Genome Advance of the Month

The evolutionary mark of Y. pestis and the Black Death

Yersinia pestis. Credit: Rocky Mountain Laboratories, NIAID, NIH
Yersinia pestis

The course of human history has been shaped not only by human thoughts and actions, but also by our interactions with the surrounding environment. This includes the trillions of microscopic viruses and bacteria that beset us on a daily basis and which, prior to the advent of 20th century medicine, were a significant contributor to disease and mortality.

January's Genome Advance features two studies that use genomics to explore the role of the Yersinia pestis (Y. pestis) bacterium in two historic plague pandemics and its evolutionary mark on the human genome.

An extremely virulent bacterium, Y. pestis is transmitted through the bite of fleas that feed on infected rodents and has emerged repeatedly to cause plague. Full genome sequencing of DNA from teeth recovered from a London plague pit confirmed the identity of Y. pestis as the cause of the Black Death (read Dissecting the cause of the Black Death: http://www.genome.gov/27546229) that wiped out an estimated 40 percent of Europe's population in the 14th century and had long-lasting economic, social and cultural ramifications. Since then, Y. pestis has had numerous other encounters with human beings, including the Third Pandemic, which hit China and India in the latter half of the 19th century along with sporadic outbreaks in the rest of the world.

More recently, Y. pestis was also identified as the causative agent of an even earlier pandemic, the Plague of Justinian dating back to the 6-8th century, which contributed to the fall of the Roman Empire. A study led by Hendrik Poinar, Ph.D., associate professor at McMaster University in Ontario, Canada, and published last month in The Lancet Infectious Diseases, investigated the evolutionary relationship between the different strains of Y. pestis bacteria responsible for the Plague of Justinian and the later epidemics. Using DNA extracted from the teeth of two individuals buried in the medieval Aschheim-Bajuwarenring cemetery of 6th century Bavaria, Germany, the scientists were able to isolate and reconstruct the genome of the infectious Y. pestis strain.
 
Interestingly, a phylogenetic tree mapping the sequence of the Justinian bacteria against the genome sequences of all other known Y. pestis strains showed that the Justinian strain occupies a separate branch of the tree with no known descendants. This means that the Y. pestis strain that later caused the Black Death (and is the ancestor of all modern infectious strains) emerged independently from rodent populations. What this also suggests is that diverse lineages of Y. pestis may be perpetually lurking in wild rodents, waiting to emerge and cause disease in humans.
 
So how have these repeated encounters with Y. pestis affected humans? And why were the Plague of Justinian and the Black Death so much more devastating than the more recent cases of the disease seen today?
 
One possibility lies in the evolutionary struggle between the human immune system, which defends us from infection, and the microbes that constantly evolve new ways to evade the defenses and invade the human body. In epidemics, natural selection favors the perpetuation of genetic variants that help individuals to better resist while individuals who are genetically susceptible succumb to the disease. Thus, the Y. pestis lineages associated with the Plague of Justinian may have become extinct due to the eventual lack of susceptible hosts - either from mutations that arose in the human genome or the selection of natural gene variants that conferred protection against the bacteria. However, due to the large amount of genetic variation present in human populations, the phenomenon of natural selection has been difficult to study.
 
A collaborative effort by Mihai Netea, M.D., Ph.D., professor at Radboud University Nijmegen Medical Center in The Netherlands, Jaume Bertranpetit, Ph.D., professor at Universitat Pompeu Fabra in Barcelona, Spain and their colleagues explored this very question by examining the genomes of two very distinct ethnic groups - the Rroma and the European Romanians - that have lived side by side in the same geographic area for centuries. Because there was very little intermarriage between the two populations following the migration of the Rroma from northern India a millennium ago, the populations continue to have distinct genetic backgrounds. This allowed researchers to scan the genomes of all three populations to investigate which genes were favored by environmental pressures experienced by the Rroma and European Romanians but not by people from Northwest India.
 
Published last month in the Proceedings for the National Academy of Sciences, the study examined almost 200,000 single-nucleotide polymorphisms (SNPs), each of which represents variation in a single letter of the DNA sequence, to search for targets of natural selection. The analysis identified about 20 genes with diverse roles, including skin pigmentation, inflammation, and susceptibility to autoimmune diseases, that evolved concurrently in the Rroma and European Romanians. Also on the list is a cluster of TLR genes, which are important for immune cells to rapidly detect and combat invading pathogens.
 
This is hardly surprising in light of the key role of the immune system in the face of pandemics. Because the Black Death was such a widespread and devastating plague, the researchers postulated that it might have been responsible for some of the driving force of selection on this area of the genome.
 
Strikingly, when researchers took immune cells from individuals of European descent who express the variant TLR genes, and exposed them to Y. pestis and Y. pseudotuberculosis (an evolutionary ancestor of Y. pestis), they detected a distinct immune response compared to cells from people without these TLR variants. This suggests that while other diseases may have also played a role, the plague likely exerted a strong influence in steering the evolution of these immune genes.
 
What this highlights is the significance of environmental factors in natural selection on human genes and the role of our historical interactions with the world around us in shaping our genetic makeup. Although convergent evolution of immune-related genes in Europeans during the Black Death may have lent protection against subsequent encounters with Y. pestis, these genetic changes may also form the evolutionary basis for why modern-day Europeans are more susceptible to many pro-inflammatory and autoimmune diseases.

Read the articles:

Yersinia pestis and the Plague of Justinian 541-543 AD: A genomic analysis. Wagner DM, Klunk J, Harbeck M, Devault A, Waglechner N, Sahl JW, Enk J, Birdsell DN, Kuch M, Lumibao C, Poinar D, Pearson T, Fourment M, Golding B, Riehm JM, Earn DJ, Dewitte S, Rouillard JM, Grupe G, Wiechmann I, Bliska JB, Keim PS, Scholz HC, Holmes EC, Poinar H. Lancet Infect Dis, [Epub ahead of print] 2014. [PubMed]

Convergent evolution in European and Rroma populations reveals pressure exerted by plague on Toll-like receptors. Laayouni H, Oosting M, Luisi P, Ioana M, Alonso S, Ricaņo-Ponce I, Trynka G, Zhernakova A, Plantinga TS, Cheng SC, van der Meer JW, Popp R, Sood A, Thelma BK, Wijmenga C, Joosten LA, Bertranpetit J, Netea MG. Proc Natl Acad Sci U S A, 111(7):2668-73. 2014. [PubMed]
 
Dissecting the cause of the Black Death. Gitlin, Jonathan. Genome Advance of the Month, Oct. 2011.

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Posted: February 28, 2014