Essential gene

Essential genes are those genes of an organism that are thought to be critical for its survival. 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.[1] Such experiments have led to the conclusion that the absolutely required number of genes for bacteria is on the order of about 250-300. These essential genes encode proteins 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. Most genes are not essential but convey selective advantages and increased fitness.

Bacteria: genome-wide studies

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, 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 inactivate the targeted genes (see figure below). Insertion mutants that are still able to survive or grow are not in essential genes. A summary of such screens is shown in the table.[1][2]

Organism Mutagenesis Method Readout ORFs Non-ess. Essential % Ess. Notes Ref.
Mycoplasma genitalium/pneumoniaeRandomPopulationSequencing482130265-35055-73%---[3]
Mycoplasma genitaliumRandomClonesSequencing48210038279%b,c[4]
Staphylococcus aureus WCUH29RandomClonesSequencing2,600n/a168n/ab,c[5]
Staphylococcus aureus RN4220RandomClonesSequencing2,892n/a65823%---[6]
Haemophilus influenzae RdRandomPopulationFootprint-PCR1,65760267040%---[7]
Streptococcus pneumoniae Rx-1TargetedClonesColony formation2,043234113n/ac[8]
Streptococcus pneumoniae D39TargetedClonesColony formation2,043560133n/ac[9]
Streptococcus sanguinis SK36TargetedClonesColony formation2,2702,052 218 10%a[10][11]
Mycobacterium tuberculosis H37RvRandomPopulationMicroarray3,9892,56761415%---[12]
Mycobacterium tuberculosis RandomTransposon? 3,989 ?40110%---[13]
Mycobacterium tuberculosis H37Rv RandomTransposonNG-Sequencing 3,989 ?77419%---[14][15]
Mycobacterium tuberculosis ---Computational Computational 3,989 ?2837%---[16]
Bacillus subtilis 168TargetedClonesColony formation4,1053,8302617%a,d,g[17][18]
Escherichia coli K-12 MG1655RandomPopulationFootprint-PCR4,3083,12662014%---[19]
Escherichia coli K-12 MG1655TargetedClonesColony formation4,3082,001n/an/aa,e[20]
Escherichia coli K-12 BW25113TargetedClonesColony formation4,3903,9853037%a[21]
Pseudomonas aeruginosa PAO1RandomClonesSequencing5,5704,78367812%a[22]
Pseudomonas aeruginosa PA14RandomClonesSequencing5,6884,4693356%a,f[23]
Salmonella typhimuriumRandomClonesSequencing4,425n/a257~11%b,c[24]
Helicobacter pylori G27RandomPopulationMicroarray1,576 1,178 34422%---[25]
Campylobacter jejuniRandomPopulationMicroarray1,654?19512%---[26][27]
Corynebacterium glutamicumRandomPopulation?3,0022,35265022%---[28]
Francisella novicidaRandomTransposon? 1,719 1,32739223%---[29]
Mycoplasma pulmonis UAB CTIP RandomTransposon? 782 47231040%---[30]
Vibrio cholerae N16961 RandomTransposon? 3,890 ?77920%---[31]
Salmonella Typhi RandomTransposon? 4,646 ?3538%---[32]
Staphylococcus aureus RandomTransposon? ~2,600 ?35114%---[33]
Caulobacter crescentus RandomTransposon?3,767?48013%---[34]
Neisseria meningitidis RandomTransposon? 2,158 ?58527%---[35]
Desulfovibrio alaskensis RandomTransposonSequencing 3,258 2,87138712%---[36]

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.[18]

Essential genes in Mycobacterium tuberculosis H37Rv as found by using transposons which insert in random positions in the genome. If no transposons are found in a gene, the gene is most likely essential as it cannot tolerate any insertion. In this example, essential heme biosynthetic genes hemA, hemB, hemC, hemD are devoid of insertions. The number of sequence reads (‘‘reads/TA’’) is shown for the indicated region of the H37Rv chromosome. Potential TA dinucleotide insertions sites are indicated. Image from Griffin et al. 2011.[14]

Eukaryotes

Yeast (Saccharomyces cerevisiae) is the only eukaryotic species in which systematic and "complete" essentiality screens have been carried out. In this species 15-20% of all genes are essential. Although similar screens are under way for other species, including mouse (as a model for humans), these screens are not as complete as for yeast and due to technical reasons less clear in their results. However, a recent study of 900 mouse genes concluded that 42% of them were essential.[37] 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.[38]

A summary of essentiality screens is shown in the table below (all based on the Database of Essential Genes[1] except Ref.[39] which was added).

Organism Method Essential genes Ref.
Arabidopsis thalianaT-DNA insertion777[40]
Caenorhabditis elegans (worm)RNA interference294[41]
Danio rerio (zebrafish)Insertion mutagenesis288[42]
Drosophila melanogaster (fruit fly)P-element insertion mutagenesis339[43]
Homo sapiens (human)Literature search118[44]
Mus musculus (mouse)Literature search2114[45]
Saccharomyces cerevisiae (yeast)Single-gene deletions878[46]
Saccharomyces cerevisiae (yeast)Single-gene deletions1,105[39]
Schizosaccharomyces pombe (yeast)Single-gene deletions1,260[47]

Viruses

Screens for essential genes have been carried out in a few viruses. For instance, human cytomegalovirus (CMV) was found to have 41 essential, 88 nonessential, and 27 augmenting ORFs (150 total ORFs). Most essential and augmenting genes are located in the central region, and nonessential genes generally cluster near the ends of the viral genome.[48]

Essential gene screens are not always reproducible

If screens for essential genes are repeated in independent laboratories, they often result in different gene lists. For instance, screens in E. coli have yielded from ~300 to ~600 essential genes (see Table 1). Such differences are even more pronounced when different bacterial strains are used (see Figure 1). A common explanation is that the experimental conditions are different or that the nature of the mutation may be different (e.g. a complete gene deletion vs. a transposon mutant).[2] Transposon screens in particular are hard to reproduce, given that a transposon can insert at many positions within a gene. Insertions towards the 3' end of an essential gene may not have a lethal phenotype (or no phenotype at all) and thus may not be recognized as such. This can lead to erroneous annotations (here: false negatives).[49]

Different genes are essential in different organisms

Different organisms have different essential genes. For instance, Bacillus subtilis has 271 essential genes.[17] About one-half (150) of the orthologous genes in E. coli are also essential. Another 67 genes that are essential in E. coli are not essential in B. subtilis, while 86 E. coli essential genes have no B. subtilis ortholog.[21]

In Mycoplasma genitalium at least 18 genes are essential that are not essential in M. bovis.[50]

Quantitative gene essentiality analysis

Most genes are neither absolutely essential nor absolutely non-essential. Ideally their contribution to cell or organismal growth needs to be measured quantitatively, e.g. by determining how much growth rate is reduced in a mutant compared to "wild-type" (which may have been chosen arbitrarily from a population). For instance, a particular gene deletion may reduce growth rate (or fertility rate or other characters) to 90% of the wild-type.

Synthetic lethality

Main article: Synthetic lethality

Two genes are synthetic lethal if neither one is essential but when both are mutated the double-mutant is lethal. Some studies have estimated that the number of synthetic lethal genes may be on the order of 45% of all genes.[51][52]

Conditionally essential genes

A schematic view of essential genes (or proteins) in lysine biosynthesis of different bacteria. The same protein may be essential in one species but not another.

Many genes are essential only under certain circumstances. For instance, if the amino acid lysine is supplied to a cell any gene that is required to make lysine is non-essential. However, when there is no lysine supplied, genes encoding enzymes for lysine biosynthesis become essential, as no protein synthesis is possible without lysine.[2]

Streptococcus pneumoniae appears to require 147 genes for growth and survival in saliva,[53] more than the 113-133 that have been found in previous studies.

The deletion of a gene may result in death or in a block of cell division. While the latter case may implicate "survival" for some time, without cell division the cell may still die eventually. Similarly, instead of blocked cell division a cell may have reduced growth or metabolism ranging from nearly undetectable to almost normal. Thus, there is gradient from "essential" to completely non-essential, again depending on the condition. Some authors have thus distinguished between genes "essential for survival" and "essential for fitness".[2]

The role of genetic background. Similar to environmental conditions, the genetic background can determine the essentiality of a gene: a gene may be essential in one individual but not another, given his or her genetic background. Gene duplications are one possible explanation (see below).

Essential genes and gene duplications

Many genes are duplicated within a genome. Such duplications (paralogs) often render essential genes non-essential because the duplicate can replace the original copy. For instance, the gene encoding the enzyme aspartokinase is essential in E. coli. By contrast, the Bacillus subtilis genome contains three copies of this gene, none of which is essential on its own. However, a triple-deletion of all three genes is lethal. In such cases, the essentiality of a gene or a group of paralogs can often be predicted based on the essentiality of an essential single gene in a different species. In yeast, few of the essential genes are duplicated within the genome: 8.5% of the non-essential genes, but only 1% of the essential genes have a homologue in the yeast genome.[39]

In the worm C. elegans, non-essential genes are highly over-represented among duplicates, possibly because duplication of essential genes causes overexpression of these genes. Woods et al. found that non-essential genes are more often successfully duplicated (fixed) and lost compared to essential genes. By contrast, essential genes are less often duplicated but upon successful duplication are maintained over longer periods.[54]

Conservation of essential genes

Conservation of essential genes in bacteria, adapted from [55]

In bacteria, essential genes appear to be more conserved than nonessential genes [56] but the correlation is not very strong. For instance, only 34% of the B. subtilis essential genes have reliable orthologs in all Firmicutes and 61% of the E. coli essential genes have reliable orthologs in all Gamma-proteobacteria.[55] Fang et al. (2005) defined persistent genes as the genes present in more than 85% of the genomes of the clade.[55] They found 475 and 611 of such genes for B. subtilis and E. coli, respectively. Furthermore, they classified genes into five classes according to persistence and essentiality: persistent genes, essential genes, persistent nonessential (PNE) genes (276 in B. subtilis, 409 in E. coli), essential nonpersistent (ENP) genes (73 in B. subtilis, 33 in E. coli), and nonpersistent nonessential (NPNE) genes (3,558 in B. subtilis, 3,525 in E. coli). Fang et al. found 257 persistent genes, which exist both in B. subtilis (for the Firmicutes) and E. coli (for the Gamma-proteobacteria). Among these, 144 (respectively 139) were previously identified as essential in B. subtilis (respectively E. coli) and 25 (respectively 18) of the 257 genes are not present in the 475 B. subtilis (respectively 611 E. coli) persistent genes. All the other members of the pool are PNE genes.[55]

In eukaryotes, 83% of the one-to-one orthologs between Schizosaccharomyces pombe and Saccharomyces cerevisiae have conserved essentiality, that is, they are nonessential in both species or essential in both species. The remaining 17% of genes are nonessential in one species and essential in the other.[57] This is quite remarkable, given that S. pombe is separated from S. cerevisiae by approximately 400 million years of evolution.[58]

Predicting essential genes

A number of criteria can be used to predict essential genes. Chen et al.[59] determined four criteria to select training sets for such predictions: (1) essential genes in the selected training set should be reliable; (2) the growth conditions in which essential genes are defined should be consistent in training and prediction sets; (3) species used as training set should be closely related to the target organism; and (4) organisms used as training and prediction sets should exhibit similar phenotypes or lifestyles. They also found that the size of the training set should be at least 10% of the total genes to yield accurate predictions. Some approaches for predicting essential genes are:

Comparative genomics. Shortly after the first genomes (of Haemophilus influenzae and Mycoplasma genitalium) became available, Mushegian et al.[60] tried to predict the number of essential genes based on common genes in these two species. It was surmised that only essential genes should be conserved over the long evolutionary distance that separated the two bacteria. This study identified approximately 250 candidate essential genes.[60] As more genomes became available the number of predicted essential genes kept shrinking because more genomes shared fewer and fewer genes. As a consequence, it was concluded that the universal conserved core consists of less than 40 genes.[61][62] However, this set of conserved genes is not identical to the set of essential genes as different species rely on different essential genes.

Minimal genomes. It was also thought that essential genes could be inferred from minimal genomes which supposedly contain only essential genes. The problem here is that the smallest genomes belong to parasitic (or symbiontic) species which can survive with a reduced gene set as they obtain many nutrients from their hosts. For instance, one of the smallest genomes is that of Hodgkinia cicadicola, a symbiont of cicadas, containing only 144 Kb of DNA encoding only 188 genes.[63] Like other symbionts, Hodgkinia receives many of its nutrients from its host, so its genes do not need to be essential.

Metabolic modelling. Essential genes may be also predicted in completely sequenced genomes by metabolic reconstruction, that is, by reconstructing the complete metabolism from the gene content and then identifying those genes and pathways that have been found to be essential in other species. However, this method can be compromised by proteins of unknown function. In addition, many organisms have backup or alternative pathways which have to be taken into account (see figure 1). Metabolic modeling was also used by Basler (2015) to develop a method to predict essential metabolic genes.[64]

Genes of unknown function. Surprisingly, a significant number of essential genes has no known function. For instance, among the 385 essential candidates in M. genitalium, no function could be ascribed to 95 genes[4] even though this number had been reduced to 75 by 2011.[62]

ZUPLS. Song et al. presented a novel method to predict essential genes that only uses the Z-curve and other sequence-based features.[65] Such features can be calculated readily from the DNA/amino acid sequences. However, the reliability of this method remains a bit obscure.

Essential gene prediction servers. Guo et al. (2015) have developed three online services to predict essential genes in bacterial genomes. These freely available tools are applicable for single gene sequences without annotated functions, single genes with definite names, and complete genomes of bacterial strains.[66]

Essential protein domains

Although most essential genes encode proteins, many essential proteins consist of a single domain. This fact has been used to identify essential protein domains. Goodacre et al. have identified hundreds of essential domains of unknown function (eDUFs).[67] Lu et al.[68] presented a similar approach and identified 3,450 domains that are essential in at least one microbial species.

See also

External links

References

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