Biomedical subjects

Richard A Nichols

Publications and source records attributed to Richard A Nichols.

13 recordsLinked to original sources

PubMed2026

European ash pangenome reveals widespread structural variation and genetic basis of low ash dieback susceptibility.

European Ash (Fraxinus excelsior) is a keystone tree species, whose populations are being decimated by ash dieback disease (ADB) - better characterisation of genetic variants associated with low susceptibility to the disease is needed. Here, we develop a F. excelsior pangenome to more fully capture sequence variability within this species compared with a linear reference genome, using a geographically diverse set of fifty F. excelsior samples. We identify 362,965 structural variants (SVs), including 174 Mb of sequence absent from the linear reference genome (22% of the linear reference size), and identify 3,412 high-confidence dispensable genes (those present only in some individuals). We use the pangenome to analyse existing genomic data from over 1,200 individuals, revealing 220 single nucleotide polymorphisms (SNPs) showing consistent allele frequency shifts between healthy individuals and those highly damaged by ADB, across UK seed sources, explicitly demonstrating the existence of a shared genetic component to low ADB susceptibility.

Polymorphism, Single Nucleotide↗

PubMed2006

Natural selection for rash-forming genotypes of the varicella-zoster vaccine virus detected within immunized human hosts.

The Oka vaccine strain is a live attenuated virus that is routinely administered to children in the United States and Europe to prevent chickenpox. It is effective and safe but occasionally produces a rash. The vaccine virus has accumulated mutations during its attenuation, but the rashes are not explained by their reversion, unlike complications reported for other viral vaccines. Indeed, most of the novel mutations distinguishing the Oka vaccine from the more virulent parental virus have not actually become fixed. Because the parental alleles are still present, the vaccine is polymorphic at >30 loci and therefore contains a mixture of related viruses. The inoculation of >40 million patients has consequently created a highly replicated evolutionary experiment that we have used to assess the competitive ability of these different viral genotypes in a human host. Using virus recovered from rash vesicles, we show that two vaccine mutations, causing amino acid substitutions in the major transactivating protein IE62, are outcompeted by the ancestral alleles. Standard interpretations of varicella disease severity concentrate on the undeniably important effects of host genotype and immune status, yet our results allow us to demonstrate that the viral genotype is associated with virulence and to identify the key sites. We propose that these loci have pleiotropic effects on the immunogenic properties of the virus, rash formation, and its epidemiological spread, which mould the evolution of its virulence. These findings are of practical importance for reducing the incidence of vaccine-associated rash and promoting public acceptance of the vaccine.

Chickenpox Vaccine↗

PubMed2006

Dates from the molecular clock: how wrong can we be?

Large discrepancies have been found in dates of evolutionary events obtained using the molecular clock. Twofold differences have been reported between the dates estimated from molecular data and those from the fossil record; furthermore, different molecular methods can give dates that differ 20-fold. New software attempts to incorporate appropriate allowances for this uncertainty into the calculation of the accuracy of date estimates. Here, we propose that these innovations represent welcome progress towards obtaining reliable dates from the molecular clock, but warn that they are currently unproven, given that the causes and pattern of the discrepancies are the subject of ongoing research. This research implies that many previous studies, even some of those using recently developed methods, might have placed too much confidence in their date estimates, and their conclusions might need to be revised.

Animals↗

PubMed2006

Ribosomal DNA in the grasshopper Podisma pedestris: escape from concerted evolution.

Eukaryote nuclear ribosomal DNA (rDNA) typically exhibits strong concerted evolution: a pattern in which several hundred rDNA sequences within any one species show little or no genetic diversity, whereas the sequences of different species diverge. We report a markedly different pattern in the genome of the grasshopper Podisma pedestris. Single individuals contain several highly divergent ribosomal DNA groups. Analysis of the magnitude of divergence indicates that these groups have coexisted in the Podisma lineage for at least 11 million years. There are two putatively functional groups, each estimated to be at least 4 million years old, and several pseudogene groups, many of which are transcribed. Southern hybridization and real-time PCR experiments show that only one of the putatively functional types occurs at high copy number. However, this group is scarcely amplified under standard PCR conditions, which means that phylogenetic inference on the basis of standard PCR would be severely distorted. The analysis suggests that concerted evolution has been remarkably ineffective in P. pedestris. We propose that this outcome may be related to the species' exceptionally large genome and the associated low rate of deletion per base pair, which may allow pseudogenes to persist.

Animals↗

PubMed2006

Vaccine Oka varicella-zoster virus genotypes are monomorphic in single vesicles and polymorphic in respiratory tract secretions.

We previously found that, after immunization with vaccine Oka varicella-zoster virus, virus obtained from a single vesicle were monomorphic, and virus obtained from different individuals were heterogeneous. Here we show that virus obtained from the lungs of a patient were a mixture of vaccine Oka variants. We hypothesize that complications after immunization are unlikely to be caused by expansion of a single, biologically more virulent clone of virus that either pre-exists in the vaccine or develops after random mutation of different clones. We hypothesize that some clones are more trophic than others for skin.

Chickenpox↗

PubMed2006

A novel approach to characterise pathogen candidate genetic polymorphisms involved in clinical outcome.

Understanding the key factors influencing the clinical outcome of an infection is crucial for early diagnosis and optimised treatment. Despite widespread recognition of the importance of the genetics composition of pathogens, most efforts so far have focused on characterising disease and susceptibility genes in humans. Here, we propose a new flexible and powerful methodological framework to detect candidate genetic polymorphisms influencing clinical outcome from pathogen genomes. The rationale is to use well-supported clades in a phylogeny as statistical predictors for clinical outcomes rather than the individual polymorphisms themselves. This greatly increases the statistical power to detect candidate polymorphisms when analysing a large number of variable sites. In a second step, the candidate polymorphisms are recovered by characterising the polymorphisms that most strongly support the clades predicting the clinical outcome. The modelling approach further allows including host factors and testing for possible interactions between factors. We illustrate the approach by an application on a dataset of hepatitis B polymerase genes. The statistical model retains age at infection as well as six candidate polymorphisms as predictors for clinical outcome (acute, chronic and fulminant). The method is straightforward to apply and computationally effective. While the approach is focused on detecting candidate polymorphisms from pathogen genomes, the method might be more broadly applied for characterising the link between genotype and phenotype while statistically controlling for environmental factors.

Hepatitis B virus↗

PubMed2004

Molecular phylogeny and morphological change in the Psittacula parakeets.

We reconstruct a phylogeny of the African and Asian Psittacula parakeets using approximately 800bp of mitochondrial cytochrome b sequence to examine their evolutionary relationships in reference to their head plumage and major morphological tail innovations. Our phylogeny identifies three groups, whose distinctiveness is also apparent from their possession of three different head plumage characters: a neck ring, a distinctive colouration of the head, and a 'moustache'-shaped pattern that extends from the chin to the cheek. We examine the extent of sexual dimorphism in tail length across the phylogeny and reveal large differences between closely related forms. We apply a range of published avian cytochrome b substitution rates to our data, as an alternative to internal calibration of a molecular clock arising from incomplete paleontological information. An ancestral Psittacula form appears to have evolved during the late Miocene-early Pliocene (3.4-9.7MYA), a time when regional geological processes on the Asian continent may have promoted subsequent diversity at the species level, and many forms diverged relatively early on in the evolutionary history of Psittacula (between 2.5 and 7.7MYA). However, others, such as the derbyan and moustached parakeets, diverged as recently as 0.2MYA. Our phylogeny also suggests that the echo parakeet from Mauritius diverged from the Indian ringneck parakeet as opposed to the African ringneck, and may have done so relatively recently. The molecular results indicate support for a southwards radiation from India across the Indian Ocean to Mauritius, where the arrival-date of the echo parakeet appears consistent with the island's volcanic formation.

Africa↗

PubMed2003

Application of DNA microarrays to study the evolutionary genomics of Yersinia pestis and Yersinia pseudotuberculosis.

Yersinia pestis, the causative agent of plague, diverged from Yersinia pseudotuberculosis, an enteric pathogen, an estimated 1500-20,000 years ago. Genetic characterization of these closely related organisms represents a useful model to study the rapid emergence of bacterial pathogens that threaten mankind. To this end, we undertook genome-wide DNA microarray analysis of 22 strains of Y. pestis and 10 strains of Y. pseudotuberculosis of diverse origin. Eleven Y. pestis DNA loci were deemed absent or highly divergent in all strains of Y. pseudotuberculosis. Four were regions of phage origin, whereas the other seven included genes encoding a vitamin B12 receptor and the insect toxin sepC. Sixteen differences were identified between Y. pestis strains, with biovar Antiqua and Mediaevalis strains showing most divergence from the arrayed CO92 Orientalis strain. Fifty-eight Y. pestis regions were specific to a limited number of Y. pseudotuberculosis strains, including the high pathogenicity island, three putative autotransporters, and several possible insecticidal toxins and hemolysins. The O-antigen gene cluster and one of two possible flagellar operons had high levels of divergence between Y. pseudotuberculosis strains. This study reports chromosomal differences between species, biovars, serotypes, and strains of Y. pestis and Y. pseudotuberculosis that may relate to the evolution of these species in their respective niches.

Adaptation, Physiological↗

PubMed2002

Y genetic data support the Neolithic demic diffusion model.

There still is no general agreement on the origins of the European gene pool, even though Europe has been more thoroughly investigated than any other continent. In particular, there is continuing controversy about the relative contributions of European Palaeolithic hunter-gatherers and of migrant Near Eastern Neolithic farmers, who brought agriculture to Europe. Here, we apply a statistical framework that we have developed to obtain direct estimates of the contribution of these two groups at the time they met. We analyze a large dataset of 22 binary markers from the non-recombining region of the Y chromosome (NRY), by using a genealogical likelihood-based approach. The results reveal a significantly larger genetic contribution from Neolithic farmers than did previous indirect approaches based on the distribution of haplotypes selected by using post hoc criteria. We detect a significant decrease in admixture across the entire range between the Near East and Western Europe. We also argue that local hunter-gatherers contributed less than 30% in the original settlements. This finding leads us to reject a predominantly cultural transmission of agriculture. Instead, we argue that the demic diffusion model introduced by Ammerman and Cavalli-Sforza [Ammerman, A. J. & Cavalli-Sforza, L. L. (1984) The Neolithic Transition and the Genetics of Populations in Europe (Princeton Univ. Press, Princeton)] captures the major features of this dramatic episode in European prehistory.

Animals↗

PubMed2002

Patterns of colonization in a metapopulation of grey seals.

The colonization of a new habitat is a fundamental process in metapopulation biology, but it is difficult to study. The emigration of colonists from established populations might be induced by resource competition owing to high local population density. Migration distances are also important because they determine the frequency and scale of recolonization and hence the spatial scale of the metapopulation. Traditionally, these factors have been investigated with demographic approaches that are labour-intensive and are only possible in amenable species. In many cases, genetic differentiation is minimal, preventing traditional genetic approaches from identifying the source of colonists unambiguously. Here we present a bayesian approach that integrates genetic, demographic and geographic distance data. We apply the method to study the British metapopulation of grey seals, which has been growing at 6% per year over the last few decades. Our method reveals differential recruitment to three newly founded colonies and implicates density-dependent dispersal in metapopulation dynamics by using genetic data.

Animals↗

PubMed2002

A molecular phylogeny of African kestrels with reference to divergence across the Indian Ocean.

In this paper we examine the evolutionary relationships of kestrels from mainland Africa, Indian Ocean islands and related areas. We construct a molecular phylogeny of African kestrels, using approximately 1.0 kb of mitochondrial cytochrome b sequence. Our molecular results support an Old World origin for typical kestrels and an ancient divergence of kestrels into the New World, and indicate a more recent radiation of kestrels from Africa via Madagascar towards Mauritius and the Seychelles. Phylogenetic placement of the Australian kestrel suggests a recent origin from African kestrel stock. We compare evolutionary relationships based on kestrel plumage pattern and morphology to our molecular results for the African and Indian Ocean kestrels, and reveal some consistency with the different island forms. We apply a range of published avian cytochrome b substitution rates to our data, as an alternative to internal calibration of a molecular clock arising from incomplete paleontological information. We align these divergence estimates to the geological history of Indian Ocean island formation inferred from potassium-argon dating methods. The arrival of kestrels on Mauritius appears consistent with the cessation of volcanic activity on Mauritius. The estimated time and route of divergence of the Seychelles kestrel from Madagascar may be compatible with the emergence of smaller islands during Pleistocene sea level fluctuations.

Animals↗

PubMed2002

Using nested clade analysis to assess the history of colonization and the persistence of populations of an Iberian Lizard.

The distribution of the lizard Lacerta schreiberi is likely to have been severely affected by the climatic cycles that have influenced the Iberian Peninsula. Information about the species ecology and Iberian physiogeography was used to generate specific hypotheses about episodes of colonization and subsequent population persistence. These hypotheses generated predictions about the distribution of genetic variation, which were tested using nested clade analysis (NCA) supplemented by analysis of molecular variance (amova). Two predictions were confirmed by NCA; that is those that specified multiple and allopatric refugia. However, the remaining three predictions were not corroborated by the analyses. Firstly, a simple analysis of the distribution of genetic variability failed to detect an expected difference in the pattern of colonization between the inland mountain system and the coastal region. Moreover, while NCA did detect the expected genetic pattern in southern coastal populations, it was explained in terms of long-distance migration, which seems implausible because of the extent of unsuitable habitat. A more likely cause of the pattern is population fragmentation and a reduction in population size caused during the Holocene. Finally, NCA also failed to detect a northwestern population expansion, which is supported by other evidence. We conclude that NCA has a limited ability to detect range expansion led by individuals with more ancestral (interior) haplotypes.

Animals↗

PubMed2002

Primary care family physicians and 2 hospitalist models: comparison of outcomes, processes, and costs.

OBJECTIVES: To compare the care provided by family practice primary care physicians with that provided by 2 hospitalist models: critical care hospitalists and rotating residency faculty family physician hospitalists. STUDY DESIGN: Retrospective chart review. A health maintenance organization mandated that all patients be admitted to a critical care hospitalist team. The family physician hospitalists admitted all other residency patients and patients of some community family physicians. The primary care physicians admitted all their other patients. We adjusted for disease severity by using the Pneumonia Severity Index, age, sex, and comorbidities. POPULATION: Adults admitted with pneumonia to our private urban community hospital. Exclusions included patients with nosocomial pneumonia, human immunodeficiency virus, and acquired immunodeficiency syndrome. OUTCOMES MEASURED: Primary (adjusted for age, sex, comorbidities, and disease severity): hospital charges, length of stay, in-hospital mortality, readmissions, and returns to the emergency room. Secondary: chest radiographs, intensive care use, blood and sputum cultures, compliance with American Thoracic Society guidelines, lifestyle and end-of-life counseling. RESULTS: Of 97 patients, 21 were admitted to the critical care hospitalists, 53 to the family physician hospitalists, and 23 to primary care physicians. The mean charge ($5680) by the primary care physicians was significantly lower than that of the critical care hospitalists ($10,231; P=.005) and trended toward being lower than that of the family physician hospitalists ($7699; P=.08). The patients of critical care and family physician hospitalists had longer mean lengths of stay (critical care hospitalists, 3.8 days; family physician hospitalists, 3.9 days) than did those of the primary care physicians (2.6 days; P=.04 and.01, respectively). Compared with the primary care physicians, the critical care hospitalists were more likely to obtain at least 2 chest x-rays (odds ratio, 4.1; 95% confidence interval, 1.1-15.5) and trended toward increased odds of lengthy stay in the intensive care unit (odd ratio, 2.9; 95% confidence interval, 0.6-14.6). We found no other significant differences in primary or secondary outcomes. CONCLUSIONS: Claims of better and cheaper care by hospitalists need further investigation. Meanwhile, the use of hospitalists should not be mandated, and the use of family physicians as hospitalists should be considered a good alternative to the use of subspecialists.

Aged↗