Biomedical subjects

Simon Tavaré

Publications and source records attributed to Simon Tavaré.

22 records · Page 2Linked to original sources

PubMed2004

Colorectal pretumor progression before and after loss of DNA mismatch repair.

A pretumor progression model predicts many oncogenic cancer mutations may first accumulate in normal appearing colon. Although direct observations of early pretumor mutations are impractical, it may be possible to retrospectively reconstruct tumor histories from contemporary cancer mutations. To infer when and in what order mutations occur during occult pretumor progression, we examined 14 cancers from individuals with heterozygous germline mutations in DNA mismatch repair (MMR) genes or hereditary nonpolyposis colorectal cancer (HNPCC). Somatic inactivation of the normal allele occurs sometime during a lifetime and results in loss of MMR, elevated mutation rates, and subsequent widespread somatic microsatellite mutations in HNPCC cancers. Patient ages at MMR loss can be estimated because intervals between MMR loss and cancer removal can be inferred from numbers of microsatellite tumor mutations. The relative order of MMR loss during pretumor progression may also be inferred from its collective ages of occurrence. Somatic MMR loss preceded cancer removal by an average of 6.1 years, occurred relatively late in life (average of 41.6 versus 47.7 years at cancer removal), and was a surprisingly late (fifth or sixth) step. Calculations indicate five or six oncogenic mutations could accumulate with relatively normal replication fidelity in normal appearing colon. HNPCC pretumor progression essentially begins from birth and ends with MMR loss, implying elevated mutation rates and tumorigenesis may be unnecessary for most progression.

Adaptor Proteins, Signal Transducing↗

PubMed2004

Population-based genetic and evolutionary analysis of Chlamydia trachomatis urogenital strain variation in the United States.

Chlamydia trachomatis is a major cause of ocular and sexually transmitted diseases worldwide. While much of our knowledge about its genetic diversity comes from serotyping or ompA genotyping, no quantitative assessment of genetic diversity within serotypes has been performed. To accomplish this, 507 urogenital samples from a multicenter U.S. study were analyzed by phylogenetic and statistical modeling. No B, Da, or I serotypes were represented. Based on our analyses, all but one previous urogenital B serotype was identified as Ba. This, coupled with the lack of B serotypes in our population, suggests that B has specific tropism for ocular mucosa. We identified a Ba/D recombinant (putative crossover nucleotide 477; P < 0.0001) similar to a B/D mosaic we described previously from an African trachoma patient. Computational analyses of the Ba/D recombinant indicated that upstream changes were less important for tissue tropism than downstream incorporation of the D sequence. Since most serotypes had nonsynonymous/synonymous ratios of <1.0, the major outer membrane protein, encoded by ompA, has many functional constraints and is under purifying selection. Surprisingly, all serotype groups except for J had a unimodal population structure indicating rapid clonal expansion. Of the groups with a unimodal structure, E and Ia and, to a lesser extent, G and K were prevalent, had infrequent incorporation of mutations, and, compared to other groups, had a relatively greater degree of diversifying selection, consistent with a selective sweep of mutations within these groups. Collectively, these data suggest a diverse evolutionary strategy for different serogroups of the organism.

Adolescent↗

PubMed2002

Using the fossil record to estimate the age of the last common ancestor of extant primates.

Divergence times estimated from molecular data often considerably predate the earliest known fossil representatives of the groups studied. For the order Primates, molecular data calibrated with various external fossil dates uniformly suggest a mid-Cretaceous divergence from other placental mammals, some 90 million years (Myr) ago, whereas the oldest known fossil primates are from the basal Eocene epoch (54-55 Myr ago). The common ancestor of primates should be earlier than the oldest known fossils, but adequate quantification is needed to interpret possible discrepancies between molecular and palaeontological estimates. Here we present a new statistical method, based on an estimate of species preservation derived from a model of the diversification pattern, that suggests a Cretaceous last common ancestor of primates, approximately 81.5 Myr ago, close to the initial divergence time inferred from molecular data. It also suggests that no more than 7% of all primate species that have ever existed are known from fossils. The approach unites all the available palaeontological methods of timing evolutionary events: the fossil record, extant species and clade diversification models.

Animals↗

PubMed2002

Linkage disequilibrium: what history has to tell us.

Linkage disequilibrium has become important in the context of gene mapping. We argue that to understand the pattern of association between alleles at different loci, and of DNA sequence polymorphism in general, it is useful first to consider the underlying genealogy of the chromosomes. The stochastic process known as the coalescent is a convenient way to model such genealogies, and in this paper we set out the theory behind the coalescent and its implications for understanding linkage disequilibrium.

Genetic Variation↗