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Biomedical subjects

Michael Lynch

Publications and source records attributed to Michael Lynch.

At least 19 recordsLinked to original sources
PubMed2026

Biocontrol potential and molecular basis of predation in a marine raptorial ciliate.

Predator-prey interactions are widespread across organisms and are key drivers of morphological and behavioral evolution. Despite this, predation remains poorly understood among microbial eukaryotes, mostly due to the absence of a tractable experimental system that allows quantitative, reproducible investigation. This study establishes the marine raptorial ciliate Chaenea vorax as a highly efficient predator, with Rosenzweig-MacArthur model simulations based on predation data showing that only a few dozen individuals can eliminate the vast majority of the facultatively pathogenic ciliate Uronema marinum within 1-2 days, providing a quantitative basis for developing predator-based biocontrol strategies in aquaculture. Genomic analysis shows that C. vorax possesses a highly fragmented macronuclear genome enriched with predation-related pathways, including calcium-mediated contractility, cellular proteolysis, toxin expulsion systems, among others. Transcriptomic profiling during predation events further demonstrates significant upregulation of genes involved in cytoskeletal remodeling, proteolytic activity, and cellular detoxification. Evolutionary analyses suggest that C. vorax has an extremely long evolutionary history, exceptionally high nucleotide diversity even among ciliates, and gene family expansions linked to predatory adaptation. Although the prey possesses certain defensive mechanisms (e.g. trichocysts), these are largely ineffective against short-term predation in closed aquatic environments. These findings provide fundamental insights into the molecular basis of predation in ciliates and suggest the potential utility of C. vorax in biocontrol applications targeting pathogenic ciliates.

Ciliophora↗
PubMed2025

The mutation landscape of Daphnia obtusa reveals evolutionary forces shaping genome stability.

Spontaneous mutations are the primary source of genetic variation and play a central role in shaping evolutionary processes. To investigate mutational dynamics in Daphnia obtusa, we generated a chromosome-level genome assembly spanning 129.4 Mb across 12 chromosomes, encompassing 15,321 predicted protein-coding genes. Leveraging whole-genome sequencing of eight mutation accumulation (MA) lines propagated for an average of 482 generations (spanning over 20 years), we estimated a spontaneous single nucleotide mutation (SNM) rate of 2.23 × 10-9 and an indel mutation rate of 2.75 × 10-10 per site per generation. The SNM spectrum was strongly biased toward C:G > T:A transitions. Comparative analyses with natural population data revealed that exonic mutations observed in the MA lines were significantly less likely to be present in standing variation than intronic or intergenic mutations, suggesting that purifying selection in natural populations acts to remove deleterious alleles. We also identified 48 de novo loss-of-heterozygosity (LOH) events, comprising 8 heterozygous deletions and 40 gene conversion events. The genome-wide gene conversion rate was estimated at 2.62 × 10-5 per heterozygous site per generation. These findings provide a comprehensive view of the mutation spectrum, selective pressures, and mechanisms underlying genome stability in D. obtusa.

Daphnia obtusa↗
PubMed2006

Ameiotic recombination in asexual lineages of Daphnia.

Despite the enormous theoretical attention given to the evolutionary consequences of sexual reproduction, the validity of the key assumptions on which the theory depends rarely has been evaluated. It is often argued that a reduced ability to purge deleterious mutations condemns asexual lineages to an early extinction. However, most well characterized asexual lineages fail to exhibit the high levels of neutral allelic divergence expected in the absence of recombination. With purely descriptive data, it is difficult to evaluate whether this pattern is a consequence of the rapid demise of asexual lineages, an unusual degree of mutational stability, or recombination. Here, we show in mutation-accumulation lines of asexual Daphnia that the rate of loss of nucleotide heterozygosity by ameiotic recombination is substantially greater than the rate of introduction of new variation by mutation. This suggests that the evolutionary potential of asexual diploid species is not only a matter of mutation accumulation and reduced efficiency of selection, and [corrected] it underscores the limited utility of using neutral allelic divergence as an indicator of ancient asexuality.

Animals↗
PubMed2006

Surveillance for foodborne-disease outbreaks--United States, 1998-2002.

PROBLEM/CONDITION: Since 1973, CDC has maintained a collaborative surveillance program for collection and periodic reporting of data on the occurrence and causes of foodborne-disease outbreaks (FBDOs) in the United States. REPORTING PERIOD COVERED: 1998-2002. DESCRIPTION OF SYSTEM: The Foodborne Disease Outbreak Surveillance System reviews data on FBDOs, defined as the occurrence of two or more cases of a similar illness resulting from the ingestion of a common food. State and local public health departments have primary responsibility for identifying and investigating FBDOs. State, local, and territorial health departments use a standard form to report these outbreaks to CDC. In 1998, CDC implemented enhanced surveillance for FBDOs by increasing communication with state, local, and territorial health departments and revising the outbreak report form. Since 2001, reports of FBDOs are submitted through a web application on the Internet called the electronic Foodborne Outbreak Reporting System (eFORS). RESULTS: During 1998-2002, a total of 6,647 outbreaks of foodborne disease were reported (1,314 in 1998, 1,343 in 1999, 1,417 in 2000, 1,243 in 2001, and 1,330 in 2002). These outbreaks caused a reported 128,370 persons to become ill. Among 2,167 (33%) outbreaks for which the etiology was determined, bacterial pathogens caused the largest percentage of outbreaks (55%) and the largest percentage of cases (55%). Among bacterial pathogens, Salmonella serotype Enteritidis accounted for the largest number of outbreaks and outbreak-related cases; Listeria monocytogenes accounted for the majority of deaths of any pathogen. Viral pathogens, predominantly norovirus, caused 33% of outbreaks and 41% of cases; the proportion of outbreaks attributed to viral agents increased from 16% in 1998 to 42% in 2002. Chemical agents caused 10% of outbreaks and 2% of cases, and parasites caused 1% of outbreaks and 1% of cases. INTERPRETATION: Following implementation of measures to enhance outbreak surveillance, the annual number of FBDOs reported to CDC increased during this period compared with previous years. Viral pathogens accounted for an increased proportion of outbreaks each year during this reporting period and a higher proportion of outbreaks of known etiology during this reporting period than preceding reporting periods, probably reflecting the increased availability of improved viral diagnostic tests. S. Enteritidis continued to be a major cause of illness and L. monocytogenes was a major cause of death. In addition, multistate outbreaks caused by contaminated produce and outbreaks caused by Escherichia coli O157:H7 remained prominent. PUBLIC HEALTH ACTIONS: Methods to detect FBDOs are improving, and several changes to improve the ease and timeliness of reporting FBDO data have been implemented (e.g., a revised form to simplify FBDO reporting by state health departments and improved electronic reporting methods). State and local health departments continue to investigate and report FBDOs as part of efforts to better understand and define the epidemiology of foodborne disease in the United States. At the regional and national levels, surveillance data provide an indication of the etiologic agents, vehicles of transmission, and contributing factors associated with FBDOs and help direct public health actions to reduce illness and death caused by FBDOs.

Disease Outbreaks↗
PubMed2006

Large global effective population sizes in Paramecium.

The genetic effective population size (N(e)) of a species is an important parameter for understanding evolutionary dynamics because it mediates the relative effects of selection. However, because most N(e) estimates for unicellular organisms are derived either from taxa with poorly understood species boundaries or from host-restricted pathogens and most unicellular species have prominent phases of clonal propagation potentially subject to strong selective sweeps, the hypothesis that N(e) is elevated in single-celled organisms remains controversial. Drawing from observations on well-defined species within the genus Paramecium, we report exceptionally high levels of silent-site polymorphism, which appear to be a reflection of large N(e).

Animals↗
PubMed2006

Intron size, abundance, and distribution within untranslated regions of genes.

Most research concerning the evolution of introns has largely considered introns within coding sequences (CDSs), without regard for introns located within untranslated regions (UTRs) of genes. Here, we directly determined intron size, abundance, and distribution in UTRs of genes using full-length cDNA libraries and complete genome sequences for four species, Arabidopsis thaliana, Drosophila melanogaster, human, and mouse. Overall intron occupancy (introns/exon kbp) is lower in 5' UTRs than CDSs, but intron density (intron occupancy in regions containing introns) tends to be higher in 5' UTRs than in CDSs. Introns in 5' UTRs are roughly twice as large as introns in CDSs, and there is a sharp drop in intron size at the 5' UTR-CDS boundary. We propose a mechanistic explanation for the existence of selection for larger intron size in 5' UTRs, and outline several implications of this hypothesis. We found introns to be randomly distributed within 5' UTRs, so long as a minimum required exon size was assumed. Introns in 3' UTRs were much less abundant than in 5' UTRs. Though this was expected for human and mouse that have intron-dependent nonsense-mediated decay (NMD) pathways that discourage the presence of introns within the 3' UTR, it was also true for A. thaliana and D. melanogaster, which may lack intron-dependent NMD. Our findings have several implications for theories of intron evolution and genome evolution in general.

3' Untranslated Regions↗
PubMed2006

The relative roles of three DNA repair pathways in preventing Caenorhabditis elegans mutation accumulation.

Mutation is a central biological process whose rates and spectra are influenced by a variety of complex and interacting forces. Although DNA repair pathways are generally known to play key roles in maintaining genetic stability, much remains to be understood about the relative roles of different pathways in preventing the accumulation of mutations and the extent of heterogeneity in pathway-specific repair efficiencies across different genomic regions. In this study we examine mutation processes in base excision repair-deficient (nth-1) and nucleotide excision repair-deficient (xpa-1) Caenorhabditis elegans mutation-accumulation (MA) lines across 24 regions of the genome and compare our observations to previous data from mismatch repair-deficient (msh-2 and msh-6) and wild-type (N2) MA lines. Drastic variation in both average and locus-specific mutation rates, ranging two orders of magnitude for the latter, was detected among the four sets of repair-deficient MA lines. Our work provides critical insights into the relative roles of three DNA repair pathways in preventing C. elegans mutation accumulation and provides evidence for the presence of pathway-specific DNA repair territories in the C. elegans genome.

Animals↗
PubMed2006

A microsatellite-based genetic linkage map of the waterflea, Daphnia pulex: On the prospect of crustacean genomics.

We describe the first genetic linkage map for Daphnia pulex using 185 microsatellite markers, including 115 new markers reported in this study. Our approach was to study the segregation of polymorphisms in 129 F2 progeny of one F1 hybrid obtained by crossing two genetically divergent lineages of Daphnia isolated from two Oregon populations. The map spanned 1206 Kosambi cM and had an average intermarker distance of 7 cM. Linkage groups ranged in size from 7 to 185 cM and contained 4 to 27 markers. The map revealed 12 linkage groups corresponding to the expected number of chromosomes and covers approximately 87% of the genome. Tests for random segregation of alleles at individual loci revealed that 21% of the markers showed significant transmission ratio distortion (primarily homozygote deficiency) likely due to markers being linked to deleterious recessive alleles. This map will become the anchor for the physical map of the Daphnia genome and will serve as a starting point for mapping single and quantitative trait loci affecting ecologically important phenotypes. By mapping 342 tentative orthologous gene pairs (Daphnia/Drosophila) into the Daphnia linkage map, we facilitate future comparative projects.

Animals↗
PubMed2006

Mutation pressure and the evolution of organelle genomic architecture.

The nuclear genomes of multicellular animals and plants contain large amounts of noncoding DNA, the disadvantages of which can be too weak to be effectively countered by selection in lineages with reduced effective population sizes. In contrast, the organelle genomes of these two lineages evolved to opposite ends of the spectrum of genomic complexity, despite similar effective population sizes. This pattern and other puzzling aspects of organelle evolution appear to be consequences of differences in organelle mutation rates. These observations provide support for the hypothesis that the fundamental features of genome evolution are largely defined by the relative power of two nonadaptive forces: random genetic drift and mutation pressure.

Animals↗
PubMed2006

On the formation of novel genes by duplication in the Caenorhabditis elegans genome.

Gene duplication is thought to play the singular most important role in the formation of novel genes. The canonical model of gene duplication postulates that novel genes arise in a two-step fashion, namely, (1) the complete duplication of a gene followed by (2) the gradual accumulation of mutations in one or both copies leading to an altered function. It was previously demonstrated that more than 50% of newborn duplicates in Caenorhabditis elegans had unique exons in one or both members of a duplicate pair, indicating that many duplicates are not functionally identical to the progenitor copy at birth. Both partial and chimeric gene duplications contribute to the formation of novel genes. For chimeric duplications, the genomic sources of unique exons are diverse, including genic and intergenic regions, as well as repetitive elements. These novel genes derived from partial and chimeric duplications are equally likely to be transcriptionally active as copies derived from complete duplications of the ancestral gene. Duplication breakpoints in the ancestral copies are uniformly distributed in the genome, ruling out the role of any mechanism that restricts them to a particular type of sequence such as introns. Finally, both intron loss and gain contribute to the differential distribution of introns between two copies.

Animals↗
PubMed2006

Characteristics of several NIR tuneable diode lasers for spectroscopic based gas sensing: a comparison.

Tuneable laser diodes were characterized and compared for use as tuneable sources in gas absorption spectroscopy. Specifically, the characteristics of monolithic widely tuneable single frequency lasers, such as sampled grating distributed Bragg reflector laser and modulated grating Y-branch laser diodes, recently developed for optical communications, with operating wavelengths in the 1,520 nm<or=lambda<or=1,570 nm are compared. The assessment also includes an external cavity laser and a distributed feedback laser for water vapour detection, both emitting at 935 nm. Characteristics investigated include side-mode suppression ratio, ease of tuning, tuning range, spectral emission linewidth, frequency stability and wavelength modulation. While some characteristics differ significantly across the range of lasers, each device has a number of useful intrinsic qualities for gas sensing. Specifically, the modulated grating Y laser and the sampled grating DBR laser have wide quasi-continuous tuneability (30-40 nm) and display relatively low residual amplitude noise when grating-modulated in a harmonic detection scheme. They are particularly suitable for multi-gas sensing. ECLs are also capable of wide quasi-continuous tuneability (100 nm) but their architecture renders them unsuitable for gas sensing application outside a controlled laboratory environment. DFB devices are by far the easiest with which to work but their modest tuneability (4 nm maximum by temperature) almost invariably limits their use to single gas sensing applications.

Gases↗
PubMed2006

Detection and quantification of protein biomarkers from fewer than 10 cells.

The use of antibody microarrays continues to grow rapidly due to the recent advances in proteomics and automation and the opportunity this combination creates for high throughput multiplexed analysis of protein biomarkers. However, a primary limitation of this technology is the lack of PCR-like amplification methods for proteins. Therefore, to realize the full potential of array-based protein biomarker screening it is necessary to construct assays that can detect and quantify protein biomarkers with very high sensitivity, in the femtomolar range, and from limited sample quantities. We describe here the construction of ultramicroarrays, combining the advantages of microarraying including multiplexing capabilities, higher throughput, and cost savings with the ability to screen very small sample volumes. Antibody ultramicroarrays for the detection of interleukin-6 and prostate-specific antigen (PSA), a widely used biomarker for prostate cancer screening, were constructed. These ultramicroarrays were found to have a high specificity and sensitivity with detection levels using purified proteins in the attomole range. Using these ultramicroarrays, we were able to detect PSA secreted from 100 LNCaP cells in 3 h and from just four LNCaP cells in 24 h. Cellular PSA could also be detected from the lysate of an average of just six cells. This strategy should enable proteomic analysis of materials that are available in very limited quantities such as those collected by laser capture microdissection, neonatal biopsy microspecimens, and forensic samples.

Biomarkers↗
PubMed2006

Transitions to asexuality result in excess amino acid substitutions.

Theory predicts that linkage between genetic loci reduces the efficiency of purifying selection. Because of the permanent linkage of all heritable genetic material, asexual lineages may be exceptionally prone to deleterious-mutation accumulation in both nuclear and organelle genes. Here, we show that the ratio of the rate of amino acid to silent substitution (Ka/Ks) in mitochondrial protein-coding genes is higher in obligately asexual lineages than in sexual lineages of the microcrustacean Daphnia pulex. Using a phylogeny-based approach to quantify the frequency of mutational-effect classes, we estimate that mitochondrial protein-coding genes in asexual lineages accumulate deleterious amino acid substitutions at four times the rate in sexual lineages. These results support the hypothesis that sexual reproduction plays a prominent role in reducing the mutational burden in populations.

Amino Acid Substitution↗
PubMed2006

Viral transgenesis of embryonic cell cultures from the freshwater microcrustacean Daphnia.

The aim of this study was to determine whether a recombinant vesicular stomatitis virus (VSV) vector encoding a transgene could be used to infect and express a foreign gene in embryonic primary cell cultures derived from the freshwater microcrustacean Daphnia, the most widely used ecotoxicological model organism. To facilitate the evaluation of gene transfer, a reproducible method for establishing primary cultures from Daphnia embryonic tissues was developed. Within 24 hr after infection, transgene expression could be detected in cell culture. VSV was found to replicate in the cells with no apparent cytopathic effect. Here we report the first evidence of gene transfer and foreign gene expression in cultures of Daphnia embryonic cells using a recombinant viral vector.

Animals↗
PubMed2006

Streamlining and simplification of microbial genome architecture.

The genomes of unicellular species, particularly prokaryotes, are greatly reduced in size and simplified in terms of gene structure relative to those of multicellular eukaryotes. Arguments proposed to explain this disparity include selection for metabolic efficiency and elevated rates of deletion in microbes, but the evidence in support of these hypotheses is at best equivocal. An alternative explanation based on fundamental population-genetic principles is proposed here. By increasing the mutational target sizes of associated genes, most forms of nonfunctional DNA are opposed by weak selection. Free-living microbial species have elevated effective population sizes, and the consequent reduction in the power of random genetic drift appears to be sufficient to enable natural selection to inhibit the accumulation of excess DNA. This hypothesis provides a potentially unifying explanation for the continuity in genomic scaling from prokaryotes to multicellular eukaryotes, the divergent patterns of mitochondrial evolution in animals and land plants, and various aspects of genomic modification in microbial endosymbionts.

Animals↗
PubMed2005

The origins of eukaryotic gene structure.

Most of the phenotypic diversity that we perceive in the natural world is directly attributable to the peculiar structure of the eukaryotic gene, which harbors numerous embellishments relative to the situation in prokaryotes. The most profound changes include introns that must be spliced out of precursor mRNAs, transcribed but untranslated leader and trailer sequences (untranslated regions), modular regulatory elements that drive patterns of gene expression, and expansive intergenic regions that harbor additional diffuse control mechanisms. Explaining the origins of these features is difficult because they each impose an intrinsic disadvantage by increasing the genic mutation rate to defective alleles. To address these issues, a general hypothesis for the emergence of eukaryotic gene structure is provided here. Extensive information on absolute population sizes, recombination rates, and mutation rates strongly supports the view that eukaryotes have reduced genetic effective population sizes relative to prokaryotes, with especially extreme reductions being the rule in multicellular lineages. The resultant increase in the power of random genetic drift appears to be sufficient to overwhelm the weak mutational disadvantages associated with most novel aspects of the eukaryotic gene, supporting the idea that most such changes are simple outcomes of semi-neutral processes rather than direct products of natural selection. However, by establishing an essentially permanent change in the population-genetic environment permissive to the genome-wide repatterning of gene structure, the eukaryotic condition also promoted a reliable resource from which natural selection could secondarily build novel forms of organismal complexity. Under this hypothesis, arguments based on molecular, cellular, and/or physiological constraints are insufficient to explain the disparities in gene, genomic, and phenotypic complexity between prokaryotes and eukaryotes.

Animals↗
PubMed2005

Simultaneous multispecies gas sensing by use of a sampled grating distributed Bragg reflector and modulated grating Y laser diode.

Widely tunable laser diodes operating at 1520 < or = lambda < or = 1570 nm are characterized and compared for use as sources for tunable laser diode gas absorption spectroscopy. Three gases, hydrogen cyanide, ammonia, and acetylene, with overlapping absorption features within the 50 nm tuning range of the devices were targeted by use of wavelength modulation spectroscopy with second-harmonic detection. In addition, a method for modulating the laser to improve sensitivity by taking advantage of the unique structure of these devices is reported.

Journal Article↗