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Genomics in the Journals: Aug 22, 2013

NEW YORK (GenomeWeb News) – Inherited germline mutations in mitochondrial DNA may interact with somatic mtDNA mutations acquired throughout an individual's lifetime in ways that accelerate the aging processes, according to a study online in Nature.

A team from Sweden, Germany, and the US interbred and compared strains of inbred mutant mice in an effort to understand the potential role of inherited mtDNA mutations in aging. In addition to the inherited mtDNA mutations introduced in earlier mouse generations, some of the animals carried alterations affecting one or both copies of a DNA polymerase tasked with replicating and repairing mtDNA, making them prone to new somatic mitochondrial mutations, too.

On their own, the inherited mitochondrial mutations seemed to speed up the appearance of mouse features associated with aging, such as gray hair, enlarged heart size, and so on, the researchers reported. For mice carrying both germline and somatic mtDNA mutations, that aging effect was enhanced, they noted, and mice tended to have brain malformations hinting at developmental problems.

"Our findings show that a pre-existing mutation load will not only allow somatic mutagenesis to create a critically high total mtDNA mutation load sooner," the study's authors noted, "but will also increase clonal expansion of mtDNA mutations to enhance the normally occurring mosaic respiratory chain deficiency in aging tissues."

A PLOS Pathogens study suggests that the tuberculosis-causing pathogen Mycobacterium tuberculosis has been subject to strong purifying selection over much of its genome, potentially due to pressures exerted by its human host.

Researchers from the University of Wisconsin at Madison, Stanford University, and elsewhere used published genome sequence data from almost four-dozen clinical isolates of M. tuberculosis — along with available genome sequences for several related species — to explore natural selection's influence on the pathogen's genetic diversity.

With the help of genome sequences from 63 mycobacterial representatives, they uncovered signs of purifying selection in M. tuberculosis genomes that were more pronounced than purifying selection patterns described in most eukaryotic and prokaryotic organisms considered previously. That was especially true of M. tuberculosis genes involved in protein translation and in inorganic ion movement and metabolism.

On the other hand, the pathogen's defense genes harbored higher levels of genetic diversity, the team noted, perhaps due to diversifying selection amongst sequences used to dodge anti-tuberculosis drugs, the human immune system, and other threats.

The study's authors saw other ties between humans and M. tuberculosis diversity, too. For instance, their analysis indicates that M. tuberculosis populations around the world have expanded by around 25 times since the late 1600s, coinciding with a boom in human population sizes.

"Our results suggest that growth of [M. tuberculosis] populations parallels that of its human host population," they wrote, "and that complex influences lead to emergence and maintenance of adaptive traits in [M. tuberculosis]."

Researchers from the US and Panama used antibody assays, viral sequencing, and phylogenetics to assess viruses involved in a human outbreak of equine encephalitis in Darién, a province in eastern Panama, in 2010 — work that they described in the New England Journal of Medicine.

The team started by looking for equine encephalitis-related RNA sequences in blood samples collected at a Darién hospital during a surveillance program instigated after two patients tested positive for alphaviruses — a genus that includes western equine encephalitis, Venezualan equine encephalitis, and eastern equine encephalitis. Such viruses are not known for causing human infections in Latin America, though several eastern equine encephalitis cases are documented annually in North America.

Through their antibody-based analysis of 174 human blood samples from the hospital, the researchers identified 13 individuals infected with the eastern equine encephalitis virus and 11 infected with the Venezualan equine encephalitis virus. One individual was co-infected with both of the alphaviruses.

Meanwhile, blood samples from 155 horses in the province revealed that dozens of the horses were infected with eastern equine encephalitis virus. Eight of the horses carried Venezualan equine encephalitis virus infections and 11 were infected with both.

The group's phylogenetic analysis suggested that the viruses involved in the human infections came from viral lineages found in Panama in the past, pointing to possible changes in virulence in some equine encephalitis strains.

"Until the Darién outbreak, we had become convinced that the virus in South America was fundamentally different in its ability to infect people and cause serious disease," the study's senior author Scott Weaver, a human infections and immunity researcher at the University of Texas at Galveston, said in a statement.

"[I]f this virus has changed and become more virulent for people," Weaver said, "we need to know, number one, is it going to spread to other parts of Latin America or number two, are other Latin American strains likely to do the same thing?"

In the early, online edition of Science, a team from the University of Sussex and the UK's Institute of Cancer Research described a pair of short peptides encoded by small open reading frames, or smORFs, that have apparent roles in cardiac function.

Generally speaking, smORFs include sequences coding for peptides comprised of 100 amino acids or less. For their own smORF study, the UK researchers used a bioinformatics-based approach to sort through Drosophila RNA sequence data, looking for smORFs within transcripts previously presumed to be non-coding. The search led to two potential smORFs found in a transcript that's expressed in fruit fly somatic muscles and post-embryonic heart tissue.

The team's subsequent localization and functional experiments suggested that these smORFs — which code for peptides containing fewer than 30 amino acids apiece — both contribute to calcium transport processes that impact muscle contraction in the fruit fly's heart.

By looking for structural homologs in other species, the investigators determined that the smORFs are likely related not only to small peptides found in arthropods, but also to the human peptides sarcolipin and phospholamban, which mediate calcium trafficking in human muscles.

"These peptides seem conserved for more than 550 million years in a range of species from flies to humans, where they have been implicated in cardiac pathologies," senior author Juan Pablo Couso, a life sciences researcher at the University of Sussex, and his colleagues noted. "Such conservation suggests that the mechanisms for heart regulation are ancient, and that smORFS may be a fundamental genome component that should be studied systematically."