By D. Maan, Jadetimes News
Unraveling the Role of "Gene Deserts" in Disease
Since the completion of the Human Genome Project in 2003, scientists have increasingly focused on identifying new regions within our genetic code that could influence disease. These regions, often dismissed as "junk" DNA, are now found to harbor mutations linked to a spectrum of illnesses from Crohn's disease to cancer.
Advancements in genomic technologies have enabled comprehensive studies known as genome wide association studies (GWAS), pinpointing genetic variants associated with various chronic conditions. However, understanding how these variants contribute to disease mechanisms remains a daunting challenge. For instance, while GWAS have identified genetic segments linked to inflammatory bowel disease across 215 chromosomal sites, scientists have only decoded the specific workings of a few.
Gene deserts, vast stretches of non coding DNA initially considered biologically inert, have emerged as particularly perplexing. These areas constitute over 98% of the human genome, with less than 2% dedicated to protein coding genes. Recent research at the Francis Crick Institute has shed new light on one such region, chr21q22, long associated with multiple inflammatory diseases.
Studies have revealed that chr21q22 contains an enhancer a segment of DNA capable of regulating nearby genes, notably enhancing the activity of a gene called ETS2 in white blood cells known as macrophages. This enhancement significantly amplifies inflammatory responses, implicating ETS2 as a pivotal player in orchestrating inflammation.
Interestingly, genetic analysis indicates that the disease causing mutation in chr21q22 originated in the human genome over half a million years ago, during a time when heightened inflammatory responses were crucial for combating infections. Today, manipulating ETS2 activity shows promise as a novel therapeutic approach for conditions like inflammatory bowel disease (IBD), potentially offering targeted treatments that mitigate inflammation without compromising immune defenses.
Ongoing research aims to extend these findings to other diseases associated with chr21q22, such as primary sclerosing cholangitis, a severe liver disease lacking effective treatments. By unraveling the complexities of gene deserts and their impact on disease, scientists at the Crick Institute strive to pioneer new avenues for therapeutic intervention and improve outcomes for patients affected by these challenging conditions.
Uncovering Insights from Gene Deserts: From Cancer to Lupus
Scientists anticipate that studying gene deserts will yield crucial insights into the pathways involved in tumor development. For instance, researchers have identified a gene desert, 8q24.21, implicated in cervical cancer where the human papilloma virus integrates into the genome, enhancing the cancer driving gene Myc. This connection is also implicated in ovarian, breast, prostate, and colorectal cancers.
Richard Houlston, from the Institute of Cancer Research in London, highlights that genetic variants contributing to the heritable risk of common cancers are often found in gene deserts. Understanding these target genes holds promise for drug discovery and cancer prevention strategies.
However, translating this knowledge into effective cancer therapeutics poses challenges due to the dynamic nature of tumors, which evolve continuously. Houlston contrasts this with conditions like Crohn's disease, where treatment targets remain relatively stable over time.
Unveiling Potential in Gene Deserts: Insights into Autoimmune and Rare Genetic Diseases
James Lee is hopeful that the Crick Institute's advancements in understanding inflammatory bowel disease (IBD) will serve as a blueprint for deciphering pathways involved in various autoimmune and inflammatory conditions. Researchers at the institute are now exploring other gene deserts associated with diseases like lupus, characterized by immune system dysfunction leading to symptoms such as skin rashes and fatigue.
Similar investigations are underway worldwide, such as at the University of Basel in Switzerland, where scientists are studying how single inherited mutations in gene deserts can cause rare genetic disorders. Recently, Basel researchers identified a mutation linked to limb malformations in newborns, demonstrating the regulatory impact on nearby genes.
Lee envisions that unraveling the roles of gene deserts will revolutionize drug development processes, notoriously known for their low success rates. "Developing new drugs for these diseases is highly challenging," he remarks. "Approximately 90% of drugs entering clinical trials fail to gain approval due to inefficacy. However, targeting pathways supported by genetic insights could significantly increase the likelihood of drug approval, potentially tripling to quintupling success rates."
