Sometimes, a small error in the sequence of DNA can lead to a very serious disease. Scientists have identified many mutations that arise in a single gene to cause an illness, such as mutations in the CFTR gene that cause cystic fibrosis, or mutations in the NF gene that cause neurofibromatosis. But for many other illnesses, like heart disease the underlying causes are far more complex. Things in the environment, our habits, and lifestyles can play a significant role in some cases, while in others, changes in multiple genes can have a cumulative effect and lead to disease.
Researchers are trying to learn more about problems in gene networks that can drive disease. In a new study reported in Nature, scientists have developed a gene mapping approach that aims to decipher the genetic causes underlying more complex diseases. These maps may help clarify the causes of some disorders and could lead to new treatments.
"We can now look across every gene in the genome and get a sense of how each one affects a particular cell type. Our goal is to use this information as a map to gain new insights into how certain genes influence specific traits," said co-corresponding study author Alex Marson, MD, Ph.D., the Connie and Bob Lurie Director of the Gladstone–UCSF Institute of Genomic Immunology.
There is now a wealth of data on small changes in the genome that are associated with some trait or disease, because of the huge number of "genome-wide association studies" that have been performed. But many of those studies only identified links that could be important, and did not disentangle the complex signals and molecular networks underlying those gene-disease associations.
"Even with these studies, there remains a huge gap in understanding disease biology on a genetic level," explained first study author Mineto Ota, MD, Ph.D, a Gladstone postdoctoral researcher. "We understand that many variants are associated with disease; we just don't understand why."
To decipher complex gene networks, the researchers started with two databases: one is related to human leukemia cells. To create this database, a researcher had previously systematically eliminated each gene from this cell line, one at a time, to understand what impact the loss of each gene had. The other database used in this study was the UK Biobank, which contains genetic and health data for over 500,000 people.
The investigators mapped gene networks that affect red blood cells by bringing these databases together. This work showed that some genes can have multiple effects, which means they can reduce some functions while increasing others. For example, the gene SUPT5H, which is linked to beta thalassemia, affects the production of hemoglobin. Mutations in this gene can lead to anemia.
This study showed that SUPT5H is connected to three crucial blood-cell mechanisms: autophagy, cell cycle control, and hemoglobin production. This work identified how SUPT5H can affect those mechanisms through an increase or decrease in gene activity. The gene can control three pathways that impact hemoglobin levels.
Although this study was focused on the genetic networks of red blood cells, this approach can now be applied to many different cell types to learn more about many different diseases mechanisms and how they are affected by certain genes, and changes in those genes.
"The genetic burden associated with many autoimmune diseases, immune deficiencies, and allergies are overwhelmingly linked to T cells," Marson said. "We look forward to developing additional detailed maps that will help us really understand the genetic architecture behind these immune-mediated diseases."
Sources: Gladstone Institute, Nature