Genetic drift and anthropometric variation in Ireland

The effect of genetic drift on the genetic structure of seven Irish populations was investigated using anthropometric data collected during the 1890s on 259 adult males. These populations ranged in size from 769 to 3757, were relatively stable over time, and were located within 119 km of one another. Two populations are known to have experienced considerable English admixture. Data on ten anthropometric variables (three body measures and seven craniofacial measures) were adjusted for age and used to compute a relationship (R) matrix. The R matrix was converted into a distance measure and compared with a potential genetic drift distance measure, defined as (1/Ni + 1/Nj), where Ni and Nj are the effective population sizes of groups i and j (derivation of this formula is presented). Distances were rank-transformed, and the correlation between their pairwise elements was computed using matrix permutation methods to assess significance. Under the hypothesis that drift affects anthropometric variation, these correlations are expected to be positive. The correlation between anthropometric distance and potential genetic drift distance is 0.123, which is not significantly different from 0 (P = 0.368). When a multiple regression model is used to adjust for geographic distance and English admixture, the partial correlation (0.369) is significant (p = 0.021). As part of further analysis of the genetic structure of these populations, the same analyses were repeated using a distance matrix derived from surname frequencies. The correlation of surname distance and potential genetic drift distance is 0.164, which is not significant (p = 0.264). When the multiple regression model is applied, the correlation is 0.401, which is borderline significant (p = 0.055). These results show the influence of genetic drift, local migration, and admixture on Irish population structure.     

Correction of chromosomal point mutations in human cells with bifunctional oligonucleotides.

A sequence-specific genomic delivery system for the correction of chromosomal mutations was designed by incorporating two different binding domains into a single-stranded oligonucleotide. A repair domain (RD) contained the native sequence of the target region. A third strand-forming domain (TFD) was designed to form a triplex by Hoogsteen interactions. The design was based upon the premise that the RD will rapidly form a heteroduplex that is anchored synergistically by the TFD. Deoxyoligonucleotides were designed to form triplexes in the human adenosine deaminase (ADA) and p53 genes adjacent to known point mutations. Transfection of ADA-deficient human lymphocytes corrected the mutant sequence in 1-2% of cells. Neither the RD or TFD individually corrected the mutation. Transfection of p53 mutant human glioblastoma cells corrected the mutation and induced apoptosis in 7.5% of cells.     

Meadow Voles (Microtus pennsylvanicus, Arvicolidae) Over-mark and Adjacent-mark the Scent Marks of Same-sex Conspecifics

Scent over-marking occurs when an animal deposits its scent mark on top of the scent mark of a conspecific; adjacent-marking occurs when an animal deposits its scent mark next to the scent mark of a conspecific. Given that male rodents usually scent mark more than females and that animals spend more time investigating the odor of the top-scent donor of an over-mark, I tested the following three hypotheses. First, male meadow voles deposit more scent marks than female meadow voles. Second, male meadow voles will deposit more over-marks and adjacent-marks in response to the scent marks of a same-sex conspecific than females would. Third, meadow voles spend more time investigating the odor of the second vole placed in the arena than that of the first vole placed in the arena. To test these hypotheses, two age-matched, like-sex conspecifics (first vole and second vole) were placed successively into an arena in which they were allowed to freely explore and scent mark for 15 min. The first hypothesis was not supported. The first and second vole, independently of sex, deposited a similar number of scent marks. The second hypothesis was also not supported by the data: more conspecific scent marks were over-marked by the second female than by the second male. The third hypothesis was supported by the data. After investigating a scented arena, males and females spent more time investigating the odor of the second vole than that of the first vole. Sex differences in scent-marking behaviors of meadow voles are unlike those reported for other species of rodents.     

Homeoviscous adaptation, growth rate, and morphogenesis in bacteria.

Fluorescence polarization, P, of 1,6-diphenyl-1,3,5-hexatriene was studied in Escherichia coli B/r. Modification of nutritional conditions was not compensated by homeoviscous adaptation, demonstrated to exist for temperature variations. Cell diameter, which is known also to vary with nutrition but not with temperature, was found to be positively correlated with 1/P, and may therefore be regulated by membrane lipid order and fluidity.     

Collagen targeting using multivalent protein-functionalized dendrimers

Collagen is an attractive marker for tissue remodeling in a variety of common disease processes. Here we report the preparation of protein dendrimers as multivalent collagen targeting ligands by native chemical ligation of the collagen binding protein CNA35 to cysteine-functionalized dendritic divalent (AB₂) and tetravalent (AB₄) wedges. The binding of these multivalent protein constructs was studied on collagen-immobilized chip surfaces as well as to native collagen in rat intestinal tissues. To understand the importance of target density we also created collagen-mimicking surfaces by immobilizing synthetic collagen triple helical peptides at various densities on a chip surface. Multivalent display of a weak-binding variant (CNA35-Y175K) resulted in a large increase in collagen affinity, effectively restoring the collagen imaging capacities for the AB₄ system. In addition, dissociation of these multivalent CNA35 dendrimers from collagen surfaces was found to be strongly attenuated.