Linkage disequilibrium under recurrent bottlenecks.

To model deviations from selectively neutral genetic variation caused by different forms of selection, it is necessary to first understand patterns of neutral variation. Best understood is neutral genetic variation at a single locus. But, as is well known, additional insights can be gained by investigating multiple loci. The resulting patterns reflect the degree of association (linkage) between loci and provide information about the underlying multilocus gene genealogies. The statistical properties of two-locus gene genealogies have been intensively studied for populations of constant size, as well as for simple demographic histories such as exponential population growth and single bottlenecks. By contrast, the combined effect of recombination and sustained demographic fluctuations is poorly understood. Addressing this issue, we study a two-locus Wright-Fisher model of a population subject to recurrent bottlenecks. We derive coalescent approximations for the covariance of the times to the most recent common ancestor at two loci in samples of two chromosomes. This covariance reflects the degree of association and thus linkage disequilibrium between these loci. We find, first, that an effective population-size approximation describes the numerically observed association between two loci provided that recombination occurs either much faster or much more slowly than the population-size fluctuations. Second, when recombination occurs frequently between but rarely within bottlenecks, we observe that the association of gene histories becomes independent of physical distance over a certain range of distances. Third, we show that in this case, a commonly used measure of linkage disequilibrium, σ(2)(d) (closely related to r(2)), fails to capture the long-range association between two loci. The reason is that constituent terms, each reflecting the long-range association, cancel. Fourth, we analyze a limiting case in which the long-range association can be described in terms of a Xi coalescent allowing for simultaneous multiple mergers of ancestral lines.

Identification of functional regions within invasion plasmid antigen C (IpaC) of Shigella flexneri.

Shigella flexneri causes bacillary dysentery with symptoms resulting from the inflammation that accompanies bacterial entry into the cells of the colonic epithelium. The effectors of S. flexneri invasion are the Ipa proteins, particularly IpaB and IpaC, which are secreted at the host-pathogen interface following bacterial contact with a host cell. Of the purified Ipa proteins, only IpaC has been shown to possess quantifiable in vitro activities that are related to cellular invasion. In this study, ipaC deletion mutants were generated to identify functional regions within the IpaC protein. From these data, we now know that the N-terminus and an immunogenic central region are not required for IpaC-dependent enhancement of cellular invasion by S. flexneri. However, to restore invasiveness to an ipaC null mutant of S. flexneri, the N-terminus is essential, because IpaC mutants lacking the N-terminus are not secreted by the bacterium. Deletion of the central hydrophobic region eliminates IpaC's ability to interact with phospholipid membranes, and fusion of this region to a modified form of green fluorescent protein converts it into an efficient membrane-associating protein. Meanwhile, deletion of the C-terminus eliminates the mutant protein's ability to establish protein-protein contacts with full-length IpaC. Interestingly, the mutant form of ipaC that restores partial invasiveness to the S. flexneri ipaC null mutant also restores full contact-mediated haemolysis activity to this bacterium. These data support a model in which IpaC possesses a distinct functional organization that is important for bacterial invasion. This information will be important in defining the precise role of IpaC in S. flexneri pathogenesis and in exploring the potential effects of purified IpaC at mucosal surfaces.