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Essential gene
Essential genes are indispensable genes for organisms to grow and reproduce offspring under certain environment. However, being essential is highly dependent on the circumstances in which an organism lives. For instance, a gene required to digest starch is only essential if starch is the only source of energy. Recently, systematic attempts have been made to identify those genes that are absolutely required to maintain life, provided that all nutrients are available. Such experiments have led to the conclusion that the absolutely required number of genes for bacteria is on the order of about 250–300. Essential genes of single-celled organisms encode proteins for three basic functions including genetic information processing, cell envelopes and energy production. Those gene functions are used to maintain a central metabolism, replicate DNA, translate genes into proteins, maintain a basic cellular structure, and mediate transport processes into and out of the cell. Compared with single-celled organisms, multicellular organisms have more essential genes related to communication and development. Most of the essential genes in viruses are related to the processing and maintenance of genetic information. In contrast to most single-celled organisms, viruses lack many essential genes for metabolism, which forces them to hijack the host's metabolism. Most genes are not essential but convey selective advantages and increased fitness. Hence, the vast majority of genes are not essential and many can be deleted without consequences, at least under most circumstances.
Two main strategies have been employed to identify essential genes on a genome-wide basis: directed deletion of genes and random mutagenesis using transposons. In the first case, annotated individual genes (or ORFs) are completely deleted from the genome in a systematic way. In transposon-mediated mutagenesis, transposons are randomly inserted in as many positions in a genome as possible, aiming to disrupt the function of the targeted genes (see figure below). Insertion mutants that are still able to survive or grow suggest the transposon inserted in a gene that is not essential for survival. The location of the transposon insertions can be determined through hybridization to microarrays or through transposon sequencing . With the development of CRISPR, gene essentiality has also been determined through inhibition of gene expression through CRISPR interference. A summary of such screens is shown in the table.
Table 1. Essential genes in bacteria. Mutagenesis: targeted mutants are gene deletions; random mutants are transposon insertions. Methods: Clones indicate single gene deletions, population indicates whole population mutagenesis, e.g. using transposons. Essential genes from population screens include genes essential for fitness (see text). ORFs: number of all open reading frames in that genome. Notes: (a) mutant collection available; (b) direct essentiality screening method (e.g. via antisense RNA) that does not provide information about nonessential genes. (c) Only partial dataset available. (d) Includes predicted gene essentiality and data compilation from published single-gene essentiality studies. (e) Project in progress. (f) Deduced by comparison of the two gene essentiality datasets obtained independently in the P. aeruginosa strains PA14 and PAO1. (g) The original result of 271 essential genes has been corrected to 261, with 31 genes that were thought to be essential being in fact non-essential whereas 20 novel essential genes have been described since then. (h) Counting genes with essential domains and those that lead to growth-defects when disrupted as essential, and those who lead to growth-advantage when disrupted as non-essential. (i) Involved a fully saturated mutant library of 14 replicates, with 84.3% of possible insertion sites with at least one transposon insertion. (j) Each essential gene has been independently confirmed at least five times.
On the basis of genome-wide experimental studies and systems biology analysis, an essential gene database has been developed by Kong et al. (2019) for predicting > 4000 bacterial species.
In Saccharomyces cerevisiae (budding yeast) 15-20% of all genes are essential. In Schizosaccharomyces pombe (fission yeast) 4,836 heterozygous deletions covering 98.4% of the 4,914 protein coding open reading frames have been constructed. 1,260 of these deletions turned out to be essential.
Similar screens are more difficult to carry out in other multicellular organisms, including mammals (as a model for humans), due to technical reasons, and their results are less clear. However, various methods have been developed for the nematode worm C. elegans, the fruit fly, and zebrafish (see table). A recent study of 900 mouse genes concluded that 42% of them were essential although the selected genes were not representative.
Gene knockout experiments are not possible or at least not ethical in humans. However, natural mutations have led to the identification of mutations that lead to early embryonic or later death. Note that many genes in humans are not absolutely essential for survival but can cause severe disease when mutated. Such mutations are catalogued in the Online Mendelian Inheritance in Man (OMIM) database. In a computational analysis of genetic variation and mutations in 2,472 human orthologs of known essential genes in the mouse, Georgi et al. found strong, purifying selection and comparatively reduced levels of sequence variation, indicating that these human genes are essential too.
While it may be difficult to prove that a gene is essential in humans, it can be demonstrated that a gene is not essential or not even causing disease. For instance, sequencing the genomes of 2,636 Icelandic citizens and the genotyping of 101,584 additional subjects found 8,041 individuals who had 1 gene completely knocked out (i.e. these people were homozygous for a non-functional gene). Of the 8,041 individuals with complete knock-outs, 6,885 were estimated to be homozygotes, 1,249 were estimated to be compound heterozygotes (i.e. they had both alleles of a gene knocked out but the two alleles had different mutations). In these individuals, a total of 1,171 of the 19,135 human (RefSeq) genes (6.1%) were completely knocked out. It was concluded that these 1,171 genes are non-essential in humans — at least no associated diseases were reported. Similarly, the exome sequences of 3222 British Pakistani-heritage adults with high parental relatedness revealed 1111 rare-variant homozygous genotypes with predicted loss of gene function (LOF = knockouts) in 781 genes. This study found an average of 140 predicted LOF genotypes (per subject), including 16 rare (minor allele frequency <1%) heterozygotes, 0.34 rare homozygotes, 83.2 common heterozygotes and 40.6 common homozygotes. Nearly all rare homozygous LOF genotypes were found within autozygous segments (94.9%). Even though most of these individuals had no obvious health issue arising from their defective genes, it is possible that minor health issues may be found upon more detailed examination.
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Essential gene AI simulator
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Essential gene
Essential genes are indispensable genes for organisms to grow and reproduce offspring under certain environment. However, being essential is highly dependent on the circumstances in which an organism lives. For instance, a gene required to digest starch is only essential if starch is the only source of energy. Recently, systematic attempts have been made to identify those genes that are absolutely required to maintain life, provided that all nutrients are available. Such experiments have led to the conclusion that the absolutely required number of genes for bacteria is on the order of about 250–300. Essential genes of single-celled organisms encode proteins for three basic functions including genetic information processing, cell envelopes and energy production. Those gene functions are used to maintain a central metabolism, replicate DNA, translate genes into proteins, maintain a basic cellular structure, and mediate transport processes into and out of the cell. Compared with single-celled organisms, multicellular organisms have more essential genes related to communication and development. Most of the essential genes in viruses are related to the processing and maintenance of genetic information. In contrast to most single-celled organisms, viruses lack many essential genes for metabolism, which forces them to hijack the host's metabolism. Most genes are not essential but convey selective advantages and increased fitness. Hence, the vast majority of genes are not essential and many can be deleted without consequences, at least under most circumstances.
Two main strategies have been employed to identify essential genes on a genome-wide basis: directed deletion of genes and random mutagenesis using transposons. In the first case, annotated individual genes (or ORFs) are completely deleted from the genome in a systematic way. In transposon-mediated mutagenesis, transposons are randomly inserted in as many positions in a genome as possible, aiming to disrupt the function of the targeted genes (see figure below). Insertion mutants that are still able to survive or grow suggest the transposon inserted in a gene that is not essential for survival. The location of the transposon insertions can be determined through hybridization to microarrays or through transposon sequencing . With the development of CRISPR, gene essentiality has also been determined through inhibition of gene expression through CRISPR interference. A summary of such screens is shown in the table.
Table 1. Essential genes in bacteria. Mutagenesis: targeted mutants are gene deletions; random mutants are transposon insertions. Methods: Clones indicate single gene deletions, population indicates whole population mutagenesis, e.g. using transposons. Essential genes from population screens include genes essential for fitness (see text). ORFs: number of all open reading frames in that genome. Notes: (a) mutant collection available; (b) direct essentiality screening method (e.g. via antisense RNA) that does not provide information about nonessential genes. (c) Only partial dataset available. (d) Includes predicted gene essentiality and data compilation from published single-gene essentiality studies. (e) Project in progress. (f) Deduced by comparison of the two gene essentiality datasets obtained independently in the P. aeruginosa strains PA14 and PAO1. (g) The original result of 271 essential genes has been corrected to 261, with 31 genes that were thought to be essential being in fact non-essential whereas 20 novel essential genes have been described since then. (h) Counting genes with essential domains and those that lead to growth-defects when disrupted as essential, and those who lead to growth-advantage when disrupted as non-essential. (i) Involved a fully saturated mutant library of 14 replicates, with 84.3% of possible insertion sites with at least one transposon insertion. (j) Each essential gene has been independently confirmed at least five times.
On the basis of genome-wide experimental studies and systems biology analysis, an essential gene database has been developed by Kong et al. (2019) for predicting > 4000 bacterial species.
In Saccharomyces cerevisiae (budding yeast) 15-20% of all genes are essential. In Schizosaccharomyces pombe (fission yeast) 4,836 heterozygous deletions covering 98.4% of the 4,914 protein coding open reading frames have been constructed. 1,260 of these deletions turned out to be essential.
Similar screens are more difficult to carry out in other multicellular organisms, including mammals (as a model for humans), due to technical reasons, and their results are less clear. However, various methods have been developed for the nematode worm C. elegans, the fruit fly, and zebrafish (see table). A recent study of 900 mouse genes concluded that 42% of them were essential although the selected genes were not representative.
Gene knockout experiments are not possible or at least not ethical in humans. However, natural mutations have led to the identification of mutations that lead to early embryonic or later death. Note that many genes in humans are not absolutely essential for survival but can cause severe disease when mutated. Such mutations are catalogued in the Online Mendelian Inheritance in Man (OMIM) database. In a computational analysis of genetic variation and mutations in 2,472 human orthologs of known essential genes in the mouse, Georgi et al. found strong, purifying selection and comparatively reduced levels of sequence variation, indicating that these human genes are essential too.
While it may be difficult to prove that a gene is essential in humans, it can be demonstrated that a gene is not essential or not even causing disease. For instance, sequencing the genomes of 2,636 Icelandic citizens and the genotyping of 101,584 additional subjects found 8,041 individuals who had 1 gene completely knocked out (i.e. these people were homozygous for a non-functional gene). Of the 8,041 individuals with complete knock-outs, 6,885 were estimated to be homozygotes, 1,249 were estimated to be compound heterozygotes (i.e. they had both alleles of a gene knocked out but the two alleles had different mutations). In these individuals, a total of 1,171 of the 19,135 human (RefSeq) genes (6.1%) were completely knocked out. It was concluded that these 1,171 genes are non-essential in humans — at least no associated diseases were reported. Similarly, the exome sequences of 3222 British Pakistani-heritage adults with high parental relatedness revealed 1111 rare-variant homozygous genotypes with predicted loss of gene function (LOF = knockouts) in 781 genes. This study found an average of 140 predicted LOF genotypes (per subject), including 16 rare (minor allele frequency <1%) heterozygotes, 0.34 rare homozygotes, 83.2 common heterozygotes and 40.6 common homozygotes. Nearly all rare homozygous LOF genotypes were found within autozygous segments (94.9%). Even though most of these individuals had no obvious health issue arising from their defective genes, it is possible that minor health issues may be found upon more detailed examination.