Rigid on/off patterns found in nearly 500 human genes

Nearly 500 'switch-like' genes that are either expressed highly or not at all have been identified from a large-scale study of gene expression from almost one thousand people.

Researchers at the University at Buffalo, New York, analysed over 19,000 genes across 27 tissues from the Genotype-Tissue Expression project. Publishing their findings in Nature Communications, they found that 473 genes displayed 'bimodal' expression distributions, indicating on/off patterns, as opposed to gradual 'unimodal' distributions. These genes were associated with multiple conditions, including infertility and vaginal atrophy, and various mechanisms, including epigenetic and hormonal factors, were linked with their switch-like behaviours. The researchers hope that their findings could highlight specific mechanisms of disease and may present applications in personalised diagnostics.

'Understanding why we differ from each other, the sources of human diversity, is one of the fundamental questions in human genetics and anthropology,' said joint corresponding author, Omer Gokcumen, a professor in the department of biological sciences at Buffalo. 'Our study provides new answers.'

The expression of a gene is associated with its level of activity, and the amount it is expressed depends on a cell's given identity or situation. This is influenced by factors including genetic variation and epigenetic alterations, enabling a gene's expression to act continuously, resulting in a broadly unimodal distribution.

While switch-like genes have previously been observed, specifically in E. coli, and have also been associated with aspects of cancer biology, a broad, systematic analysis of their prevalence in humans had not been conducted.

Of the 473 genes identified by the study as bimodal in at least one tissue, 40 acted as such across all tissues, indicating hard-wired switch-like behaviours. Additionally, many of these genes showed sex-specific bias, caused by hormone-driven tissue-specific expression. In particular, of 158 breast-specific switch-like genes, 157 were specifically upregulated in women.

'Future investigations could reveal whether how toggling of these genetic switches affects human diseases in general and provides new diagnostic and therapeutic tools' said Alber Aqil, a PhD student and the study's lead author.

He added, 'Typically, lots of small factors nudge a gene, causing its activity to vary, like a dimmer, but it appears that switch-like genes are controlled by one or just a few factors that have big effects.'

The authors hope that further research into switch-like genes could highlight novel disease mechanisms, especially surrounding gene-environment interactions. However, they also caution that gene expression at the RNA level does not necessarily translate to protein expression.