These children could no longer produce normal hemoglobin. As a result, their red cells became defective and clogged their blood vessels. The condition, now known as sickle cell anemia, leads to extreme pain, difficulty with breathing, kidney failure and even strokes.
In early human societies, most children with sickle cell anemia likely died by age 5. Yet the protection afforded by a single copy of the sickle cell mutation against malaria kept fueling 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 300,000 children each year with sickle cell anemia.
How humans got the sickle cell mutation is a sprawling saga that emerges from new research carried out at the Center for Research on Genomics and Global Health, part of the National Institutes of Health, by Daniel Shriner, a staff scientist, and Charles N. Rotimi, the center’s director. Their study was published on Thursday in the American Journal of Human Genetics.
Dr. Shriner and Dr. Rotimi analyzed 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 anemia with it.
Today, sickle cell anemia remains a heavy burden on public health. In many poor countries, most children with the disease still die young. In the United States, the average life span of sufferers has been extended into the early 40s.
Dr. Rotimi said that an improved understanding of the history of sickle cell anemia could lead to better medical care. It might allow researchers to predict who will suffer severe symptoms and who will only experience mild ones.
“It would definitely help physicians to treat patients at a global level,” he said.
Doctors in the United States first noticed sickle cell anemia 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 percent of African-Americans had at least some sickle-shaped blood cells, even though the vast majority had no symptoms at all.
By 1950, researchers had resolved this paradox, discovering the difference between carrying one mutated copy of the hemoglobin gene and carrying two copies. By then it had also become clear that sickle cell anemia was not unique to the United States.
In Africa, researchers found sickle-shaped red blood cells in people across a broad belt, from Nigeria in West Africa to Tanzania in the east. The cells also turned up at high rates in people in parts of the Near East and India, and in southern European countries such as Greece.
Genetically speaking, this made no sense. Because inheriting two copies of the gene is so deadly, the mutation should have become rarer with passing generations, not more common.
In 1954, a South African-born geneticist named Anthony C. Allison observed that people in Uganda who carried a copy of the sickle cell mutation suffered fewer malaria infections than people with normal hemoglobin.
Later research confirmed Dr. Allison’s finding. The sickle cell mutation seemed to defend against malaria by starving the single-celled parasite that causes the disease. The parasite feeds on hemoglobin, and so it’s possible that it can’t grow on the sickle cell version of the molecule.
“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 anemia, 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,” said Dr. Penman.
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.
“We said, ‘How do we jump into this forty-year debate?’” said Dr. Rotimi.
He and Dr. Shriner examined the genomes of 2,932 people from around the world. They found that 156 of the subjects — mostly from Africa, but also from Barbados, the United States, Colombia and Qatar — 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,” said Dr. Penman.
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, Dr. Shriner and Dr. Rotimi 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.
Some West Africans captured in the slave trade brought the sickle cell mutation to the Americas. But in places like the United States, where malaria was uncommon or nonexistent, the mutation offered less of an evolutionary advantage. As a result, African-Americans have a lower rate of sickle cell anemia than Africans today.
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.
Dr. Penman 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 can’t explain.
“This knowledge might inspire treatments in itself,” she said.
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