OGEE v2: an update of the online gene essentiality database with special focus on differentially essential genes in human cancer cell lines

Liu

et al. 2015

Preprint

Human genes exhibit different effects on fitness in cancer and normal cells. Here, we present an evolutionary approach to measure the selection pressure on human genes, using the well-known ratio of the nonsynonymous to synonymous substitution rate in both cancer genomes (C N /C S ) and normal populations (p N /p S ). A new mutationprofile-based method that adopts sample-specific mutation rate profiles instead of conventional substitution models was developed. We found that cancer-specific selection pressure is quite different from the selection pressure at the species and population levels. Both the relaxation of purifying selection on passenger mutations and the positive selection of driver mutations may contribute to the increased C N /C S values of human genes in cancer genomes compared with the p N /p S values in human populations. The C N /C S values also contribute to the improved classification of cancer genes and a better understanding of the onco-functionalization of cancer genes during oncogenesis. The use of our computational pipeline to identify cancerspecific positively and negatively selected genes may provide useful information for understanding the evolution of cancers and identifying possible targets for therapeutic intervention.

“…We also used the human orthologs of mouse essential genes from OGEE (the database of Online GEne Essentiality) [50] to confirm these results (Supplementary Table 2). …”

Section: Selection Pressures On Cancer-associated Genesmentioning

confidence: 92%

Mutation-Profile-Based Methods for Understanding Selection Forces in Cancer Somatic Mutations: A Comparative Analysis

Liu

et al. 2015

Preprint

“…Gene essentiality, or the requirement of a gene for an organism's survival, is known to correlate with intolerance to variation 12 and has been directly assessed in a number of species using high-throughput cellular and animal models [13][14][15] . In humans, essentiality has been investigated at the cellular level using cancer cell line screens based on gene-trap, RNAi or CRISPR-Cas9 approaches with the findings that ~10% of protein-coding genes are essential for cell proliferation and survival [16][17][18][19] .…”

Section: Introductionmentioning

confidence: 99%

Human and mouse essentiality screens as a resource for disease gene discovery

Cacheiro

Muñoz-Fuentes

Murray

et al. 2019

Preprint

Although genomic sequencing has been transformative in the study of rare genetic diseases, identifying causal variants remains a considerable challenge that can be addressed in part by new gene-specific knowledge. Here, we integrate measures of how essential a gene is to supporting life, as inferred from the comprehensive viability and phenotyping screens performed on knockout mice by the International Mouse Phenotyping Consortium and from human cell line essentiality screens. We propose a novel, cross-species gene classification across the Full

“…"f" values were obtained through SnIPRE (48) following (47), based on the comparison of polymorphism and divergence at synonymous and non-synonymous sites. Data on the number of human paralogs for each gene were collected from the OGEE database (78). Human essential genes were obtained from (33).…”

Section: Gene-level Annotationsmentioning

confidence: 99%

Common homozygosity for predicted loss-of-function variants reveals both redundant and advantageous effects of dispensable human genes

Rausell

Luo

Lopez

et al. 2019

Preprint

Humans homozygous or hemizygous for variants predicted to cause a loss of function of the corresponding protein do not necessarily present with overt clinical phenotypes. However, the set of effectively dispensable genes in the human genome has not yet been fully characterized. We report here 190 autosomal genes with 207 predicted loss-of-function variants, for which the frequency of homozygous individuals exceeds 1% in at least one human population from five major ancestry groups.No such genes were identified on the X and Y chromosomes. Manual curation revealed that 28 variants (15%) had been misannotated as loss-of-function, mainly due to linkage disequilibrium with different compensatory variants. Of the 179 remaining variants in 166 genes (0.82% of 20,232 genes), only 11 alleles in 11 genes had previously been confirmed experimentally to be loss-of-function. The set of 166 dispensable genes was enriched in olfactory receptor genes (41 genes), but depleted of genes expressed in a wide range of organs and in leukocytes. The 125 dispensable non-olfactory receptor genes displayed a relaxation of selective constraints both between species and within humans, consistent with greater redundancy. In total, 62 of these 125 genes were found to be dispensable in at least three human populations, suggesting possible evolution toward pseudogenes. Out of the 179 common loss-of-function variants, 72 could be tested for two neutrality selection statistics, and eight displayed robust signals of positive selection. These variants included the known FUT2 mutant allele conferring resistance to intestinal viruses and an APOL3 variant involved in resistance to parasitic infections. Finally, the 41 dispensable olfactory receptor genes also displayed a strong relaxation of selective constraints similar to that observed for the 341 non-dispensable olfactory receptor genes.Overall, the identification of 166 genes for which a sizeable proportion of humans are homozygous for predicted loss-of-function alleles reveals both redundancies and advantages of such deficiencies for human survival. Significance statement.Human genes homozygous for seemingly loss of function (LoF) variants are increasingly reported in a sizeable proportion of individuals without overt clinical phenotypes. Here, we found 166 genes with 179 predicted LoF variants for which the frequency of homozygous individuals exceeds 1% in at least one of the populations present in databases ExAC and gnomAD. This set of putatively dispensable genes showed relaxation of selective constraints suggesting that a large number of these genes are 3 undergoing pseudogenization. Eight of the common LoF variants displayed robust signals of positive selection including two variants located in genes involved in resistance to infectious diseases. The identification of dispensable genes will allow identifying functions that are, at least nowadays, redundant, or possibly advantageous, for human survival. 4