Variants at gene linked to kidney disease, sleeping sickness resistance

July 31, 2013, University of Pennsylvania

(Medical Xpress)—A new study led by University of Pennsylvania researchers involves a classic case of evolution's fickle nature: a genetic mutation that protects against a potentially fatal infectious disease also appears to increase the risk of developing a chronic, debilitating condition.

Such a relationship exists between malaria and sickle cell anemia. Individuals who carry a gene to resist the former are carriers for the latter. And recently scientific evidence has suggested that individuals who are resistant to human African trypanosomiasis, or sleeping sickness, are predisposed to developing . That could explain why African-Americans, who derive much of their ancestry from regions where sleeping sickness is endemic, suffer from at high rates.

In a study published in the American Journal of Human Genetics, Penn researchers and colleagues offer further insights into the unfinished story of the sleeping sickness-kidney disease connection by looking at a variety of African populations which had not been included in prior studies. Sequencing a portion of a gene believed to play a role in both diseases, the scientists discovered new candidate variants that are targeted by recent natural selection. Their findings lend support to the idea that the advantages of resistance to sleeping sickness, a disease which continues to affect tens of thousands of sub-Saharan Africans each year, may have played a role in the evolution of populations across Africa.

The research was led by Wen-Ya Ko and Sarah Tishkoff of the Department of Genetics in Penn's Perelman School of Medicine. Tishkoff, a Penn Integrates Knowledge professor, also has an appointment in the School of Arts and Sciences' Department of Biology. Ko now holds a research position at the Universidade do Porto in Portugal.

Earlier research had shown that African-Americans with kidney disease frequently had one of two mutations in the gene that codes for the ApoL1 protein, endowing it with the ability to kill the parasite species that causes the form of sleeping sickness found in eastern Africa. But, puzzlingly, these variants were found at high frequencies in the Yoruba, who live in western Africa's Nigeria.

"That was an interesting finding, but nobody had ever done a sequencing analysis of this gene across other African populations," Tishkoff said. "We wanted to know if we would find the same variants and would they be as common."

Using the earlier findings as a starting point, the Penn-led study expanded the sequencing effort to look at a region of the ApoL1 gene in 10 different African populations, encompassing groups from both eastern and western Africa.

They found the G1 and G2 haplotypes in some of the other populations but only at low frequencies, suggesting there may be other variants playing a similar role. Sure enough, the researchers also turned up another variant shared across groups, which they called G3.

"This novel G3 was quite common in some of the populations but surprisingly absent in the Yoruba," Tishkoff said.

Not only was this variant present in the other nine groups studied, but the Ko-Tishkoff team found signs that it had been positively selected, or ferried through generations at a rate above chance, perhaps because it exerted a protective effect against sleeping sickness.

And interestingly, G3 was most common in the Fulani, a pastoralist group which lives in western and central Africa. The authors note that human African sleeping sickness, which is typically transmitted by tse tse flies, might have been an important factor driving the migration patterns of the Fulani throughout history.

Because the Fulani "practice cattle herding, tse tse flies and the parasites they carry may have been more of a problem … than for some other groups," Ko said. "It may have been particularly advantageous for them to be able to resist the disease."

The different variants, therefore, may reflect a variety of selective pressures, including population movements around Africa and the historical and ongoing evolutionary arms race between the sleeping sickness parasite and the human immune system. The fact that the Yoruba can resist a form of the disease that is no longer present in the area in which they live might be the result of changes either in the parasite or in the movement patterns of the Yoruba themselves. Kidney disease might thus be considered an evolutionary trade-off, the unintended consequence of a battle to resist a powerful and prevalent infectious disease.

In future work, the researchers hope to distinguish the role, if any, of G3 in resisting . Tishkoff will also collaborate with a team of investigators studying kidney disease in Africans from both eastern and western regions of the continent. The goal is to get a more-complete picture of what genetic profiles may predispose certain groups to renal failure. Additionally, Tishkoff will continue to characterize genetic variation and signatures of natural selection in other regions of this gene in order to better understand the evolutionary forces influencing diversity among Africans.

"This study shows that the picture is much more complicated than we previously thought," Tishkoff said. "And it's another great example of why it is so important to look at diverse African groups when studying genomes. There is so much diversity in this one continent."

Explore further: Wild animals may contribute to the resurgence of African sleeping sickness

More information: dx.doi.org/10.1016/j.ajhg.2013.05.014

Related Stories

Wild animals may contribute to the resurgence of African sleeping sickness

January 17, 2013
Wild animals may be a key contributor to the continuing spread of African sleeping sickness, new research published in PLOS Computational Biology shows. The West African form of the disease, also known as Gambiense Human ...

Researchers show new evidence of genetic 'arms race' against malaria

June 9, 2011
For tens of thousands of years, the genomes of malaria parasites and humans have been at war with one another. Now, University of Pennsylvania geneticists, in collaboration with an international team of scientists, have developed ...

Gene variant increases risk of kidney disease in African-Americans

October 24, 2011
African-Americans with two copies of the APOL1 gene have about a 4 percent lifetime risk of developing a form of kidney disease, according to scientists at the National Institutes of Health. The finding brings scientists ...

Climate to widen sleeping sickness risk to southern Africa

November 9, 2011
Sleeping sickness could threaten tens of millions more people as the tsetse fly which transmits the disease spreads to southern Africa as a result of global warming, a study published on Wednesday says.

Recommended for you

Researchers identify gene responsible for mesenchymal stem cells' stem-ness'

January 22, 2018
Many doctors, researchers and patients are eager to take advantage of the promise of stem cell therapies to heal damaged tissues and replace dysfunctional cells. Hundreds of ongoing clinical trials are currently delivering ...

Genes contribute to biological motion perception and its covariation with autistic traits

January 22, 2018
Humans can readily perceive and recognize the movements of a living creature, based solely on a few point-lights tracking the motion of the major joints. Such exquisite sensitivity to biological motion (BM) signals is essential ...

Peers' genes may help friends stay in school, new study finds

January 18, 2018
While there's scientific evidence to suggest that your genes have something to do with how far you'll go in school, new research by a team from Stanford and elsewhere says the DNA of your classmates also plays a role.

Two new breast cancer genes emerge from Lynch syndrome gene study

January 18, 2018
Researchers at Columbia University Irving Medical Center and NewYork-Presbyterian have identified two new breast cancer genes. Having one of the genes—MSH6 and PMS2—approximately doubles a woman's risk of developing breast ...

A centuries-old math equation used to solve a modern-day genetics challenge

January 18, 2018
Researchers developed a new mathematical tool to validate and improve methods used by medical professionals to interpret results from clinical genetic tests. The work was published this month in Genetics in Medicine.

Can mice really mirror humans when it comes to cancer?

January 18, 2018
A new Michigan State University study is helping to answer a pressing question among scientists of just how close mice are to people when it comes to researching cancer.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.