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A new research method, a more complex DNA map

Published in the journal Cell on Thursday, Whitehead Institute Member Jonathan Weissman and his colleagues’ study presents the first comprehensive and functional map of genes in human cells.

(CN) — Researchers can now dive deeper into human DNA.

In 2003, the Human Genome Project completed a collaborative effort involving research institutions around the world to sequence human DNA. Published in the journal Cell on Thursday, Whitehead Institute Member Jonathan Weissman and his colleagues’ study presents the first comprehensive and functional map of genes in human cells.

The study states that one key element of their research was their use of Perturb-seq, a reverse genetics approach to investigate phenotypes. The study adds that the method uses CRISPR/Cas9 genome editing to introduce genetic charges into cells. This was important because the researchers wanted to test cancerous cells and noncancerous against each other to detective any distinct genotypes and phenotypes. Specifically, for genes that caused chromosomes to be lost or gained, something that previous studies struggled with.

“Because the patterns of chromosome gain and loss inherently require many chromosomes to be detected in every cell, no one had been able to screen for chromosomal changes, known as aneuploidy, in the past,” wrote Joseph Replogle, an MD-PhD student in Weissman’s lab via email.

Replogle added, “Because Perturb-seq measures thousands of genes in every cell, it made it easy to do this for the first time. This new kind of study could help us eventually understand why cancer cells gain and lose chromosomes.”

After receiving the data, the researchers said that they first looked at the genes with unknown functions. They used the data to compare unknown genes with known ones with the idea to check for similarly transcriptional outcomes. According to the researchers, this could suggest that gene products “worked together as part of a larger complex.”

The researchers took notice of one gene in particular — C7orf26. They noted that if they removed a gene and it resulted in similar phenotype’s creations, that meant that they were part of a protein complex called the Integrator. Previous studies suggested that 14 individual proteins made up the Integrator complex.

The researchers' efforts confirmed that C7orf26 acted as the fifteenth previously unknown protein.

Additionally, the study states that Perturb-seq is that it can allowed researchers to look at more complex phenotypes in greater detail. In previous studies, if researchers encountered a "muddied" gene while examining a genome, they used similar cells' data to bridge the gap in their knowledge.

“We often take all the cells were ‘gene X’ is knocked down and average them together to look at how they changed,” explained Weissman. “But sometimes when you knock down a gene, different cells that are losing that same gene behave differently, and that behavior may be missed by the average.”

The researchers said that when they experimented on mitochondria-related genes, to see how mitochondria responded to stress, they found that the nuclear genome responded to many different genetic changes. However, each mitochondrial genome responded in a different way.

“If you have one mitochondrion that’s broken, and another that is broken in a different way, those mitochondria could be responding differentially,” explained Weissman. 

Ultimately, the researchers said that they hope to use Perturb-seq on different types of cells besides the cancer cell line.

“By combining new technologies for genome engineering — like CRISPR — and tools for measuring many cellular traits simultaneously in this study, we have been able to better understand the function of many of the genes in the genome,” wrote Replogle. “Yet, there are still so many genes whose function is mysterious. In future studies, we hope to build on the work here applying Perturb-seq and similar tools in new cell types and contexts to learn more and more.”

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