Celebrity Genes of the Human Genome

Scientists have identified ~200,000 genes in the human genome. However, the majority of research focuses on a far narrower subset of around 2,000 genes. Out of these 2,000 genes, a few have risen to the level of superstardom. Here are four genes that dominate the ‘top hits’ list of the DNA world. 

A micrograph showing cells with abnormal p53 expression (brown) in a brain tumor. Nephron, CC BY-SA 3.0 via Wikimedia Commons

Leading the pack is TP53 a 20,000 bp tumor suppressor gene with the impressive nickname of “Guardian of the Genome”. This gene codes for proteins (p53 and several p53 isoforms) that can activate DNA repair proteins, pause a cell between the G1 and S phases of the cell cycle, initiate programmed cell death (apoptosis), and completely stop cell division in cells with short telomeres. This impressive skills list means that p53 plays a huge role both in regulating cell division and cell death and in promoting genomic stability. It also means that mutations in the TP53 gene that change the functionality of its proteins have serious implications. Over 50% of human cancers show a mutation in this one gene! TP53’s prominent role in tumor suppression has caught the attention of researcher. According to the NCBI, there are over ten thousand (10,783 to be precise) pub med articles focusing on this gene.

Epidermal growth factor (red) and its receptor (blue). David Goodsell, CC BY 3.0 via Wikimedia Commons.

Another popular gene is EGFR which codes for a transmembrane protein known as the epidermal growth factor receptor. This protein helps translate external environmental clues into internal cell actions related to cell differentiation and proliferation. A decrease in the signaling power of EGFR has been associated with Alzheimer’s disease. Atypical signaling of EGFR has also been linked to psoriasis and eczema as well as the more serious conditions of atherosclerosis, myocardial fibrosis, liver cirrhosis, and chronic kidney disease. However, most research focuses on EGFR overexpression which can cause several types of lung, colon, neck, and head cancers. Over 6,000 articles (6,245 as of this post) focus on EGFR. This research has helped pave the way for treatments that interrupt the EGFR signaling to slow or stop the growth of cancerous tumors. 

Crystal structure of TNF alpha created from the Protein Data Bank. Ramin Herati, Public domain, via Wikimedia Commons

A close runner of the EGFR at 6,159 articles is TNF. This gene first came into the spotlight as another gene therapy candidate. It codes for a protein known as the tumor necrosis factor which helps regulate immune cells and can kill cancer cells. However, most TNF focused cancers treatments have been unsuccessful. In addition, continued research has shown that the gene’s primary function is to regulate our inflammatory responses. As a result, research has shifted to developing drugs that control the TNF gene to treat other diseases, particularly arthritis. TNF therapies are also being investigated to treat narcolepsy, Guillain-barre syndrome, Crohn’s disease, and idiopathic inflammatory myopathy. 

A structural model of apolipoprotein. Ajpolino, CC0, via Wikimedia Commons

The gene APOE has a similar bait and switch history. This gene codes for the protein Apolipoprotein E which transports cholesterol and mediates fat metabolism. Initially, researchers thought that understanding and targeting this gene would be a powerful way to treat heart disease. However, APOE based treatments proved far less effective than the now standard statin treatments. APOE research got a second wind in the 1990s when a neuroscientist noticed that a particular form of the gene, APOE4, was linked to a higher risk of Alzheimer’s disease. Today this variant is considered the largest known genetic risk factor for late-onset Alzheimer’s although the link is complex. APOE continues to be a popular study focus and with 4,755 articles written about it to date, it is fast approaching the 5,000 milestone. 

So how did these four genes become such megahits? Their rise is likely due to a confluence of factors. A probable and reassuring reason in their medical importance. For example, mutations in TP53 are associated with 50% of cancers making understanding this gene a crucial part of addressing this leading cause of death. In other cases, it may be due to timing, societal pressures, market interest, and luck! 

However it rises to fame, a gene’s popularity gains a momentum of its own. Established and powerful lab methods together with an abundance of background information make studying established genes more approachable. There’s also evidence that funding often favors more studied genes. That said, the number of genes being intensely studied has grown in recent years. This is due both to powerful and more universal gene research tools and a conscious push by funding agencies to investigate a wider range of genes. 

Want to discover more? Check out this Nature article that described the first top ten gene list. Then go straight to the source and check out NCBI’s gene page to find out the article count of your favorite gene!

Ryan L. Collins (http://ryanlcollins.com/), CC BY 4.0, via Wikimedia Commons

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