Dead gene that resurrected to save elephants from cancer

African elephants are the largest land animals, weighing an average of 6,000 kilogrammes and standing tall at more than 10 feet, but elephants started out more than 10 times smaller as little groundhog-sized animals, 25 to 30 million years ago.

Then evolution happened and they started to grow bigger, until they reached the size of modern elephants.

Being bigger came with benefits such as not being easy prey like mice, squirrels and groundhogs, which are eaten by animals bigger than them.

But being bigger also came with trade-offs. Bigger animals have many more cells and tend to live longer (70 years or more for elephants), which means more time and opportunities to accumulate cancer-causing mutations.

“Large, long-lived animals evolved robust mechanisms to either suppress or eliminate cancerous cells in order to live as long as they do and reach their adult sizes,” said study co-author Juan Manuel Vazquez.

Huge animals are more likely to develop cancerous cells. Taller humans, for example, have a slightly higher incidence of several types of cancer than average-sized people, and shorter people face a lower risk of those cancers.

For every 10 centimetres of increased height, women face an 18 per cent higher risk for some cancers, while men face an 11 per cent higher risk for some cancers for every additional 10 centimetres, according to a Swedish study published in 2015.

HIGH RISK

This is especially true for skin cancer, for which every additional 10 centimetres comes with a 30 per cent higher risk. Being tall is also linked to breast cancer in women. The explanation is that taller people have more cells that could turn cancerous. And so it is with the biggest land animal.

Elephants have 100 times as many potentially cancerous cells as humans, because of their large size. Then why do only five per cent of elephants die from cancer compared to 17 per cent of humans?

Humans have one copy of the master tumour suppressor gene P53, while elephants have 20 copies.P53 enables the body to recognise unrepaired DNA damage, which is a precursor to cancer.

Once it recognises the unrepaired damage, it acts to cause the death of the damaged cells.

Given that elephants have more copies of P53, their cells are significantly more sensitive to damaged DNA, which then makes them respond faster to kill the damaged cells.

But that’s not all, when elephants began to grow bigger millions of years ago, they reactivated a dead gene – the leukemia inhibitory factor 6 or LIF6 – to help suppress cancer, one of the risks of being huge.

When genes duplicate, sometimes they make mistakes, producing non-functional versions known as pseudogenes.

“We often refer to these pseudogenes dismissively as dead genes,” said senior author and assistant professor of human genetics Vincent Lynch.

LIF6, was once considered a pseudogene, but while studying the master tumour suppressor gene (P53) in elephants, researchers found that LIF6 had somehow returned from the dead and evolved an “on” switch.
Back from the dead, LIF6, became a valuable gene, responding to damaged DNA by killing the cell, when activated by P53.

LIF6 makes a protein that goes quickly into the mitochondria (a cell’s main source of energy) poking holes into it and causing the cell to die, explained Lynch.

“This is beneficial because LIF6 acts in response to genetic mistakes, that is, errors made when the DNA is being repaired. Getting rid of that cell quickly can prevent cancer,” he added.

Interestingly, elephants have eight LIF genes, but only LIF6 is known to be functional, and it appears to have been helping ele-phants for a long time.

“We can use the tricks of evolution to try to figure out when this defunct gene became functional again,” said Lynch, in findings published in the journal Cell Reports.