Powerful decomposition of complex traits in a diploid model

Hallin, Johan; Märtens, Kaspar; Young, Alexander I.; Zackrisson, Martin; Salinas, F.; Parts, Leopold; Warringer, Jonas; Liti, Gianni

doi:10.1038/ncomms13311

Cited by 32 publications

(46 citation statements)

References 57 publications

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“…However, it also accommodates quantitative changes in the effect magnitude or sign of epistatically interacting variants (Fig 3). These quantitative epistatic interactions have received limited discussion in the Hsp90 literature but are prevalent in nature [23,24,42]. …”

Section: Hsp90 Is a Global Modifier That Shows Extensive Epistasismentioning

confidence: 99%

Modifiers of the Genotype–Phenotype Map: Hsp90 and Beyond

2016

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Disruption of certain genes alters the heritable phenotypic variation among individuals. Research on the chaperone Hsp90 has played a central role in determining the genetic basis of this phenomenon, which may be important to evolution and disease. Key studies have shown that Hsp90 perturbation modifies the effects of many genetic variants throughout the genome. These modifications collectively transform the genotype–phenotype map, often resulting in a net increase or decrease in heritable phenotypic variation. Here, we summarize some of the foundational work on Hsp90 that led to these insights, discuss a framework for interpreting this research that is centered upon the standard genetics concept of epistasis, and propose major questions that future studies in this area should address.

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Section: Hsp90 Is a Global Modifier That Shows Extensive Epistasismentioning

confidence: 99%

Modifiers of the Genotype–Phenotype Map: Hsp90 and Beyond

2016

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“…Haploid parents were combined into diploid hybrids with varying levels of heterozygosity which were evolved in different laboratory settings. Remarkably, the hybridization process can be easily automated [74] and as the number of available annotated assemblies increases, the number of potential hybrids grows quadratically. The presence of single-nucleotide markers provided a reliable quality threshold for filtering de novo small variants, thus bypassing the need of multiple hard filters.…”

Section: Discussionmentioning

confidence: 99%

Accurate tracking of the mutational landscape of diploid hybrid genomes

Tattini

Tellini

Mozzachiodi

et al. 2018

Preprint

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Background Genome evolution promotes diversity within a population via mutations, recombination, and whole-genome duplication. However, quantifying precisely these factors in diploid hybrid genomes is challenging. Here we present an integrated experimental and computational workflow to accurately track the mutational landscape of yeast diploid hybrids (MuLoYDH) in terms of single-nucleotide variants, small insertions/deletions, copy-number variants and loss-of-heterozygosity. ResultsHaploid Saccharomyces parents were combined into diploid hybrids with fully phased genome and controlled levels of heterozygosity. The resulting hybrids represented the ancestral state and were evolved under different laboratory protocols. Variant simulations enabled to efficiently integrate competitive and standard mapping, depending on local levels of heterozygosity and read length. Experimental validations proved high accuracy and resolution of our computational approach. Finally, applying MuLoYDH to four different diploids revealed striking genetic background effects. Homozygous S. cerevisiae showed ∼4-fold higher mutation rate compared to S. paradoxus. In contrast, interspecies hybrids exhibited mutation rates similar to intraspecies hybrids despite 10-fold higher heterozygosity. MuLoYDH unveiled that a substantial fraction of the genome (∼200 bp per generation) was shaped by loss-of-heterozygosity and this process was strongly inhibited by high levels of heterozygosity. ConclusionsWe report a comprehensive framework for characterizing the mutational spectrum of yeast diploid hybrids with unprecedented resolution, which can be generalised to other genetic systems. Applying MuLoYDH to laboratory-evolved hybrids provided novel quantitative insights into the evolutionary processes that mould yeast genomes.

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“…We crossed a long-lived North American (NA) oak tree bark strain (YPS128) with a short-lived West African (WA) palm wine strain (DBVPG6044) which differ at 0.53% of nucleotide sites (Liti et al 2009;Parts et al 2011). A pool of F12 segregants of opposite mating types were then mated to generate 1056 diploids with hybrid, phased genomes, termed Phased Outbred Lines (POLs) (Hallin et al 2016).…”

Section: Calorie Restriction and Rapamycin Extend Life Span Through Dmentioning

confidence: 99%

“…86 F12 haploid segregants of each mating type were isolated, sequenced and their genotype was inferred using a set of 52466 markers (Illingworth et al 2013). Phased Outbred Lines (POLs) were obtained as described (Hallin et al 2016) with minor modifications. F12 segregants of opposite mating type were randomly paired and mated (YPD) in 96 well plates, and 1056 unique diploids with known, phased genomes were then selected during 3 consecutive diploid selective cultivations on minimal media.…”

Section: Strainsmentioning

confidence: 99%

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Intragenic repeat expansions control yeast chronological aging

Barré

Hallin

Persson

et al. 2019

Preprint

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Aging varies among individuals due to both genetics and environment but the underlying molecular mechanisms remain largely unknown. Using a highly recombined Saccharomyces cerevisiae population, we found 30 distinct Quantitative Trait Loci (QTLs) that control chronological life span (CLS) in calorie rich and calorie restricted environments, and under rapamycin exposure. Calorie restriction and rapamycin extended life span in virtually all genotypes, but through different genetic variants. We tracked the two major QTLs to massive expansions of intragenic tandem repeats in the cell wall glycoproteins FLO11 and HPF1, which caused a dramatic life span shortening. Life span impairment by N-terminal HPF1 repeat expansion was partially buffered by rapamycin but not by calorie restriction. The HPF1 repeat expansion shifted yeast cells from a sedentary to a buoyant state, thereby increasing their exposure to surrounding oxygen. The higher oxygenation perturbed methionine, lipid, and purine metabolism, which likely explains the life span shortening. We conclude that fast evolving intragenic repeat expansions can fundamentally change the relationship between cells and their environment with profound effects on cellular life style and longevity.atypical (Warringer et al. 2011), maintained as haploids rather than diploids (Peter et al. 2018), carry auxotrophies that alter life span (Boer, Amini, and Botstein 2008;Gomes et al. 2007), and have never been exposed to natural selection. Thus, genetic variants that regulate natural life span variation are still largely unknown. Crosses between natural yeast strains have the potential to uncover these variants (Brem 2002;Steinmetz et al. 2002), but remain poorly explored. Previous work linked natural polymorphisms in the ribosomal DNA and in the sirtuin SIR2 (Kwan et al. 2013;Stumpferl et al. 2012), as well as telomere maintenance (Kwan et al. 2011) and serine biosynthesis (Jung et al. 2018) to life span variation. Lack of genetic diversity, mapping resolution and power has prevented more exhaustive exploration.We unravelled the genetic basis of CLS variation using advanced intercrosses between two natural S. cerevisiae isolates with very different life spans. We measured CLS in calorie rich and calorie restricted media, and under rapamycin treatment. We mapped 30 unique QTLs of which the two major were explained by massive intragenic tandem repeat expansions in the cell wall glycoproteins FLO11 and HPF1 that dramatically shortened life span. Serine/threonine repeat expansions close to the HPF1 N-terminus shifted cells from a sedentary to a buoyant life style, thereby increasing exposure to oxygen and perturbing methionine, lipid and purine homeostasis. Interestingly, the downstream effects of buoyancy were partially recovered by rapamycin treatment, suggesting that they can be targeted by TORC1 repression. Results Calorie restriction and rapamycin extend life span through different genetic variantsWe crossed a long-lived North American (NA) oak tree bark strain (YPS128) with a sho...

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Powerful decomposition of complex traits in a diploid model

Cited by 32 publications

References 57 publications

Modifiers of the Genotype–Phenotype Map: Hsp90 and Beyond

Modifiers of the Genotype–Phenotype Map: Hsp90 and Beyond

Accurate tracking of the mutational landscape of diploid hybrid genomes

Intragenic repeat expansions control yeast chronological aging

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