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Human gene essentiality

Nature Reviews Genetics volume 19, pages 5162 (2018) | Download Citation


A gene can be defined as essential when loss of its function compromises viability of the individual (for example, embryonic lethality) or results in profound loss of fitness. At the population level, identification of essential genes is accomplished by observing intolerance to loss-of-function variants. Several computational methods are available to score gene essentiality, and recent progress has been made in defining essentiality in the non-coding genome. Haploinsufficiency is emerging as a critical aspect of gene essentiality: approximately 3,000 human genes cannot tolerate loss of one of the two alleles. Genes identified as essential in human cell lines or knockout mice may be distinct from those in living humans. Reconciling these discrepancies in how we evaluate gene essentiality has applications in clinical genetics and may offer insights for drug development.

Key points

  • A gene is considered essential when loss of its function compromises the viability or fitness of the organism.

  • Large-scale, population genome analyses in humans allow the observation of genes that do not tolerate loss of function, that is, are essential, and genes that tolerate biallelic loss of function, that is, are dispensable.

  • Human essential genes may not be captured in mouse knockout mouse models or recapitulated in cellular assays.

  • Observing the phenotypic consequences of loss-of-function variants is now used to anticipate drug safety and efficacy and guide drug discovery.

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The authors thank Drs Ewen Kirkness and Michael Hicks for valuable comments. The authors are employees of Human Longevity, Inc.

Author information


  1. Human Longevity Inc., San Diego, California 92121, USA.

    • István Bartha
    • , Julia di Iulio
    • , J. Craig Venter
    •  & Amalio Telenti
  2. J. Craig Venter Institute, Capricorn Lane, La Jolla, California 92037, USA.

    • J. Craig Venter
    •  & Amalio Telenti


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All authors substantially contributed to discussion of content and to reviewing/editing the manuscript before submission. I.B., J.d.I. and A.T. researched data for the article and contributed to writing the manuscript.

Competing interests

The authors are employees of Human Longevity, Inc. There is no commercial interest or intellectual property associated with this work.

Corresponding authors

Correspondence to J. Craig Venter or Amalio Telenti.

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Minimal genome

A genome limited to the essential genes for life.


The ability of a biological system to keep its behaviour unchanged under perturbation.


The possibility of having a function encoded by more than one gene.


The degree to which an organism can generate adaptive solutions to future environments through heritable phenotypic variation.


The subset of the genome that is part of mature RNAs and translated into proteins.

Protein truncation

A truncated, incomplete and usually nonfunctional protein product. Generally, the result of stop-gain, frameshift or splice-donor genetic variants.

Loss-of-function variants

Genetic variants that severely disrupt the function of a protein. These can be missense (a change of the codon resulting in a change in the amino acid) or nonsense and protein-truncating variants.


In a diploid organism, having only a single functional copy of a gene (with the other copy inactivated by mutation), which is insufficient to maintain proper gene function.

Stop-gain variants

Also known as nonsense variants, changes in the genetic material that result in premature termination of the translated protein.


When referring to the generation of gene variants genome-wide, the sample size at which all positions in the genome are seen variant at least once.

Frameshift variants

Deletions or insertions in the protein-coding region, the lengths of which are not divisible by three, thus disrupting the reading frame of the gene.

Synonymous variants

A change of nucleotide that does not lead to changes in the amino-acid sequence of a protein.

Neutral variation

Genetic variants that are not subjects of natural selection.

ROC curve

(Receiver operating characteristic curve). A visual and quantitative method of evaluating the performance of binary classifiers. The true positive rate of a classifier is plotted against the false-positive rate.

Expression quantitative trait loci

(eQTLs). Loci where variation is associated with differential expression of a gene.


Of cells, containing a single set of chromosomes.


The number of sets of chromosomes in a cell.


The absence of one copy of a gene in diploid cells.

Compound heterozygosity

The state in which both alleles of a gene carry a (deleterious) variant, but those variants are different.

Nonsense-mediated mRNA decay

(NMD). A cellular pathway that serves to recognize and degrade mRNAs with translation termination codons that are positioned in abnormal contexts.

Haplotype phasing

The assignment of an allele to one of the two copies of the chromosomes (maternal and paternal).

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