Biomedical subjects

Scott Williamson

Publications and source records attributed to Scott Williamson.

11 recordsLinked to original sources

PubMed2006

Biomechanical evaluation of the less invasive stabilization system and the 95-degree angled blade plate for the internal fixation of distal femur Fractures in human cadaveric bones with high bone mineral density.

BACKGROUND: The less invasive stabilization system (LISS) is an internal fixator that utilizes unicortical locked screws for fixation of distal femur fractures. A question is whether locked unicortical screw fixation is sufficient, when compared with a standard implant such as a blade plate. METHODS: Eight matched pairs of fresh-frozen cadaveric femora were instrumented with either the LISS or a 95-degree blade plate. A 4-cm supracondylar gap fracture model was created and all bone-implant constructs were tested to failure in axial loading. RESULTS: All constructs failed by plastic deformation of the implant. There was no significant difference between the LISS and the blade plate constructs with respect to load to failure. CONCLUSIONS: Despite unicortical fixation axial loading to failure of the LISS did not result in implant/screw pull-out neither proximally nor distally. However, there does not appear to be a biomechanical advantage of using the LISS as opposed to a blade plate in bones with high bone mineral density.

Biomechanical Phenomena↗

PubMed2005

Natural selection on protein-coding genes in the human genome.

Comparisons of DNA polymorphism within species to divergence between species enables the discovery of molecular adaptation in evolutionarily constrained genes as well as the differentiation of weak from strong purifying selection. The extent to which weak negative and positive darwinian selection have driven the molecular evolution of different species varies greatly, with some species, such as Drosophila melanogaster, showing strong evidence of pervasive positive selection, and others, such as the selfing weed Arabidopsis thaliana, showing an excess of deleterious variation within local populations. Here we contrast patterns of coding sequence polymorphism identified by direct sequencing of 39 humans for over 11,000 genes to divergence between humans and chimpanzees, and find strong evidence that natural selection has shaped the recent molecular evolution of our species. Our analysis discovered 304 (9.0%) out of 3,377 potentially informative loci showing evidence of rapid amino acid evolution. Furthermore, 813 (13.5%) out of 6,033 potentially informative loci show a paucity of amino acid differences between humans and chimpanzees, indicating weak negative selection and/or balancing selection operating on mutations at these loci. We find that the distribution of negatively and positively selected genes varies greatly among biological processes and molecular functions, and that some classes, such as transcription factors, show an excess of rapidly evolving genes, whereas others, such as cytoskeletal proteins, show an excess of genes with extensive amino acid polymorphism within humans and yet little amino acid divergence between humans and chimpanzees.

Amino Acid Substitution↗

PubMed2005

Molecular evidence for an activator-inhibitor mechanism in development of embryonic feather branching.

The developmental basis of morphological complexity remains a central question in developmental and evolutionary biology. Feathers provide a unique system to analyze the development of complex morphological novelties. Here, we describe the interactions between Sonic hedgehog (Shh) and bone morphogenetic protein 2 (Bmp2) signaling during feather barb ridge morphogenesis. We demonstrate that activator-inhibitor models of Shh and Bmp2 signaling in the tubular feather epithelium are sufficient to explain the initial formation of a meristic pattern of barb ridges and the observed variation in barb morphogenesis in chick natal down feathers. Empirical tests support the assumptions of the model that, within the feather ectoderm, Shh (activator) up-regulates its own transcription and that of Bmp2 (inhibitor), whereas Bmp2 signaling down-regulates Shh expression. More complex models incorporating a second activator and dorsal/ventral polarized modification of activator signaling can produce all of the barb morphogenesis patterns observed during the growth of more complex branched pennaceous feathers: new barb ridge formation, helical growth, and barb ridge fusion. An integrated model of feather morphogenesis and evolution suggests that plumulaceous feather structure evolved by the establishment of activator-inhibitor interactions between Shh and Bmp2 signaling in the basal epithelium of the feather germ. Subsequently, pennaceous feather structure evolved through the integration of barb ridge morphogenesis with a second, local inhibitor and a dorsal/ventral signal gradient within the feather. The model is congruent with paleontological evidence that plumulaceous feathers are primitive to pennaceous feathers.

Animals↗

PubMed2005

Genomic scans for selective sweeps using SNP data.

Detecting selective sweeps from genomic SNP data is complicated by the intricate ascertainment schemes used to discover SNPs, and by the confounding influence of the underlying complex demographics and varying mutation and recombination rates. Current methods for detecting selective sweeps have little or no robustness to the demographic assumptions and varying recombination rates, and provide no method for correcting for ascertainment biases. Here, we present several new tests aimed at detecting selective sweeps from genomic SNP data. Using extensive simulations, we show that a new parametric test, based on composite likelihood, has a high power to detect selective sweeps and is surprisingly robust to assumptions regarding recombination rates and demography (i.e., has low Type I error). Our new test also provides estimates of the location of the selective sweep(s) and the magnitude of the selection coefficient. To illustrate the method, we apply our approach to data from the Seattle SNP project and to Chromosome 2 data from the HapMap project. In Chromosome 2, the most extreme signal is found in the lactase gene, which previously has been shown to be undergoing positive selection. Evidence for selective sweeps is also found in many other regions, including genes known to be associated with disease risk such as DPP10 and COL4A3.

Black or African American↗

PubMed2004

A statistical characterization of consistent patterns of human immunodeficiency virus evolution within infected patients.

Within-patient HIV populations evolve rapidly because of a high mutation rate, short generation time, and strong positive selection pressures. Previous studies have identified "consistent patterns" of viral sequence evolution. Just before HIV infection progresses to AIDS, evolution seems to slow markedly, and the genetic diversity of the viral population drops. This evolutionary slowdown could be caused either by a reduction in the average viral replication rate or because selection pressures weaken with the collapse of the immune system. The former hypothesis (which we denote "cellular exhaustion") predicts a simultaneous reduction in both synonymous and nonsynonymous evolution, whereas the latter hypothesis (denoted "immune relaxation") predicts that only nonsynonymous evolution will slow. In this paper, we present a set of statistical procedures for distinguishing between these alternative hypotheses using DNA sequences sampled over the course of infection. The first component is a new method for estimating evolutionary rates that takes advantage of the temporal information in longitudinal DNA sequence samples. Second, we develop a set of probability models for the analysis of evolutionary rates in HIV populations in vivo. Application of these models to both synonymous and nonsynonymous evolution affords a comparison of the cellular-exhaustion and immune-relaxation hypotheses. We apply the procedures to longitudinal data sets in which sequences of the env gene were sampled over the entire course of infection. Our analyses (1) statistically confirm that an evolutionary slowdown occurs late in infection, (2) strongly support the immune-relaxation hypothesis, and (3) indicate that the cessation of nonsynonymous evolution is associated with disease progression.

Acquired Immunodeficiency Syndrome↗

PubMed2004

Biomechanical evaluation of the less invasive stabilization system, angled blade plate, and retrograde intramedullary nail for the internal fixation of distal femur fractures.

OBJECTIVE: To evaluate the stability of the retrograde intramedullary nail (IMN), angled blade plate (ABP), and a locked internal fixator (Less Invasive Stabilization System [LISS], Synthes, Paoli, PA) for internal fixation of distal femur fractures. DESIGN: Destructive biomechanical testing of matched pairs of fresh-frozen human cadaveric bone-implant constructs. SETTING: Biomechanical laboratory. METHODS: A fracture model was created to simulate an AO/OTA33-A3 fracture. Forty-eight matched pairs of specimens were used. Six groups of 8 pairs each were tested to failure: LISS versus ABP and LISS versus IMN (axial, torsional, and cyclical axial). MAIN OUTCOME MEASUREMENT: Load to failure, mode of failure, energy to failure, displacement at the load to failure, and stiffness. RESULTS: Fixation strength (load/moment to failure) of the LISS constructs was 34% greater in axial loading (P = 0.01) and 32% less in torsional loading (P = 0.05) compared with ABP constructs and 13% greater in axial loading (P = 0.35) and 45% less in torsional loading (P < 0.01) compared with IMN constructs. Loss of distal fixation in axial loading occurred in 1 of 16 cases with the LISS, in 3 of 8 cases with the ABP, and in 8 of 8 cases with the IMN. Cyclical axial loading demonstrated significantly less plastic deformation for the LISS construct compared with ABP constructs (P < 0.01) and similar plastic deformation compared with IMN constructs (P = 0.98). CONCLUSIONS: All 3 fixation devices (LISS, ABP, and IMN) offer sufficient torsional stability and sufficient proximal fixation that withstands axial loading without failing. The LISS provides improved distal fixation, especially in osteoporotic bone, at the expense of more displacement at the fracture site.

Aged↗

PubMed2004

Population genetics of polymorphism and divergence for diploid selection models with arbitrary dominance.

We develop a Poisson random-field model of polymorphism and divergence that allows arbitrary dominance relations in a diploid context. This model provides a maximum-likelihood framework for estimating both selection and dominance parameters of new mutations using information on the frequency spectrum of sequence polymorphisms. This is the first DNA sequence-based estimator of the dominance parameter. Our model also leads to a likelihood-ratio test for distinguishing nongenic from genic selection; simulations indicate that this test is quite powerful when a large number of segregating sites are available. We also use simulations to explore the bias in selection parameter estimates caused by unacknowledged dominance relations. When inference is based on the frequency spectrum of polymorphisms, genic selection estimates of the selection parameter can be very strongly biased even for minor deviations from the genic selection model. Surprisingly, however, when inference is based on polymorphism and divergence (McDonald-Kreitman) data, genic selection estimates of the selection parameter are nearly unbiased, even for completely dominant or recessive mutations. Further, we find that weak overdominant selection can increase, rather than decrease, the substitution rate relative to levels of polymorphism. This nonintuitive result has major implications for the interpretation of several popular tests of neutrality.

Computer Simulation↗

PubMed2003

Linking dynamical and population genetic models of persistent viral infection.

This article develops a theoretical framework to link dynamical and population genetic models of persistent viral infection. This linkage is useful because, while the dynamical and population genetic theories have developed independently, the biological processes they describe are completely interrelated. Parameters of the dynamical models are important determinants of evolutionary processes such as natural selection and genetic drift. We develop analytical methods, based on coupled differential equations and Markov chain theory, to predict the accumulation of genetic diversity within the viral population as a function of dynamical parameters. These methods are first applied to the standard model of viral dynamics and then generalized to consider the infection of multiple host cell types by the viral population. Each cell type is characterized by specific parameter values. Inclusion of multiple cell types increases the likelihood of persistent infection and can increase the amount of genetic diversity within the viral population. However, the overall rate of gene sequence evolution may actually be reduced.

Biological Evolution↗

PubMed2003

Adaptation in the env gene of HIV-1 and evolutionary theories of disease progression.

The exact mechanisms by which HIV overwhelms the immune system remain poorly understood. Among the several explanations of HIV disease progression, most include adaptation of the viral genome to the host environment as a causal factor. Therefore, quantifying the rate and pattern of adaptive evolution within infected patients is critical to understanding the development of AIDS. Using sequence data from infected individuals sampled at multiple time points, I estimate the within-host adaptation rate of the HIV-1 env gene for viral populations from 50 different patients. I find that, averaging across patients, one adaptive substitution occurs every 3.3 months. Also, one adaptive mutation is driven to a high frequency (>50% but <100%) every 2.5 months. Taken together, such adaptive events occur once every 25 viral generations, which is the fastest adaptation rate ever recorded for a single protein-coding gene. Within the entire env gene, I estimate that a majority ( approximately 55%) of both nonsynonymous substitutions and high-frequency polymorphisms are adaptive. Further, in the C2-V5 region of env, I find that patients with longer asymptomatic periods have virus populations with higher adaptation rates, corroborating the notion that a broad, strong immune response against epitopes in the env gene product leads to longer asymptomatic periods. I conclude by discussing the distribution of nonsynonymous changes over the env gene.

Adult↗

PubMed2002

Reaction-diffusion models of within-feather pigmentation patterning.

Feathers are complex, branched keratin structures that exhibit a diversity of pigmentation patterns. Feather pigments are transferred into developing feather keratinocytes from pigment cells that migrate into the tubular feather germ from the dermis. Within-feather pigment patterns are determined by differential pigmentation of keratinocytes within independent barb ridges during feather development. Little is known about the molecular mechanisms that determine which keratinocytes receive pigment. We apply reaction-diffusion models to the growth of within-feather pigment patterns based on a realistic model of feather growth. These models accurately simulate the growth of a diversity of the within-feather pigmentation patterns found in real feathers, including a central patch, a 'hollow' central patch, concentric central patches, bars, chevrons, a central circular spot, rows of paired spots, and arrays of offset dots. The models can also simulate the complex transitions between distinct pigmentation patterns among feathers observed in real avian plumages, including transitions from bars to chevrons, bars to paired dots, and bars to arrays of dots. The congruence between the developmental dynamics of the simulated and observed feather patterns indicates that the reaction-diffusion models provide a realistic and accurate description of the determination of pigment pattern within avian feather follicles. The models support the hypothesis that within-feather pigmentation patterning is determined by antagonistic interactions among molecular expression gradients within the tubular follicle and feather germ.

Animals↗

PubMed2002

The genealogy of a sequence subject to purifying selection at multiple sites.

We investigate the effect of purifying selection at multiple sites on both the shape of the genealogy and the distribution of mutations on the tree. We find that the primary effect of purifying selection on a genealogy is to shift the distribution of mutations on the tree, whereas the shape of the tree remains largely unchanged. This result is relevant to the large number of coalescent estimation procedures, which generally assume neutrality for segregating polymorphisms--applying these estimators to evolutionarily constrained sequences could lead to a significant degree of bias. We also estimate the statistical power of several neutrality tests in detecting weak to moderate purifying selection and find that the power is quite good for some parameter combinations. This result contrasts with previous studies, which predicted low statistical power because of the minor effect that weak purifying selection has on the shape of a genealogy. Finally, we investigate the effect of Hill-Robertson interference among linked deleterious mutations on patterns of molecular variation. We find that dependence among selected loci can substantially reduce the efficacy of even fairly strong purifying selection.

Evolution, Molecular↗