EMBL scientists discovered that common mutations can change the shape of gene promoters
Scientists in Eileen Furlong and Oliver Stegle’s labs at EMBL have revealed, for the first time, that genetic differences between individuals can affect promoter shape. Promoters are sequences of DNA that turn genes on. The EMBL scientists also discovered that a promoter’s shape – the area of genetic sequence that it controls – influences how much its output varies from cell to cell. The work is published today in Nature Genetics.
Scientists have known for some time that promoters have a defined shape. ‘Narrow’ promoters turn genes on very precisely at a given position in the genome, while ‘broad’ promoters turn genes on in an area spanning several hundred bases. But until now, the functional differences between promoters with different shapes were unclear. The factors that determine these differences across individuals in a population were also a mystery.
Ignacio Schor, a postdoc in the Furlong lab, found that changes to single letters of genetic code often affect promoter shape. These single-letter mutations, called SNPs, are common. This explains why promoter shape for the same gene can vary dramatically from one individual to another. The scientists also discovered that such SNPs, which alter promoter shape, frequently cause increased variability in promoter output between cells. These ‘noisy’ SNPs could have lethal effects, and hence are only tolerated in individuals whose genetic makeup also contains other SNPs that counteract this effect.
The same team, involving scientists at EMBL Heidelberg and EMBL-EBI, has recently uncovered similar SNP interactions in another context. In that study, they pinpointed thousands of mutations that disrupt gene regulation during embryonic development.