Biomedical subjects

Michael Lynch

Publications and source records attributed to Michael Lynch.

At least 37 records · Page 2Linked to original sources

PubMed2005

The transcriptional consequences of mutation and natural selection in Caenorhabditis elegans.

The evolutionary importance of gene-expression divergence is unclear: some studies suggest that it is an important mechanism for evolution by natural selection, whereas others claim that most between-species regulatory changes are neutral or nearly neutral. We examined global transcriptional divergence patterns in a set of Caenorhabditis elegans mutation-accumulation lines and natural isolate lines to provide insights into the evolutionary importance of transcriptional variation and to discriminate between the forces of mutation and natural selection in shaping the evolution of gene expression. We detected the effects of selection on transcriptional divergence patterns and characterized them with respect to coexpressed gene sets, chromosomal clustering of expression changes and functional gene categories. We directly compared observed transcriptional variation patterns in the mutation-accumulation and natural isolate lines to a neutral model of transcriptome evolution to show that strong stabilizing selection dominates the evolution of transcriptional change for thousands of C. elegans expressed sequences.

Animals↗

PubMed2005

Behavioral degradation under mutation accumulation in Caenorhabditis elegans.

Spontaneous mutations play a fundamental role in the maintenance of genetic variation in natural populations, the nature of inbreeding depression, the evolution of sexual reproduction, and the conservation of endangered species. Using long-term mutation-accumulation lines of the nematode Caenorhabditis elegans, we estimate the rate and magnitude of mutational effects for a suite of behaviors characterizing individual chemosensory responses to a repellant stimulus. In accordance with evidence that the vast majority of mutations are deleterious, we find that behavioral responses degrade over time as a result of spontaneous mutation accumulation. The rate of mutation for behavioral traits is roughly of the same order or slightly smaller than those previously estimated for reproductive traits and the average size of the mutational effects is also comparable. These results have important implications for the maintenance of genetic variation for behavior in natural populations as well as for expectations for behavioral change within endangered species and captive populations.

Animals↗

PubMed2005

Spontaneous mutational correlations for life-history, morphological and behavioral characters in Caenorhabditis elegans.

The pattern of mutational covariance among traits plays a central, but largely untested, role in many theories in evolutionary genetics. Here we estimate the pattern of phenotypic, environmental, and mutational correlations for a set of life-history, behavioral, and morphological traits using 67 self-fertilizing lines of Caenorhabditis elegans, each having independently experienced an average of 370 generations of spontaneous mutation accumulation. Bivariate relationships of mutational effects indicate the existence of extensive pleiotropy. We find that mutations may tend to produce manifold effects on suites of functionally related traits; however, our data do not support the idea of completely parcelated pleiotropy, in which functional units are separately affected by mutations. Positive net phenotypic and mutational correlations are common for life-history traits, with environmental correlations being comparatively smaller and of the same sign for most pairs of traits. Observed mutational correlations are shown to be higher than those produced by the chance accumulation of nonpleiotropic mutations in the same lines.

Animals↗

PubMed2005

MRI diffusion-based filtering: a note on performance characterisation.

Frequently MRI data is characterised by a relatively low signal to noise ratio (SNR) or contrast to noise ratio (CNR). When developing automated Computer Assisted Diagnostic (CAD) techniques the errors introduced by the image noise are not acceptable. Thus, to limit these errors, a solution is to filter the data in order to increase the SNR. More importantly, the image filtering technique should be able to reduce the level of noise, but not at the expense of feature preservation. In this paper we detail the implementation of a number of 3D diffusion-based filtering techniques and we analyse their performance when they are applied to a large collection of MR datasets of varying type and quality.

Algorithms↗

PubMed2005

Comparative evolutionary genetics of spontaneous mutations affecting fitness in rhabditid nematodes.

Deleterious mutations are of fundamental importance to all aspects of organismal biology. Evolutionary geneticists have expended tremendous effort to estimate the genome-wide rate of mutation and the effects of new mutations on fitness, but the degree to which genomic mutational properties vary within and between taxa is largely unknown, particularly in multicellular organisms. Beginning with two highly inbred strains from each of three species in the nematode family Rhabditidae (Caenorhabditis briggsae, Caenorhabditis elegans, and Oscheius myriophila), we allowed mutations to accumulate in the relative absence of natural selection for 200 generations. We document significant variation in the rate of decay of fitness because of new mutations between strains and between species. Estimates of the per-generation mutational decay of fitness were very consistent within strains between assays 100 generations apart. Rate of mutational decay in fitness was positively associated with genomic mutation rate and negatively associated with average mutational effect. These results provide unambiguous experimental evidence for substantial variation in genome-wide properties of mutation both within and between species and reinforce conclusions from previous experiments that the cumulative effects on fitness of new mutations can differ markedly among related taxa.

Animals↗

PubMed2005

The origin of subfunctions and modular gene regulation.

Evolutionary explanations for the origin of modularity in genetic and developmental pathways generally assume that modularity confers a selective advantage. However, our results suggest that even in the absence of any direct selective advantage, genotypic modularity may increase through the formation of new subfunctions under near-neutral processes. Two subfunctions may be formed from a single ancestral subfunction by the process of fission. Subfunction fission occurs when multiple functions under unified genetic control become subdivided into more restricted functions under independent genetic control. Provided that population size is sufficiently small, random genetic drift and mutation can conspire to produce changes in the number of subfunctions in the genome of a species without necessarily altering the phenotype. Extensive genotypic modularity may then accrue in a near-neutral fashion in permissive population-genetic environments, potentially opening novel pathways to morphological evolution. Many aspects of gene complexity in multicellular eukaryotes may have arisen passively as population size reductions accompanied increases in organism size, with the adaptive exploitation of such complexity occurring secondarily.

Biological Evolution↗

PubMed2005

Mutation rates, spectra and hotspots in mismatch repair-deficient Caenorhabditis elegans.

Although it is clear that postreplicative DNA mismatch repair (MMR) plays a critical role in maintaining genomic stability in nearly all forms of life surveyed, much remains to be understood about the genome-wide impact of MMR on spontaneous mutation processes and the extent to which MMR-deficient mutation patterns vary among species. We analyzed spontaneous mutation processes across multiple genomic regions using two sets of mismatch repair-deficient (msh-2 and msh-6) Caenorhabditis elegans mutation-accumulation (MA) lines and compared our observations to mutation spectra in a set of wild-type (WT), repair-proficient C. elegans MA lines. Across most sequences surveyed in the MMR-deficient MA lines, mutation rates were approximately 100-fold higher than rates in the WT MA lines, although homopolymeric nucleotide-run (HP) loci composed of A:T base pairs mutated at an approximately 500-fold greater rate. In contrast to yeast and humans where mutation spectra vary substantially with respect to different specific MMR-deficient genotypes, mutation rates and patterns were overall highly similar between the msh-2 and msh-6 C. elegans MA lines. This, along with the apparent absence of a Saccharomyces cerevisiae MSH3 ortholog in the C. elegans genome, suggests that C. elegans MMR surveillance is carried out by a single Msh-2/Msh-6 heterodimer.

Animals↗

PubMed2005

The evolution of transcription-initiation sites.

Unlike the situation in prokaryotes, most eukaryotic messenger RNAs contain a moderately long 5' untranslated region (UTR). Such leader sequences impose a burden on eukaryotic genes by providing substrate for the mutational origin of premature translation-initiation codons, which generally result in defective proteins. To gain an insight into the expansion of 5' UTRs in eukaryotic genomes, we present a simple null model in which the evolution of transcription-initiation sites is entirely driven by the stochastic mutational flux of core-promoter sequences and premature translation-initiation codons. This model yields results consistent with a variety of heretofore disconnected observations, including the form of length distributions of 5' UTRs, the relatively low variance in UTR features among distantly related eukaryotes, the universal reliance on relatively simple core-promoter sequences, and the elevated density of introns in the 5' UTR. We suggest that the reduced effective population sizes of most eukaryotes impose a population-genetic environment conducive to the movement of core promoters to random positions, subject to the constraint imposed by the upstream accumulation of premature translation-initiation codons. If this hypothesis is correct, then selection for gene-specific regulatory features need not be invoked to explain either the origin of lengthy eukaryotic 5' UTRs or the 1,000-fold range of 5'-UTR lengths among genes within species. Nevertheless, once permanently established, expanded 5' UTRs may have provided a novel substrate for the evolution of mechanisms for posttranscriptional regulation of eukaryotic gene expression. These results provide a further example of how an increase in the power of random genetic drift can passively promote the evolution of forms of gene architecture that ultimately facilitate the evolution of organismal complexity.

5' Untranslated Regions↗

PubMed2005

Simple evolutionary pathways to complex proteins.

A recent paper in this journal has challenged the idea that complex adaptive features of proteins can be explained by known molecular, genetic, and evolutionary mechanisms. It is shown here that the conclusions of this prior work are an artifact of unwarranted biological assumptions, inappropriate mathematical modeling, and faulty logic. Numerous simple pathways exist by which adaptive multi-residue functions can evolve on time scales of a million years (or much less) in populations of only moderate size. Thus, the classical evolutionary trajectory of descent with modification is adequate to explain the diversification of protein functions.

Evolution, Molecular↗

PubMed2005

Conserved ontogeny and allometric scaling of resource acquisition and allocation in the Daphniidae.

Life histories vary widely among taxa, but within phylogenetic groups there may be a fundamental framework around which trait variation is organized, perhaps as a consequence of lineage-specific developmental constraints. In organisms with indeterminate growth, there is an ongoing problem of optimally allocating resources between growth and reproduction, and that allocation decision may manifest itself through allometric scaling. Previous work on freshwater zooplankton has shown that the ontogenetic pattern of resource allocation can be described by simple mathematical functions. An important component of understanding how such functions can explain life-history variation is to discover which parameters in these functions are robust, with respect to both resource availability and evolutionary diversification, and which parameters exhibit interspecific allometry. To shed light on these issues, detailed life table experiments were conducted on eight species in the family Daphniidae (Crustacea) at high and low levels of resources. Using data on growth, reproduction, and instar duration, the ontogeny of resource allocation to growth and reproduction could be described as functions that plateau at or shortly after the onset of maturity. To be sure that the results were not an artifact of phylogenetic structure, the parameters were tested in a phylogenetically controlled fashion. The results suggest a simple set of resource allocation rules for daphniids, whereby all species exhibit a similar form of ontogenetic change in allocation, and reach a plateau where approximately 94% of available resources are allocated to reproduction. The asymptotically maximal rate of net resources incorporated in growth and reproduction was positively related to size at maturity, whereas the rates of approach to plateaus (for both net resource assimilation and proportional allocation to reproduction) were negatively related to body size. Per-offspring investment was positively related to the square root of size at maturity. Using this approach, a wide range of interspecific variation in life-history features can be related to a single underlying trait, the size at first reproductive investment.

Adaptation, Physiological↗

PubMed2005

Evolutionary history of contagious asexuality in Daphnia pulex.

Asexual taxa are short-lived, suggesting that transitions to asexuality represent evolutionary dead-ends. However, with high rates of clonal origin and coexistence of asexuals and sexuals via selective asymmetries, asexuality may persist in the long term as a result of a dynamic equilibrium between clonal origin and extinction. Few such systems have been studied in detail. Here, we investigate the evolutionary history of asexual lineages of Daphnia pulex, which are derived from sexual relatives via the inheritance of a dominant female-limited meiosis-suppressing locus and inhabit ponds throughout northeastern North America (NA). Our extensive sampling and subsequent phylogenetic analysis using mitochondrial sequence data reveals a young and genetically diverse asexual assemblage, reflecting high rates of clonal origin due to the contagious nature of asexuality. Yet, asexuality is restricted to two phylogroups (B and C) with historical and/or present associations with northeastern NA and is absent from a northwestern phylogroup (A), supporting a recent northeastern origin of asexuality in this species. Furthermore, macrogeographic patterns of genetic variability indicate that phylogroups B and C recolonized northeastern NA from opposite directions, yet their presently overlapping geographic distributions are similarly divided into an eastern asexual and a western sexual region. We attribute these patterns to a recent contagious spread of asexuality from a northeastern source. If environment-mediated selective asymmetries play no significant role in determining the outcome of competitive interactions between sexuals and asexuals, regions of contact may be setting the stage for continued asexual conquests.

Adaptation, Physiological↗

PubMed2004

High mutation rate and predominance of insertions in the Caenorhabditis elegans nuclear genome.

Mutations have pivotal functions in the onset of genetic diseases and are the fundamental substrate for evolution. However, present estimates of the spontaneous mutation rate and spectrum are derived from indirect and biased measurements. For instance, mutation rate estimates for Caenorhabditis elegans are extrapolated from observations on a few genetic loci with visible phenotypes and vary over an order of magnitude. Alternative approaches in mammals, relying on phylogenetic comparisons of pseudogene loci and fourfold degenerate codon positions, suffer from uncertainties in the actual number of generations separating the compared species and the inability to exclude biases associated with natural selection. Here we provide a direct and unbiased estimate of the nuclear mutation rate and its molecular spectrum with a set of C. elegans mutation-accumulation lines that reveal a mutation rate about tenfold higher than previous indirect estimates and an excess of insertions over deletions. Because deletions dominate patterns of C. elegans pseudogene variation, our observations indicate that natural selection might be significant in promoting small genome size, and challenge the prevalent assumption that pseudogene divergence accurately reflects the spontaneous mutation spectrum.

Animals↗

PubMed2004

The phylogenetic mixed model.

The phylogenetic mixed model is an application of the quantitative-genetic mixed model to interspecific data. Although this statistical framework provides a potentially unifying approach to quantitative-genetic and phylogenetic analysis, the model has been applied infrequently because of technical difficulties with parameter estimation. We recommend a reparameterization of the model that eliminates some of these difficulties, and we develop a new estimation algorithm for both the original maximum likelihood and new restricted maximum likelihood estimators. The phylogenetic mixed model is particularly rich in terms of the evolutionary insight that might be drawn from model parameters, so we also illustrate and discuss the interpretation of the model parameters in a specific comparative analysis.

Algorithms↗

PubMed2004

Functional protein nanoarrays for biomarker profiling.

The use of microarrays for parallel screening of nucleic acid profiles has become an industry standard. Similar efforts for screening protein-protein interactions are gaining momentum, however, they remain limited by the requirement for relatively large sample volumes. One strategy for overcoming this problem is to significantly decrease the size and consequently the sample volume of the protein interaction assay. We report here on our progress over the last two years in the construction of ultraminiaturized, functional protein capture assays. Each one micron spot in these array-based assays covers less than 1/1000(th) of the surface area of a conventional microarray spot while still maintaining enough antibodies to provide a useful dynamic range. These nanoarray assays can be read by conventional optical fluorescence microscopy as well as by novel label-free methods such as atomic force microscopy. The size reduction realized by functional protein nanoarrays also creates opportunities for novel applications including highly multiplexed single cell analysis and integration with microfluidics and other "lab-on-a-chip" technologies.

Biomarkers↗

PubMed2004

Abundance, distribution, and mutation rates of homopolymeric nucleotide runs in the genome of Caenorhabditis elegans.

Homopolymeric nucleotide runs, also called mononucleotide microsatellites, are a ubiquitous, dominant, and mutagenic feature of eukaryotic genomes. A clear understanding of the forces that shape patterns of homopolymer evolution, however, is lacking. We provide a focused investigation of the abundance, chromosomal distribution, and mutation spectra of the four strand-specific homopolymer types (A, T, G, C) >or=8 bp in the genome of Caenorhabditis elegans. A and T homopolymers vastly outnumber G and C HPs, and the run-length distributions of A and T homopolymers differ significantly from G and C homopolymers. A scanning window analysis of homopolymer chromosomal distribution reveals distinct clusters of homopolymer density in autosome arms that are regions of high recombination in C. elegans. Dramatic biases are detected among closely spaced homopolymers; for instance, we observe 994 A homopolymers immediately followed by a T homopolymer (5' to 3') and only 8 instances of T homopolymers directly followed by an A homopolymer. Empirical homopolymer mutation assays in a set of C. elegans mutation-accumulation lines reveal an approximately 20-fold higher mutation rate for G and C homopolymers compared to A and T homopolymers. Nuclear A and T homopolymers are also found to mutate approximately 100-fold more slowly than mitochondrial A and T homopolymers. This integrative approach yields a total nuclear genome-wide homopolymer mutation rate estimate of approximately 1.6 mutations per genome per generation.

Animals↗

PubMed2004

The altered evolutionary trajectories of gene duplicates.

Gene duplication is widely regarded as the predominant mechanism by which genes with new functions and associated phenotypic novelties arise. However, the mutational events and population-genetic mechanisms that lead to the short-term preservation of duplicate genes are not necessarily the same as those exhibited by well-established paralogs en route to the origin of new beneficial features. Thus, although recent genome-wide analyses have revealed striking patterns of protein-sequence divergence among the members of surviving paralogous gene families, the mechanisms responsible for the historical development of these patterns remain unclear.

Animals↗

PubMed2004

Biogeographic patterns and current distribution of molecular-genetic variation among populations of speckled dace, Rhinichthys osculus (Girard).

We examined genetic diversity within- and among-populations of speckled dace (Rhinichthys osculus) in five major drainage systems in the state of Oregon in western North America. Analysis of sequence variation in a 670-bp segment of the mitochondrial cytochrome b gene revealed deep divergence among basins and high genetic diversity within basins. Application of a molecular clock indicated that the divergence time among basins reflects vicariant events during the late Miocene to early Pliocene. The high levels of genetic diversity observed within basins is likely due to large historic population sizes, in particular, within the Klamath Basin. Two highly divergent mtDNA lineages were found to co-occur in populations in the Klamath Basin. This result may be indicative of a complex history of isolation and reconnection in this basin and/or multiple colonization events. Based on the observed level of mtDNA divergence these lineages may represent two reproductively isolated sympatric taxa. We recommend that major basins be regarded as distinct ESUs based on high levels of subdivision, deep divergences, and reciprocal monophyly among basins.

Animals↗

PubMed2004

Microfabricated quill-type surface patterning tools for the creation of biological micro/nano arrays.

Novel quill-type cantilever-based surface patterning tools (SPTs) were designed and constructed for use in controlled placement of femtoliter volumes of biological molecules on surfaces for biological applications. These tools were fabricated from silicon dioxide using microelectromechanical systems (MEMS) techniques. They featured a 1 microm split gap, fluidic transport microchannels and self-replenishing reservoirs. Experimental trials were performed using these tools on NanoArrayer molecular deposition instrumentation. Cy3-streptavidin was loaded as a biological sample and patterned on an amine-reactive dithiobis-succinimidyl undecanoate (DSU) monolayer on gold. Results showed these tools were capable of generating high quality biological arrays with routine spot sizes of 2-3 microm. The spot size could potentially achieve sub-micron dimensions if these SPT designs are reduced in size by more precise microfabrication techniques. The geometric designs of these tools facilitated sample replenishment from the local reservoir on the cantilever which allowed printing of large numbers of spots without sample reloading.

Adsorption↗