Human genome study finds many genes have no effect on human health

Many mutations or ‘knock-outs’ may have no effect on human health, researchers find. Science Editor Steve Connor explains

‘Redundancy’ could explain why some mutations have no effect on health (AFP/Getty)

A study into the genomes of British-Asians has forced scientists to re-examine their text books on medical genetics. It turns out that many supposedly vital genes are in fact quite superfluous to a healthy life, while some allegedly damaging mutations have turned out to be harmless.

At the end of the 20th century, most geneticists thought the human genome contained between 80,000 and 100,000 genes. But when the human genome was fully decoded and analysed 15 years ago the true number was found to be nearer to 20,000 – a shock, given that a grape, for instance, has 10,000 genes more than a human.

And now the study of thousands of Britons of Pakistani descent has thrown up another surprise, suggesting that as many as 17,000 of those 20,000 human genes can be lost completely with no apparent ill effects for the people who have “mislaid” them.

The findings suggest a remarkable, built-in redundancy to the human genome. As genetic conundrums go, this is one of the most puzzling, given the fact that the smallest possible changes in the human genome can, when they occur at certain points in its structure, lead to serious illnesses or death.

In another bizarre finding, the scientists investigated a particular gene that causes infertility in mice when lost or “knocked out”. However, the researchers found that one woman in the study who had lost both copies of this fertility gene was the proud mother of three healthy children.

One of the reasons the scientists chose to investigate the genomes of British-Pakistani men and women was because of the common practice in Pakistani culture of first-cousin marriages, which means there is a high proportion of gene “knock-outs” in their offspring.

After the human genome was fully decoded and analysed 15 years ago the number of genes contained was found to be nearer to 20,000 (Science Photo Library)

A gene knock-out is when both copies of the gene – one from the mother and one from the father – are missing or non-functional because of mutations or DNA deletions. Parents who are closely related are more likely to have children with a relatively high number of gene knock-outs because of the effects of genetic inbreeding which brings the same gene mutations together in a son or daughter.

Gene knock-outs are widely used in laboratory mice as animal models of many human illnesses caused by genetic defects. But the researchers now believe that past studies may have given the wrong impression of how vital any one particular gene is for a healthy life.

“This is the first time anyone has looked for complete gene knock-outs in healthier adult people at a large scale. We found that there are lots of complete gene knock-outs in human adults and that, often, these have no adverse effects,” said Professor David van Heel, who co-lead the study at Queen Mary University of London.

“We suggest that many previous genetic studies may have overestimated or inaccurately estimated risk of disease given a genetic variant, when taken into larger populations,” Professor van Heel said.

Two sets of studies into the genes of British Asians, one called Born in Bradford and the other East London Genes and Health, have provided a potential cohort of 100,000 individuals who can take part in the research. This particular gene knock-out study, however, involved genomic analyses of 3,222 British-Pakistani adults whose parents were closely related.

“Studying healthy people with related parents allowed us to estimate that only around 3,000 of the 20,000 human genes are essential for life,” said Richard Durban of the Wellcome Trust Sanger Institute in Cambridge, the co-leader of the study published in the journal Science last week.

Vagheesh Narasimhan, a PhD student at the Sanger Institute and first author of the study, said about one in four of the genomes analysed carried rare but naturally occurring gene knock-outs.

“We found over 20 people with knock-outs of genes that were previously thought to have been causative for disease, without any sign of the expected disease,” Mr Narasimhan said.

But the biggest surprise, perhaps, was finding a woman who was lacking both of her PRDM9 genes – which mouse experiments had shown to be critical for fertility.

“To our surprise, the woman with a knock-out for this gene was a healthy mother of three children, clearly not infertile!” he said.

But the study also indicated that many gene knock-outs can still be lethal. The scientists had expected to find more than 900 gene knock-outs in this group of people, but found just 781, suggesting that the missing number was because these individuals had not survived.

As Mr Narasimhan explained: “We could estimate that approximately 15 per cent of genes when knocked out would have led to lethality or severe disease.”