two single nucleotide polymorphism (SNPs), to mitotic calli cells by particle bombardment. We estimated recombination events by next generation sequencing (NGS) and droplet digital PCR (ddPCR). While NGS analysis grieved from confounding effects of PCR recombination, ddPCR analysis allowed us to associate RNP treatment on heterozygous individuals with significant increase of homologous directed repair (HDR) between cultivated and wild alleles, with recombination rate ranging between zero to 57%. These results show for the first time in plants a directed and transgene free mitotic recombination driven by Cas9 RNP, and provide a starting point for precise breeding and fine scale mapping of beneficial alleles from crop wild relatives. Amunugama R, Fishel R (2012) Homologous recombination in eukaryotes. Prog. Mol. Biol. Transl. Sci. Elsevier B.V., pp 155-206 Barcelo P, Lazzeri PA (1995) Transformation of cereals by microprojectile bombardment of immature inflorescence and scutellum tissues. Methods Mol Biol. Bloom JS, Boocock J, Treusch S, Sadhu MJ, Day L, Oates-Barker H, Kruglyak L (2019) Rare variants contribute disproportionately to quantitative trait variation in yeast. Elife 8: 8-10 Brachi B, Faure N, Horton M, Flahauw E, Vazquez A, Nordborg M, Bergelson J, Cuguen J, Roux F (2010) Linkage and association mapping of Arabidopsis thaliana flowering time in nature. PLoS Genet 6: 40 Chu VT, Weber T, Wefers B, Wurst W, Sander S, Rajewsky K, Kühn R (2015) Increasing the efficiency of homology-directed repair for CRISPR-Cas9-induced precise gene editing in mammalian cells. Nat Biotechnol. Edwards KD, Lynn JR, Gyula P, Nagy F, Millar AJ (2005) Natural allelic variation in the temperature-compensation mechanisms of the Arabidopsis thaliana circadian clock. Genetics 170: 387-400 Fernandes JB, Séguéla-Arnaud M, Larchevêque C, Lloyd AH, Mercier R (2018) Unleashing meiotic crossovers in hybrid plants. Proc Natl Acad Sci U S A 115: 2431-2436 Fernández-Calleja M, Casas AM, Pérez-Torres A, Gracia MP, Igartua E (2019) Rachis brittleness in a hybrid-parent barley (Hordeum vulgare) breeding germplasm with different combinations at the non-brittle...

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Rare variants contribute disproportionately to quantitative trait variation in yeast

Cited by 83 publications

References 60 publications

Ancient balancing selection maintains incompatible versions of a conserved metabolic pathway in yeast

Ancient balancing selection maintains incompatible versions of a conserved metabolic pathway in yeast

Pleiotropy and epistasis within and between signaling pathways defines the genetic architecture of fungal virulence

RECAS9: Recombining wild species introgression via mitotic gene editing in barley

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