The curious case of sickle cell mutation

Thousands of years ago, a special child was born in the Sahara. At the time, this was not a desert; it was a green belt of savannahs, woodlands, lakes, and rivers. Bands of hunter-gatherers thrived there, catching fish and spearing hippos. A genetic mutation had altered the child's haemoglobin, the molecule in red blood cells that ferries oxygen through the body. It was not harmful; there are two copies of every gene, and the child's other haemoglobin gene was normal. The child survived, had a family and passed down the mutation to future generations.

As the greenery turned to desert, the descendants of the hunter-gatherers became cattle-herders and farmers and moved to other parts of Africa. The mutation endured over generations, and for good reason. People who carried one mutated gene were protected against one of the biggest threats to humans in the region: malaria.

There was just one problem with this genetic advantage: from time to time, two descendants of that child would meet and start a family. Some of their children inherited two copies of the mutant haemoglobin gene instead of one. These children could no longer produce normal haemoglobin. As a result, their red cells became defective and clogged their blood vessels. The condition, now known as sickle cell anaemia, leads to extreme pain, difficulty with breathing, kidney failure, and even strokes.

Sprawling saga

In early human societies, most children with sickle cell anaemia likely died by age 5. Yet, the protection afforded by a single copy of the sickle cell mutation against malaria kept fuelling its spread. Today, over 250 generations later, the sickle cell mutation has been inherited by millions of people. While the majority of carriers live in Africa, many others live in southern Europe, the Near East, and India. Those carriers have about 3,00,000 children each year with sickle cell anaemia.

How humans got the sickle cell mutation is a sprawling saga that emerges from new research carried out at the Centre for Research on Genomics and Global Health, part of the National Institutes of Health, USA, by Daniel Shriner, a staff scientist, and Charles N Rotimi, the centre's director. Their study was published recently in the American Journal of Human Genetics.

Daniel and Charles analysed the genomes of nearly 3,000 people to reconstruct the genetic history of the disease. They conclude that the mutation arose roughly 7,300 years ago in West Africa. Later, migrants spread the mutation across much of Africa and then to other parts of the world. Wherever people suffered from malaria, the protective gene thrived - but brought sickle cell anaemia with it.

Today, sickle cell anaemia remains a heavy burden on public health. In many poor countries, most children with the disease still die young. Charles said that an improved understanding of the history of sickle cell anaemia could lead to better medical care. It might allow researchers to predict who will suffer severe symptoms and who will only experience mild ones.

Doctors in the United States first noticed sickle cell anaemia in the early 1900s. The disease got its name from the way it changed the shape of red blood cells from healthy disks to abnormal curves. Most cases turned up in African-Americans, doctors found. But 8% of African-Americans had at least some sickle-shaped blood cells, even though the vast majority had no symptoms at all. "Sickle cell is a rare example of human evolution where we have a good idea of what happened and why," said Bridget Penman, a malaria expert at the University of Warwick in England.

Early genetic studies suggested that five different kinds of DNA, known as haplotypes, surround the mutation. These are named for the places where they were most common: Arabian/Indian, Benin, Cameroon, Central African Republic and Senegal. These haplotypes became important for diagnosing sickle cell anaemia because some appeared to cause more severe disease than others.

But the haplotypes also gave scientists a chance to explore the history of the mutation. "It has been an open question as to whether the actual sickle cell mutation itself emerged several times or just once," Bridget said. Some researchers saw the five haplotypes as evidence that the mutation arose on five separate occasions in five different places. Other researchers thought it unlikely that genetic lightning could strike so many times.

Tracing the journey

"We said, 'How do we jump into this 40-year debate?'" Charles said. He and Daniel examined the genomes of 2,932 people from around the world. They found that 156 of the subjects carried a copy of the sickle cell mutation. The researchers scanned the DNA surrounding the mutation in those people. While most of it was identical from person to person, in some spots it differed.

Combining their findings, the researchers concluded that all 156 people inherited the same mutation from a single person who lived roughly 7,300 years ago. "This alone is a big contribution to our understanding," Bridget said. The new study also offers hints as to how the mutation spread to millions of descendants. The oldest version of the sickle cell mutation is found in people from western and central Africa. They may have inherited it from an ancestor in the green Sahara. The mutation might have spread to other parts of Africa with the expansion of a people called the Bantu. Arising about 5,000 years ago around what is now Cameroon and Nigeria, they converted woodlands to farm fields on a massive scale.

As they cleared land for agriculture, they may have promoted the spread of malaria by mosquitoes. The insects thrived by laying eggs in standing water around the farms and feeding on the growing population of farmers. The intensification of malaria in human populations may also have accelerated the spread of the protective sickle cell mutation.

Over the next few thousand years, the Bantu carried the mutation across much of eastern, central and southern Africa, Daniel and Charles conclude. In places where malaria was prevalent, the mutation offered protection. But malaria is rarer in southern Africa, and there the sickle cell mutation became rarer, too. Later, the study suggests, Africans carried the mutation to other parts of the world. Waves of migrants made their way to the Near East. As people from different ancestries interbred, the mutation made its way further afield, into Europe and India.

Frederick B Piel, an epidemiologist at Imperial College London, said he looked forward to bigger genome-based studies on the sickle cell mutation. It remains to be seen if these patterns can be found in thousands of carriers, instead of just 156, he said. Bridget said that scientists also should study the different genetic variations identified in the new research. These may help explain why the sickle cell mutation leads to deadly symptoms in some people and only mild ones in others - something that scientists still cannot explain. "This knowledge might inspire treatments in itself," she said.

The New York Times