COPENHAGEN (GenomeWeb) – Genes that resulted from a duplication event and are similar in sequence – so-called paralogs – might explain in part why many hereditary diseases are confined to certain tissues, according to research presented at the European Society of Human Genetics annual meeting here this week.
Esti Yeger-Lotem, a professor of clinical biochemistry and pharmacology at Ben-Gurion University of the Negev in Israel, said during a talk on Sunday that many hereditary diseases only affect specific tissues – for example, just skeletal muscle or only the brain – despite the fact that the mutated disease gene is present in the DNA of all the cells.
In part, this might be because the disease gene is expressed in certain tissues but not others. However, Yeger-Lotem said this explains only a fraction of cases. Many mutated genes are actually expressed in a number of tissues that don’t manifest the disease phenotype.
Another possibility is that the disease gene acts in tandem with a partner that is only expressed in the affected tissues, but again, this only accounts for a small percentage of cases. In almost half the diseases with tissue-specific pathology, she said, the reason is unknown.
Yeger-Lotem and her colleagues speculated that paralogous genes may also play a role in tissue-selective hereditary diseases. Paralogs often maintain somewhat similar functions and can sometimes compensate for each other in a dosage-dependent manner, she said, so it is conceivable that a paralog can compensate for a defective gene in the unaffected tissue. However, this hypothesis had never been tested quantitatively on a large scale before, she said, because the data were not available.
This changed with the Genotype-Tissue Expression (GTEx) project, which has been generating an atlas of human gene expression across more than 40 tissue types collected from deceased donors. The project, launched in 2010 and funded by the US National Institutes of Health, aims to help with the functional interpretation of genetic associations with disease.
For their study, the researchers first analyzed 120 tissue-selective hereditary diseases that affect a variety of organs, including the brain, heart, liver, and skeletal muscle, and found that for around 45 percent of them, the disease-causing gene has a single paralog. For most, there was also some evidence that the paralog provides functional redundancy for the affected gene.
They then took GTEx data and computed the ratio between the expression level of the disease-causing gene and that of its paralog. In disease-affected tissue, they found this ratio to be higher than in unaffected tissue.
This shift in balance might be caused by the disease gene being upregulated, the paralog being downregulated, or a combination of both, she said. When her team conducted a differential expression analysis, they indeed found examples of all three.
One specific example is pontocerebellar hypoplasia type 1, which is caused by a mutation in the VRK1 gene and results in muscle atrophy as well as defects of the cerebellum and brain stem. In this case, the paralog is downregulated in the cerebellum, the researchers found.
Overall, it appears that the paralog contributes significantly to tissue specificity for a significant fraction of hereditary diseases, she said.