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Simon Myers

Publications and source records attributed to Simon Myers.

10 recordsLinked to original sources
PubMed2006

A model-based approach to capture genetic variation for future association studies.

Genome-wide association studies are still constrained by the cost of genotyping. For this reason, the selection of a reduced set of markers or tags able to capture a significant proportion of the genetic variation is an important aspect of these studies. Most tagging SNP selection methods have been successful in capturing the genetic variation of the data from which the tags have been chosen. However, when these tags are used in an independent data set, a significant proportion of the remaining SNPs (non-tags) are not captured and, in most cases, there is no information on which SNPs are captured. We propose to use a probabilistic model to predict the non-tags based on a set of tags, as a way to capture genetic variation. An important advantage of this method is that it directly predicts the genotype of the non-tags with which we can test for association with the phenotype and which could help to elucidate the location of genes responsible for increasing disease susceptibility. Additionally, this method provides an estimate of the probabilities with which the predictions are made, which reflects the confidence of the probabilistic model. We also propose new methods to select the tagging SNPs. We empirically show by using HapMap data that our approach is able to capture significantly more genetic variation than methods based solely on a pairwise LD measure.

Algorithms↗
PubMed2006

The influence of recombination on human genetic diversity.

In humans, the rate of recombination, as measured on the megabase scale, is positively associated with the level of genetic variation, as measured at the genic scale. Despite considerable debate, it is not clear whether these factors are causally linked or, if they are, whether this is driven by the repeated action of adaptive evolution or molecular processes such as double-strand break formation and mismatch repair. We introduce three innovations to the analysis of recombination and diversity: fine-scale genetic maps estimated from genotype experiments that identify recombination hotspots at the kilobase scale, analysis of an entire human chromosome, and the use of wavelet techniques to identify correlations acting at different scales. We show that recombination influences genetic diversity only at the level of recombination hotspots. Hotspots are also associated with local increases in GC content and the relative frequency of GC-increasing mutations but have no effect on substitution rates. Broad-scale association between recombination and diversity is explained through covariance of both factors with base composition. To our knowledge, these results are the first evidence of a direct and local influence of recombination hotspots on genetic variation and the fate of individual mutations. However, that hotspots have no influence on substitution rates suggests that they are too ephemeral on an evolutionary time scale to have a strong influence on broader scale patterns of base composition and long-term molecular evolution.

Animals↗
PubMed2006

Intermediate forms of Charcot-Marie-Tooth neuropathy: a review.

The Charcot-Marie-Tooth (CMT) neuropathies divide into two main electrophysiological groups with slow and near normal conduction velocities corresponding to Schwann cell and axonal pathology. An intermediate group also exists with nerve conduction velocities, which overlaps the two main groups. Families with intermediate CMT can be recognized in which different affected individuals in the same family have motor conduction velocities in both the CMT type 1 and 2 ranges (i.e., above and below 38 m/s). The intermediate group is caused by a limited number of distinct gene mutations in dynamin2 (DNM2), gap-junction protein 1 (GJB1), neurofilament light polypeptide (NF-L) genes, and a rare mutation and as yet unknown genes on chromosome 1 and 10 loci. Intermediate forms of CMT may be associated with unique disease mechanisms affecting both Schwann cells and axons. It is useful to recognize this unique group of neuropathies for diagnostic and management purposes.

Charcot-Marie-Tooth Disease↗
PubMed2005

A fine-scale map of recombination rates and hotspots across the human genome.

Genetic maps, which document the way in which recombination rates vary over a genome, are an essential tool for many genetic analyses. We present a high-resolution genetic map of the human genome, based on statistical analyses of genetic variation data, and identify more than 25,000 recombination hotspots, together with motifs and sequence contexts that play a role in hotspot activity. Differences between the behavior of recombination rates over large (megabase) and small (kilobase) scales lead us to suggest a two-stage model for recombination in which hotspots are stochastic features, within a framework in which large-scale rates are constrained.

Animals↗
PubMed2005

Human recombination hot spots hidden in regions of strong marker association.

The fine-scale distribution of meiotic recombination events in the human genome can be inferred from patterns of haplotype diversity in human populations but directly studied only by high-resolution sperm typing. Both approaches indicate that crossovers are heavily clustered into narrow recombination hot spots. But our direct understanding of hot-spot properties and distributions is largely limited to sperm typing in the major histocompatibility complex (MHC). We now describe the analysis of an unremarkable 206-kb region on human chromosome 1, which identified localized regions of linkage disequilibrium breakdown that mark the locations of sperm crossover hot spots. The distribution, intensity and morphology of these hot spots are markedly similar to those in the MHC. But we also accidentally detected additional hot spots in regions of strong association. Coalescent analysis of genotype data detected most of the hot spots but showed significant differences between sperm crossover frequencies and historical recombination rates. This raises the possibility that some hot spots, particularly those in regions of strong association, may have evolved very recently and not left their full imprint on haplotype diversity. These results suggest that hot spots could be very abundant and possibly fluid features of the human genome.

Chromosomes, Human, Pair 1↗
PubMed2005

The role of hyaluronic acid in wound healing: assessment of clinical evidence.

Hyaluronic acid (hyaluronan), a naturally occurring polymer within the skin, has been extensively studied since its discovery in 1934. It has been used in a wide range of medical fields as diverse as orthopedics and cosmetic surgery, but it is in tissue engineering that it has been primarily advanced for treatment. The breakdown products of this large macromolecule have a range of properties that lend it specifically to this setting and also to the field of wound healing. It is non-antigenic and may be manufactured in a number of forms, ranging from gels to sheets of solid material through to lightly woven meshes. Epidermal engraftment is superior to most of the available biotechnologies and, as such, the material shows great promise in both animal and clinical studies of tissue engineering. Ongoing work centers around the ability of the molecule to enhance angiogenesis and the conversion of chronic wounds into acute wounds.

Adjuvants, Immunologic↗
PubMed2004

Estimation of breast burn size.

It is the authors' opinion that the size of chest burns on large-breasted women can be significantly underestimated, especially if the methods of calculation rely on burn charts, such as the Lund and Browder burns chart. This latter chart is based on data derived from only three women and eight men. The surface area of the torsos of 60 volunteers (20 men, 20 small-breasted women, and 20 large-breasted women) was measured using two well-established techniques. The torso surface area was divided into two parts: the anterior trunk and the posterior trunk (i.e., torso surface area = posterior trunk + anterior trunk). The anterior trunk was subdivided and the area above the costal margins defined as the pectoral region. These areas were measured separately for each individual. The volunteers' total body surface area was calculated using normograms, based on their weight and height. The area of each torso section was recorded as a percentage of the total body surface area and torso surface area. Whereas the torso surface area/total body surface area ratio did not vary significantly between the groups, the proportion of anterior to posterior trunk size did depend on the sex and on breast size. There was a direct correlation between the woman's bra cup size and the ratio of anterior-to-posterior trunk surface area. A simple chart was therefore derived that estimates the relative size of a woman's torso surface area once her bra cup size is known. Such a chart can be used to improve accuracy in adult female chest burn estimation, when used in conjunction with a burns chart. Breast burns in larger breasted women are underestimated when calculated using current burn charts. We recommend that a correction be made when estimating chest burns in women to account for the increased surface area of the breasts. A chart, such as the one we have developed, could be used in conjunction with a burn chart (e.g., Lund and Browder) to make this correction.

Adult↗
PubMed2004

Application of coalescent methods to reveal fine-scale rate variation and recombination hotspots.

There has been considerable recent interest in understanding the way in which recombination rates vary over small physical distances, and the extent of recombination hotspots, in various genomes. Here we adapt, apply, and assess the power of recently developed coalescent-based approaches to estimating recombination rates from sequence polymorphism data. We apply full-likelihood estimation to study rate variation in and around a well-characterized recombination hotspot in humans, in the beta-globin gene cluster, and show that it provides similar estimates, consistent with those from sperm studies, from two populations deliberately chosen to have different demographic and selectional histories. We also demonstrate how approximate-likelihood methods can be used to detect local recombination hotspots from genomic-scale SNP data. In a simulation study based on 80 100-kb regions, these methods detect 43 out of 60 hotspots (ranging from 1 to 2 kb in size), with only two false positives out of 2000 subregions that were tested for the presence of a hotspot. Our study suggests that new computational tools for sophisticated analysis of population diversity data are valuable for hotspot detection and fine-scale mapping of local recombination rates.

DNA↗