Everyday, Scientist Live turns its eyes to the Web around it and highlights news and research across the Internet. Today we look take an extended look at genome rearrangement, HIV/SIV infection, and the relation between RNA sequence and structure.
GENETICS
Genome structure variation has profound impacts on phenotype in organisms ranging from microbes to humans, yet little is known about how natural selection acts on genome arrangement. Pathogenic bacteria such as Yersinia pestis, which causes bubonic and pneumonic plague, often exhibit a high degree of genomic rearrangement.
The recent availability of several Yersinia genomes offers an unprecedented opportunity to study the evolution of genome structure and arrangement. We introduce a set of statistical methods to study patterns of rearrangement in circular chromosomes and apply them to the Yersinia. We constructed a multiple alignment of eight Yersinia genomes using Mauve software to identify 78 conserved segments that are internally free from genome rearrangement. Based on the alignment, we applied Bayesian statistical methods to infer the phylogenetic inversion history of Yersinia.
The sampling of genome arrangement reconstructions contains seven parsimonious tree topologies, each having different histories of 79 inversions. Topologies with a greater number of inversions also exist, but were sampled less frequently. The inversion phylogenies agree with results suggested by SNP patterns. We then analyzed reconstructed inversion histories to identify patterns of rearrangement. We confirm an over-representation of "symmetric inversions"-inversions with endpoints that are equally distant from the origin of chromosomal replication. Ancestral genome arrangements demonstrate moderate preference for replichore balance in Yersinia.
We found that all inversions are shorter than expected under a neutral model, whereas inversions acting within a single replichore are much shorter than expected. We also found evidence for a canonical configuration of the origin and terminus of replication. Finally, breakpoint reuse analysis reveals that inversions with endpoints proximal to the origin of DNA replication are nearly three times more frequent.
Our findings represent the first characterization of genome arrangement evolution in a bacterial population evolving outside laboratory conditions. Insight into the process of genomic rearrangement may further the understanding of pathogen population dynamics and selection on the architecture of circular bacterial chromosomes.
- Darling AE, Miklós I, Ragan MA (2008) Dynamics of Genome Rearrangement in Bacterial Populations. PLoS Genet 4(7): e1000128. doi:10.1371/journal.pgen.1000128
IMMUNOLOGY
Several studies have shown that cytotoxic T lymphocytes (CTLs) play an important role in controlling HIV/SIV infection. Notably, the observation of escape mutants suggests a selective pressure induced by the CTL response. However, it remains difficult to assess the definite role of the cellular immune response.
We devise a computational model of HIV/SIV infection having a broad cellular immune response targeting different viral epitopes. The CTL clones are stimulated by viral antigen and interact with the virus population through cytotoxic killing of infected cells. Consequently, the virus population reacts through the acquisition of CTL escape mutations. Our model provides realistic virus dynamics and describes several experimental observations. We postulate that inter-clonal competition and immunodominance may be critical factors determining the sequential emergence of escapes. We show that even though the total killing induced by the CTL response can be high, escape rates against a single CTL clone are often slow and difficult to estimate from infrequent sequence measurements.
Finally, our simulations show that a higher degree of immunodominance leads to more frequent escape with a reduced control of viral replication but a substantially impaired replicative capacity of the virus. This result suggests two strategies for vaccine design: Vaccines inducing a broad CTL response should decrease the viral load, whereas vaccines stimulating a narrow but dominant CTL response are likely to induce escape but may dramatically reduce the replicative capacity of the virus.
- Althaus CL, De Boer RJ (2008) Dynamics of Immune Escape during HIV/SIV Infection. PLoS Comput Biol 4(7): e1000103. doi:10.1371/journal.pcbi.1000103
GENETICS
Evolution by natural selection is fundamentally shaped by the fitness landscapes in which it occurs. Yet fitness landscapes are vast and complex, and thus we know relatively little about the long-range constraints they impose on evolutionary dynamics. Here, we exhaustively survey the structural landscapes of RNA molecules of lengths 12 to 18 nucleotides, and develop a network model to describe the relationship between sequence and structure. We find that phenotype abundance-the number of genotypes producing a particular phenotype-varies in a predictable manner and critically influences evolutionary dynamics. A study of naturally occurring functional RNA molecules using a new structural statistic suggests that these molecules are biased toward abundant phenotypes. This supports an "ascent of the abundant" hypothesis, in which evolution yields abundant phenotypes even when they are not the most fit.
- Cowperthwaite MC, Economo EP, Harcombe WR, Miller EL, Meyers LA (2008) The Ascent of the Abundant: How Mutational Networks Constrain Evolution. PLoS Comput Biol 4(7): e1000110. doi:10.1371/journal.pcbi.1000110
