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Chapter 5 : Essential Genes in

Authors: Wenqi Hu1, Jiang Bo2, Terry Roemer3
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Affiliations: 1: Merck Frosst Center for Fungal Genetics, Merck and Company., Inc., Montreal, Quebec H2X 3Y8, Canada; 2: Merck Frosst Center for Fungal Genetics, Merck and Company., Inc., Montreal, Quebec H2X 3Y8, Canada; 3: Merck Frosst Center for Fungal Genetics, Merck and Company., Inc., Montreal, Quebec H2X 3Y8, Canada
Content Type: Monograph
Publication Year: 2009

Category: Clinical Microbiology; Fungi and Fungal Pathogenesis

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Abstract:

This chapter discusses recent developments in the identification of essential genes and validation of potential antifungal drug targets in . Essential genes were identified based on (i) the inability to construct haploid insertional mutants or (ii) identification of temperature-sensitive conditional mutants. The compendium of recently defined conserved essential genes in , , and other fungi has provided important insights for predicting essential genes in . Essential genes that are required for fungal survival and growth provide potential antifungal drug targets. genes which have been experimentally demonstrated to be essential for growth are summarized. This essential gene set includes genes involved in various biological and biochemical functions, such as amino acid, cell wall, ergosterol, heme, and lipid biosynthesis, as well as cell cycle control, cellular metabolism, protein transport, ribosome biogenesis, and RNA splicing. Additional essential genes involved in ergosterol biosynthesis include ERG10, ERG12, ERG7, ERG8, and ERG20 and as such, provide new targets for therapeutic intervention. Currently, identification of essential genes largely depends on the following four approaches: conventional gene deletion and disruption, parasexual genetics, RNAi knockdown, and conditional promoter replacement strategies. Completion of the genome sequence, however, combined with current molecular genetic strategies and their inevitable refinements, has now made large-scale genetic analysis of possible for the first time, thus expanding our knowledge of its biology, pathogenesis, and potential antifungal targets.

Citation: Hu W, Bo J, Roemer T. 2009. Essential Genes in , p 39-59. In Latgé J, Steinbach W (ed), and Aspergillosis. ASM Press, Washington, DC. doi: 10.1128/9781555815523.ch5

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Essential Genes in Aspergillus fumigatus
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Citation: Hu W, Bo J, Roemer T. 2009. Essential Genes in , p 39-59. In Latgé J, Steinbach W (ed), and Aspergillosis. ASM Press, Washington, DC. doi: 10.1128/9781555815523.ch5
/content/10.1128/9781555815523.ch05.ch05fig01
Figure 1.
Outline of the GRACE method of target validation in . Step 1: A heterozygote strain of the target gene was constructed by transforming a wild-type strain with a PCR-generated disruption cassette flanked with homologous sequences to precisely delete one copy of the target gene. Step 2: The heterozygote strain obtained in step 1 was further transformed with a PCR-generated conditional promoter replacement cassette. Each cassette contains a SAT-1 dominant selectable marker and a conditional promoter (pTet) flanked with homologous DNA sequences to precisely replace the endogenous promoter of the remaining wild-type allele with pTet. Gene essentiality of the target gene was directly assessed by comparing the growth phenotype under inducing and repressing conditions ( ).
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Image of Figure 1.
Figure 1.

Outline of the GRACE method of target validation in . Step 1: A heterozygote strain of the target gene was constructed by transforming a wild-type strain with a PCR-generated disruption cassette flanked with homologous sequences to precisely delete one copy of the target gene. Step 2: The heterozygote strain obtained in step 1 was further transformed with a PCR-generated conditional promoter replacement cassette. Each cassette contains a SAT-1 dominant selectable marker and a conditional promoter (pTet) flanked with homologous DNA sequences to precisely replace the endogenous promoter of the remaining wild-type allele with pTet. Gene essentiality of the target gene was directly assessed by comparing the growth phenotype under inducing and repressing conditions ( ).

Citation: Hu W, Bo J, Roemer T. 2009. Essential Genes in , p 39-59. In Latgé J, Steinbach W (ed), and Aspergillosis. ASM Press, Washington, DC. doi: 10.1128/9781555815523.ch5
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Figure 2.
Schematic overview of gene disruption and deletion methods. (A) Schematic representation of a gene disruption event. The open arrow represents the ORF of a gene of interest. A gene disruption plasmid was constructed by cloning a truncated fragment of the target gene into a plasmid containing a selectable marker. Following a single-crossover homologous recombination, the plasmid integrates into the target gene, leading to a disruption of the gene. (B) Schematic representation of the gene deletion method. The open arrow represents the ORF of a gene of interest. A gene deletion cassette containing a selectable marker flanked with appropriate homologous DNA sequence was used to transform . Following a double-crossover homologous recombination, the ORF of the target gene was precisely replaced by the selectable marker.
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Image of Figure 2.
Figure 2.

Schematic overview of gene disruption and deletion methods. (A) Schematic representation of a gene disruption event. The open arrow represents the ORF of a gene of interest. A gene disruption plasmid was constructed by cloning a truncated fragment of the target gene into a plasmid containing a selectable marker. Following a single-crossover homologous recombination, the plasmid integrates into the target gene, leading to a disruption of the gene. (B) Schematic representation of the gene deletion method. The open arrow represents the ORF of a gene of interest. A gene deletion cassette containing a selectable marker flanked with appropriate homologous DNA sequence was used to transform . Following a double-crossover homologous recombination, the ORF of the target gene was precisely replaced by the selectable marker.

Citation: Hu W, Bo J, Roemer T. 2009. Essential Genes in , p 39-59. In Latgé J, Steinbach W (ed), and Aspergillosis. ASM Press, Washington, DC. doi: 10.1128/9781555815523.ch5
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Figure 3.
Schematic overview of the parasexual strategy. A diploid (heterozygous) strain was first created by gene disruption or transposon mutagenesis and contains one inactivated allele of the target gene (gene X) as well as a wild-type allele. The heterozygous strain is used to perform haploidization analysis using benomyl as an inducer on selective and nonselective medium in two independent tests. The haploidization process will result in two subpopulations of haploid cells: one bearing the inactivated allele of the target gene and one bearing a wild-type allele. If gene X is essential for growth, haploid progenies cannot be obtained from selective medium, as haploids with the inactivated allele will not be viable and haploids with the wild-type allele lack the selectable marker. Replicated from Firon and with permission from the publisher and the authors.
10.1128/9781555815523/f0045-01_thmb.gif
10.1128/9781555815523/f0045-01.gif
Image of Figure 3.
Figure 3.

Schematic overview of the parasexual strategy. A diploid (heterozygous) strain was first created by gene disruption or transposon mutagenesis and contains one inactivated allele of the target gene (gene X) as well as a wild-type allele. The heterozygous strain is used to perform haploidization analysis using benomyl as an inducer on selective and nonselective medium in two independent tests. The haploidization process will result in two subpopulations of haploid cells: one bearing the inactivated allele of the target gene and one bearing a wild-type allele. If gene X is essential for growth, haploid progenies cannot be obtained from selective medium, as haploids with the inactivated allele will not be viable and haploids with the wild-type allele lack the selectable marker. Replicated from Firon and with permission from the publisher and the authors.

Citation: Hu W, Bo J, Roemer T. 2009. Essential Genes in , p 39-59. In Latgé J, Steinbach W (ed), and Aspergillosis. ASM Press, Washington, DC. doi: 10.1128/9781555815523.ch5
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Figure 4.
Schematic overview of the RNAi method. (A) Representative example of the RNAi cassette used to silence the target gene in The RNAi cassette was constructed with inverted repeats of 500 bp of the coding region of the target gene separated by a spacer segment of GFP sequence. (B) Representative example of the -based RNAi cassette.
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Image of Figure 4.
Figure 4.

Schematic overview of the RNAi method. (A) Representative example of the RNAi cassette used to silence the target gene in The RNAi cassette was constructed with inverted repeats of 500 bp of the coding region of the target gene separated by a spacer segment of GFP sequence. (B) Representative example of the -based RNAi cassette.

Citation: Hu W, Bo J, Roemer T. 2009. Essential Genes in , p 39-59. In Latgé J, Steinbach W (ed), and Aspergillosis. ASM Press, Washington, DC. doi: 10.1128/9781555815523.ch5
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Figure 5.
Conditional promoter replacement strategy. (A) Schematic overview of the p-CPR strategy. A conditional promoter replacement cassette containing a selectable marker and a p conditional promoter flanked with 1.5 kb of homologous DNA sequence (L-arm and R-arm) was used to transform the CEA17 strain ( ). Following homologous recombination, the endogenous promoter of the target gene was precisely replaced by the p condition promoter ( ). (B) Representative example of gene essentiality validation with a p- mutant. The p- mutant displayed a no-growth phenotype under repressing conditions, suggesting its essential role for growth. Images are reprinted from with permission from the publisher and the authors.
10.1128/9781555815523/f0051-01_thmb.gif
10.1128/9781555815523/f0051-01.gif
Image of Figure 5.
Figure 5.

Conditional promoter replacement strategy. (A) Schematic overview of the p-CPR strategy. A conditional promoter replacement cassette containing a selectable marker and a p conditional promoter flanked with 1.5 kb of homologous DNA sequence (L-arm and R-arm) was used to transform the CEA17 strain ( ). Following homologous recombination, the endogenous promoter of the target gene was precisely replaced by the p condition promoter ( ). (B) Representative example of gene essentiality validation with a p- mutant. The p- mutant displayed a no-growth phenotype under repressing conditions, suggesting its essential role for growth. Images are reprinted from with permission from the publisher and the authors.

Citation: Hu W, Bo J, Roemer T. 2009. Essential Genes in , p 39-59. In Latgé J, Steinbach W (ed), and Aspergillosis. ASM Press, Washington, DC. doi: 10.1128/9781555815523.ch5
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Figure 6.
In vivo validation of gene essentiality using -CPR mutants. (A) ICR male mice were immunocompromised by administrating cyclophosphamide at 150 mg/kg of body weight twice prior to infection and then 100 mg/kg twice a week after infection. Approximately 10 viable conidia from individual mutants were injected into the tail vein of immunocompromised mice (five mice per group). CEA10 (wild-type) and CEA17 (a PyrG–auxotroph of CEA10) were included as controls for virulence and avirulence, respectively. (B) Genetic inactivation of the gene family promotes avirulence in an immunocompromised murine model of systemic infection. Pathogenesis of and an double mutant was similarly analyzed but over a longer postinfection period (22 days), and animal survival was compared to CEA10 and CEA17 control strains. Figures are reprinted from with permission from the publisher and the authors.
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Image of Figure 6.
Figure 6.

In vivo validation of gene essentiality using -CPR mutants. (A) ICR male mice were immunocompromised by administrating cyclophosphamide at 150 mg/kg of body weight twice prior to infection and then 100 mg/kg twice a week after infection. Approximately 10 viable conidia from individual mutants were injected into the tail vein of immunocompromised mice (five mice per group). CEA10 (wild-type) and CEA17 (a PyrG–auxotroph of CEA10) were included as controls for virulence and avirulence, respectively. (B) Genetic inactivation of the gene family promotes avirulence in an immunocompromised murine model of systemic infection. Pathogenesis of and an double mutant was similarly analyzed but over a longer postinfection period (22 days), and animal survival was compared to CEA10 and CEA17 control strains. Figures are reprinted from with permission from the publisher and the authors.

Citation: Hu W, Bo J, Roemer T. 2009. Essential Genes in , p 39-59. In Latgé J, Steinbach W (ed), and Aspergillosis. ASM Press, Washington, DC. doi: 10.1128/9781555815523.ch5
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Tables

Essential Genes in Aspergillus fumigatus
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Citation: Hu W, Bo J, Roemer T. 2009. Essential Genes in , p 39-59. In Latgé J, Steinbach W (ed), and Aspergillosis. ASM Press, Washington, DC. doi: 10.1128/9781555815523.ch5
/content/10.1128/9781555815523.ch05.ch05tab01
Table 1.
Experimentally validated essential genes
Generic image for table
Table 1.

Experimentally validated essential genes

Citation: Hu W, Bo J, Roemer T. 2009. Essential Genes in , p 39-59. In Latgé J, Steinbach W (ed), and Aspergillosis. ASM Press, Washington, DC. doi: 10.1128/9781555815523.ch5

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