Essential genes: a cross-species perspective

Cacheiro, Pilar; Smedley, Damian

doi:10.1007/s00335-023-09984-1

Cited by 4 publications

(5 citation statements)

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“…We identified an increase in the number of publications, antibody counts, and monoclonal antibody counts for essential genes compared with non-essential genes, suggesting a focus on essential genes in research [65][66][67][68][69][70] . However, we also found that Tdark proteins had the least amount of associated data, indicating a knowledge deficit 27,29,30,36 .…”

Section: Discussionmentioning

confidence: 88%

Shedding Light on the Dark Genome: Insights into the Genetic, CRISPR-based, and Pharmacological Dependencies of Human Cancers and Disease Aggressiveness

Kafita,

Nkhoma,

Dzobo

et al. 2023

Preprint

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Investigating the human genome is vital for identifying risk factors and devising effective therapies to combat genetic disorders and cancer. Despite the extensive knowledge of the "light genome", the poorly understood "dark genome" remains understudied. In this study, we integrated data from 20,412 protein-coding genes in Pharos and 8,395 patient-derived tumours from The Cancer Genome Atlas (TCGA) to examine the genetic and pharmacological dependencies in human cancers and their treatment implications. We discovered that dark genes exhibited high mutation rates in certain cancers, similar to light genes. By combining the drug response profiles of cancer cells with cell fitness post-CRISPR-mediated gene knockout, we identified the crucial vulnerabilities associated with both dark and light genes. Our analysis also revealed that tumours harbouring dark gene mutations displayed worse overall and disease-free survival rates than those without such mutations. Furthermore, dark gene expression levels significantly influenced patient survival outcomes. Our findings demonstrated a similar distribution of genetic and pharmacological dependencies across the light and dark genomes, suggesting that targeting the dark genome holds promise for cancer treatment. This study underscores the need for ongoing research on the dark genome to better comprehend the underlying mechanisms of cancer and develop more effective therapies.

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Section: Discussionmentioning

confidence: 88%

Shedding Light on the Dark Genome: Insights into the Genetic, CRISPR-based, and Pharmacological Dependencies of Human Cancers and Disease Aggressiveness

Kafita,

Nkhoma,

Dzobo

et al. 2023

Preprint

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“…We identified an increase in the number of publications, antibody counts, and monoclonal antibody counts for essential genes compared with non-essential genes, suggesting a focus on essential genes in research [ 67 – 72 ]. However, we also found that Tdark proteins had the least amount of associated data, indicating a knowledge deficit [ 28 , 30 , 31 , 37 ].…”

Section: Discussionmentioning

confidence: 99%

Shedding light on the dark genome: Insights into the genetic, CRISPR-based, and pharmacological dependencies of human cancers and disease aggressiveness

Kafita,

Nkhoma,

Dzobo

et al. 2023

PLoS ONE

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Investigating the human genome is vital for identifying risk factors and devising effective therapies to combat genetic disorders and cancer. Despite the extensive knowledge of the "light genome”, the poorly understood "dark genome" remains understudied. In this study, we integrated data from 20,412 protein-coding genes in Pharos and 8,395 patient-derived tumours from The Cancer Genome Atlas (TCGA) to examine the genetic and pharmacological dependencies in human cancers and their treatment implications. We discovered that dark genes exhibited high mutation rates in certain cancers, similar to light genes. By combining the drug response profiles of cancer cells with cell fitness post-CRISPR-mediated gene knockout, we identified the crucial vulnerabilities associated with both dark and light genes. Our analysis also revealed that tumours harbouring dark gene mutations displayed worse overall and disease-free survival rates than those without such mutations. Furthermore, dark gene expression levels significantly influenced patient survival outcomes. Our findings demonstrated a similar distribution of genetic and pharmacological dependencies across the light and dark genomes, suggesting that targeting the dark genome holds promise for cancer treatment. This study underscores the need for ongoing research on the dark genome to better comprehend the underlying mechanisms of cancer and develop more effective therapies.

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“…The current evidence on essential genes in humans comes from various sources providing insights into the phenotypic impact on a gene's LoF at distinct levels, as recently reviewed 8 and illustrated in Figure 1.…”

Section: Introduction Defining Essentiality and Sources Of Evidencementioning

confidence: 99%

“…The current evidence on essential genes in humans comes from various sources providing insights into the phenotypic impact on a gene’s LoF at distinct levels, as recently reviewed 8 and illustrated in Figure 1 . Genes essential for cell proliferation, identified primarily through RNA interference and CRISPR-Cas9 disruption in human cancer cell lines 9 .…”

Section: Introductionmentioning

confidence: 99%

“…As previously noted, the definition and subsequent genes identified as lethal in humans can differ. Consequently, we categorised the entire set of OMIM disease associated genes into different lethality categories according to the earliest age of death reported using HPO age of death terms and definitions 8,18 , from prenatal death to death in adulthood to genes with no reports of early death (non-lethal genes). In this manuscript, we characterise the genes across the different lethality categories, explore how this information combined with phenotypic similarity measures and gene family information could be used for novel gene discovery and examine the evidence on mouse viability.…”

Section: Introductionmentioning

confidence: 99%

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Lethal phenotypes in Mendelian disorders

Cacheiro,

Lawson,

Van den Veyver

et al. 2024

Preprint

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Essential genes are those whose function is required for cell proliferation and/or organism survival. A gene's intolerance to loss-of-function can be allocated within a spectrum, as opposed to being considered a binary feature, since this function might be essential at different stages of development, genetic backgrounds or other contexts. Existing resources that collect and characterise the essentiality status of genes are based on either proliferation assessment in human cell lines, embryonic and postnatal viability evaluation in different model organisms, and gene metrics such as intolerance to variation scores derived from human population sequencing studies. There are also several repositories available that document phenotypic annotations for rare disorders in humans such as the Online Mendelian Inheritance in Man (OMIM) and the Human Phenotype Ontology (HPO) knowledgebases. This raises the prospect of being able to use clinical data, including lethality as the most severe phenotypic manifestation, to further our characterisation of gene essentiality. Here we queried OMIM for terms related to lethality and classified all Mendelian genes into categories, according to the earliest age of death recorded for the associated disorders, from prenatal death to no reports of premature death. To showcase this curated catalogue of human essential genes, we developed the Lethal Phenotypes Portal (https://lethalphenotypes.research.its.qmul.ac.uk), where we also explore the relationships between these lethality categories, constraint metrics and viability in cell lines and mouse. Further analysis of the genes in these categories reveals differences in the mode of inheritance of the associated disorders, physiological systems affected and disease class. We highlight how the phenotypic similarity between genes in the same lethality category combined with gene family/group information can be used for novel disease gene discovery. Finally, we explore the overlaps and discrepancies between the lethal phenotypes observed in mouse and human and discuss potential explanations that include differences in transcriptional regulation, functional compensation and molecular disease mechanisms. We anticipate that this resource will aid clinicians in the diagnosis of early lethal conditions and assist researchers in investigating the properties that make these genes essential for human development.

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Essential genes: a cross-species perspective

Cited by 4 publications

References 53 publications

Shedding Light on the Dark Genome: Insights into the Genetic, CRISPR-based, and Pharmacological Dependencies of Human Cancers and Disease Aggressiveness

Shedding Light on the Dark Genome: Insights into the Genetic, CRISPR-based, and Pharmacological Dependencies of Human Cancers and Disease Aggressiveness

Shedding light on the dark genome: Insights into the genetic, CRISPR-based, and pharmacological dependencies of human cancers and disease aggressiveness

Lethal phenotypes in Mendelian disorders

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