This web page was produced as an assignment for an undergraduate course at Davidson College.
What was the research project?
The article The indispensable genome published in Science refers to three independent studies that describe systematic, genome-scale approaches to defining human genes that are essential for the life of human cells. This pages explores two of those. Blomen et. al. (2015) studied the genetic interactions in haploid human cells for viability under culture conditions. Wang et. al. (2015) reported on essential genes for proliferation and survival in a human cancer cell line.
Were they testing a hypothesis or doing discovery science?
Gene essentiality had been identified in yeast before; however, technological barriers had prevented previous analysis of human cell viability. The reports are more similar to discovery science, than a hypothesis-based research due to their genome-wide library scanning approach.
What genomic technology was used in the project?
Blomen et. al (2015) used gene-trapping insertional mutagenesis used to introduced mutations into the genome via the intron of the expressed gene and thus, the transcription process will encode for a non-functional version. The cohort also utilized genetic tools to test essentiality. The cohort also carried out synthetic lethal double-mutant screens, which occurs when two mutations, neither lethal on its own, combine to generate a lethal double-mutant and therefore, test for essentiality. Wang et. al. (2015) used gene-editing tools CRISPR/Cas to build a genome-wide RNA library as well as gene-trap-based screen
Figure 1. Properties of new and old essential genes compared with the human genome. Figure 1D in Blomen et. al. (2015)
What was the take home message?
The cohorts reported that ~2000 genes out of ~20,000 are indispensable for viability in human cells. This core set of essential genes are highly conserved and associated with fewer detrimental single-nucleotide polymorphism, tend not to duplicate, and have high evolutionary constraints. However, they also highlight that essentiality of some genes is context-dependent and affects viability in a cell type-specific manner. Finally, a substantial amount of the core genes involved in RNA processing set were uncharacterized.
Figure 2. Of the 1,878 cell-essential genes identified in the KBM7 cell line, 330 genes had no known function. Wang et. al. (2015)
What is your evaluation of the project?
The argumentation in both projects based on the data substantiated the
claims made. A strategy that I found interesting by both cohorts was the used of previous
identified yeast essential genes and knockouts to further test and validate their finding in relation
to human cell lines. A caveat that Bloment et. al. (2015) does mention is that their lethality
screens were done in vitro studies. This leaves open the possibility of organism-level genetic
interactions that could also be labeled essential
. It is also important to highlight the
~18,000 labeled non-essential genes under laboratory conditions. Overall, I think that both
projects express the potentiality for genome-scale screenings to reveal underlying cell biology
functionality as well as the potential to investigate cellular division in the hopes of applying
and identifying cell vulnerabilities that can be used as targets for personalized therapeutic strategies.
Works Cited
Blomen VA, Majek P, Jae LT, Bigenzahn JW, Nieuwenhuis J,
Staring J, Sacco R, van Diemen FR, Olk N, Stukalov A, Marceau C, Janssen
H, Carette JE, Bennett KL, Colinge J, Superti-Furga G, Brummmelkamp TR.
2015. Gene essentiality and synthetic lethality in haploid
human cells. Science. 350(6264):1092-1096.
Boone C, Andrews BJ. 2015. The indispensable genome. Science.
350(6264):1028-1029.
Wang T, Birsoy K, Hughes NW, Krupczak KM, Post Y, Wei
JJ, Lander ES, Sabatini DM. 2015. Identification and characterization of
essential genes in the human genome. Science. 350(6264)1096-1101.