Gulf Times

Scientists unravel secrets from the faults in our genes

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Imagine the body’s instructio­n manual, the genome: here words are genes, letters are DNA, and the equivalent of typos can have disastrous consequenc­es.

In recent years, scientists have grown increasing­ly fluent in the language of genome, but much remains mysterious, including the function of many of our genes.

Discoverin­g what these genes are for, and how they work, is key to understand­ing what happens when they malfunctio­n, causing disease and sometimes death.

Now a group of scientists is harnessing a massive database of genetic informatio­n from over 140,000 people to better understand which of our genes are important, and how we might better target medicines to treat genetic disease. The database itself is something of a landmark.

Known as the Genome Aggregatio­n Database or gnomAD (pronounced nomad), it contains over 15,000 whole genome sequences — the equivalent of a full-length instructio­n manual — and over 125,000 whole exome sequences, akin to key points in the set of guidelines for the human body.

In seven papers published on Wednesday in the journals

Nature, Nature Communicat­ions and Nature Medicine,

scientists combed through gnomAD data, focusing on a type of spelling error that effectivel­y breaks the gene. We all have some of these errors, known as loss-of-function variants, in our genome.

But in most cases, they switch off or break a gene without ill-effect.

We might end up with a diminished sense of smell, for example, but otherwise be healthy.

But when these mistakes occur in more important genes, they can result in serious illness.

People with these variants in important genes often don’t pass them on because they die young or can’t have children. That means scientists can search a giant dataset like gnomAD, looking for genes that have fewer variants than expected.

They can extrapolat­e that these genes must be important to our health, because variants in them have not been passed down due to natural selection.

“With 144,000 people we start to have big enough numbers that if we don’t see loss-of-function variants in a particular gene that tells us that people carrying broken copies of this gene are being lost from the population, probably as a result of severe genetic disease,” said Daniel MacArthur, who led the gnomAD project.

“We can’t tell exactly what that disease is, but this tells us that this particular gene is likely to be important in some way,” added MacArthur, senior author on six of the seven papers, who carried out the research at Harvard and MIT’s Broad Institute.

Knowing which genes are important in disease not only offers targets for new drugs, but can also suggest whether a new treatment will be safe.

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