Friday, November 28, 2014

The Slow Track of the Host-Pathogen Arms Race: Human Evolution in Response Pathogen Pressures

Mutation and evolution are inescapable considerations in the study of infectious disease.  Microbes have comparatively small genomes and short replication times so they mutate quite frequently and favorable mutations are selected for and come to pervade the population quickly.  Hosts have developed ways of circumnavigating this rapid mutation.  One example would be the encoded and recombinate diversity of human T and B cell specificity in the human immune system.  Even if a microorganism mutates away from one immune-detected epitope the host can generate immune cells with specificity to the new epitope.

Because the timescales of host and pathogen replication and evolution are so different, the evolution of hosts in response to pathogens is less frequently investigated.  Not all researchers, however, shy away from such questions.  One research team, based at Harvard and led by Dr. Pardis Sabeti, is leveraging large datasets of human genome sequences and the computational tools of bioinformatics to investigate how the Lassa fever virus has influenced conserved changes in the human genome in regions where the disease is endemic.

Lassa fever virus, a member of the Arenaviridae family, is endemic to west Africa.  Although it rarely appears beyond that area, within west Africa Lassa fever generates a substantial disease burden.  According to the CDC, the virus infects about 200,000 individuals per year, kills about 5,000 and is present in about 10-16% of individuals admitted to hospitals in the area.  The virus has a rodent reservoir, the multimammate rat," which sheds the virus in urine and feces.  Humans are most commonly infected when they inhale or ingest the excretions of an infected rat, but can also be infected through contact with infected humans as well.  Most infected individuals (80%) present with a mild feverish malaise after an incubation period 1-3 weeks long.  In the remaining 20% of cases, severe symptoms develop that can include hemorrhaging, vomiting, respiratory distress, and shock and can result in death from multi-organ failure.

Sabeti's team, in a paper published in Nature in 2012, hypothesized that the endemicity of Lassa in west Africa might have placed a consistent pressure on human evolution in the region to favor the retention of alleles that confer resistance to Lassa or improve disease outcomes.   Using human full-genome sequence data from the International Haplotype Map Consortium and the 1000 Genomes Consortium, these researchers identified conserved changes in two regions, a gene called LARGE and the gene encoding immune mediator interleukin-21, that had been determined through previous work to be involved in the infection of a host with Lassa and the development of immunity against Lassa.  These findings, like most in science, generated as many questions as they answered, particularly with respect to the physiological implications of these genetic changes.  However, the team was able to posit that the positively-selected variants of these genes were associated with increased alternative splicing and differential gene expression.  The implications of these findings extend beyond the particular disease of Lassa fever, however, because these results pave the way for similar investigations into the effects of related pathogens on human evolution.  However, pathogen influence on human evolution will likely be substantially less challenging to uncover for diseases that have a consistently strong presence over time and localized endemicity, like Lassa fever.

--Laurie Rumker

Check out the full published paper via DOI: 10.1098/rstb.2011.0299

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