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Biomedical subjects

Michael Lynch

Publications and source records attributed to Michael Lynch.

At least 55 records · Page 3Linked to original sources
PubMed2004

Genetic screening of infertile men.

Male infertility is an extraordinarily common medical condition, affecting 1 in 20 men. According to the World Health Organization, this condition is now considered to be a complex disease involving physical, genetic and environmental factors. With continuing advances in our understanding of male reproductive physiology and endocrinology, together with the availability of the complete sequence of the human genome and powerful functional genomic techniques, the stage is now set to identify the genes that are essential for spermatogenesis. Given that the process of spermatogenesis, from the germ cell to mature sperm, is complex, the challenge for research is to develop the strategies for identifying new genetic causes of idiopathic male infertility and defining genotypes associated with specific defects in semen parameters and testicular pathologies. Such information will form the basis of new genetic tests that will allow the clinician to make an accurate diagnosis of the male partner and a more informed decision about treatment options for the couple.

Genetic Testing↗
PubMed2004

Mutation accumulation in populations of varying size: the distribution of mutational effects for fitness correlates in Caenorhabditis elegans.

The consequences of mutation for population-genetic and evolutionary processes depend on the rate and, especially, the frequency distribution of mutational effects on fitness. We sought to approximate the form of the distribution of mutational effects by conducting divergence experiments in which lines of a DNA repair-deficient strain of Caenorhabditis elegans, msh-2, were maintained at a range of population sizes. Assays of these lines conducted in parallel with the ancestral control suggest that the mutational variance is dominated by contributions from highly detrimental mutations. This was evidenced by the ability of all but the smallest population-size treatments to maintain relatively high levels of mean fitness even under the 100-fold increase in mutational pressure caused by knocking out the msh-2 gene. However, we show that the mean fitness decline experienced by larger populations is actually greater than expected on the basis of our estimates of mutational parameters, which could be consistent with the existence of a common class of mutations with small individual effects. Further, comparison of the total mutation rate estimated from direct sequencing of DNA to that detected from phenotypic analyses implies the existence of a large class of evolutionarily relevant mutations with no measurable effect on laboratory fitness.

Amino Acid Substitution↗
PubMed2003

The origins of genome complexity.

Complete genomic sequences from diverse phylogenetic lineages reveal notable increases in genome complexity from prokaryotes to multicellular eukaryotes. The changes include gradual increases in gene number, resulting from the retention of duplicate genes, and more abrupt increases in the abundance of spliceosomal introns and mobile genetic elements. We argue that many of these modifications emerged passively in response to the long-term population-size reductions that accompanied increases in organism size. According to this model, much of the restructuring of eukaryotic genomes was initiated by nonadaptive processes, and this in turn provided novel substrates for the secondary evolution of phenotypic complexity by natural selection. The enormous long-term effective population sizes of prokaryotes may impose a substantial barrier to the evolution of complex genomes and morphologies.

Alleles↗
PubMed2003

Absorption line shift with temperature and pressure: impact on laser-diode-based H2O sensing at 1.393 microm.

High-resolution absorption measurements of the H2O line in the v1 + v3 band at 1.3928 microm were made in the temperature range of 296-1100 K by use of an InGaAsP distributed-feedback laser diode operating at 1.39 microm. Spectral line shift, line strength, and N2 broadening on the water-vapor line and their impact on the accuracy of optical-absorption-based gas sensing have been investigated. The results obtained were compared with values obtained from the HITRAN database and values reported in the literature, facilitating H2O sensing in a nonstandard temperature and pressure environment.

Journal Article↗
PubMed2003

An evolutionary analysis of the helix-hairpin-helix superfamily of DNA repair glycosylases.

The helix-hairpin-helix (HhH) superfamily of base excision repair DNA glycosylases is composed of multiple phylogenetically diverse enzymes that are capable of excising varying spectra of oxidatively and methyl-damaged bases. Although these DNA repair glycosylases have been widely studied through genetic, biochemical, and biophysical approaches, the evolutionary relationships of different HhH homologs and the extent to which they are conserved across phylogeny remain enigmatic. We provide an evolutionary framework for this pervasive and versatile superfamily of DNA glycosylases. Six HhH gene families (named AlkA: alkyladenine glycosylase; MpgII: N-methylpurine glycosylase II; MutY/Mig: A/G-specific adenine glycosylase/mismatch glycosylase; Nth: endonuclease III; OggI: 8-oxoguanine glycosylase I; and OggII: 8-oxoguanine glycosylase II) are identified through phylogenetic analysis of 234 homologs found in 94 genomes (16 archaea, 64 bacteria, and 14 eukaryotes). The number of homologs in each gene family varies from 117 in the Nth family (nearly every genome surveyed harbors at least one Nth homolog) to only five in the divergent OggII family (all from archaeal genomes). Sequences from all three domains of life are included in four of the six gene families, suggesting that the HhH superfamily diversified very early in evolution. The phylogeny provides evidence for multiple lineage-specific gene duplication events, most of which involve eukaryotic homologs in the Nth and AlkA gene families. We observe extensive variation in the number of HhH superfamily glycosylase genes present in different genomes, possibly reflecting major differences among species in the mechanisms and pathways by which damaged bases are repaired and/or disparities in the basic rates and spectra of mutation experienced by different genomes.

DNA↗
PubMed2003

Messenger RNA surveillance and the evolutionary proliferation of introns.

The mechanisms responsible for the proliferation and subsequent stabilization of introns within the eukaryotic lineage have remained elusive. In the early stages of eukaryotic evolution, most introns may have been mildly deleterious at the time of insertion, but enough of them eventually acquired integral roles in transcript processing that few eukaryotic species can any longer survive without them. We suggest that the proliferation of spliceosomal introns was facilitated by the evolution of nonsense-mediated decay, an ancient and (in many cases) intron-dependent mechanism for eliminating aberrant mRNA molecules resulting from errors in transcription and splicing and from mutations at the DNA level. The spatial distribution of introns, as revealed by whole-genome analysis, is consistent with expectations for a model in which maximum protective coverage of a gene stochastically evolves over time.

Alternative Splicing↗
PubMed2003

God's signature: DNA profiling, the new gold standard in forensic science.

In the mid-1980s, when the first DNA profiling techniques were developed, the name DNA 'fingerprinting' was widely used. At the time, fingerprinting was a well-established forensic method, and it was rarely questioned in the courts. Fingerprint examiners were permitted to describe matching prints as evidence of individual identity, and they were not required to give probability estimates. Despite its nominal association with the older technique, DNA 'fingerprinting' went through a period of controversy, especially in the US courts. The association with fingerprinting was questioned, and experts were required to qualify their testimony with probability figures. Heated debate occurred in scientific publications and law courts about the statistical and population genetic assumptions that went into the probability calculations presented in court cases. However, by the late 1990s DNA profiling was so widely accepted that it became a basis for invidious comparison with all other forms of forensic evidence, including fingerprinting. In the past three years, the admissibility of fingerprint evidence has been challenged in several US federal and state courts. This article discusses the socio-legal and socio-technical issues that led to the inversion of credibility that characterized the intertwined history of the two techniques.

Criminal Law↗
PubMed2003

Correlated evolution of life-history with size at maturity in Daphnia pulicaria: patterns within and between populations.

Explaining the repeated evolution of similar sets of traits under similar environmental conditions is an important issue in evolutionary biology. The extreme alternative classes of explanations for correlated suites of traits are optimal adaptation and genetic constraint resulting from pleiotropy. Adaptive explanations presume that individual traits are free to evolve to their local optima and that convergent evolution represents particularly adaptive combinations of traits. Alternatively, if pleiotropy is strong and difficult to break, strong selection on one or a few particularly important characters would be expected to result in consistent correlated evolution of associated traits. If pleiotropy is common, we predict that the pattern of divergence among populations will consistently reflect the within-population genetic architecture. To test the idea that the multivariate life-history phenotype is largely a byproduct of strong selection on body size, we imposed divergent artificial selection on size at maturity upon two populations of the cladoceran Daphnia pulicaria, chosen on the basis of their extreme divergence in body size. Overall, the trajectory of divergence between the two natural populations did not differ from that predicted by the genetic architecture within each population. However, the pattern of correlated responses suggested the presence of strong pleiotropic constraints only for adult body size and not for other life-history traits. One trait, offspring size, appears to have evolved in a way different from that expected from the within-population genetic architecture and may be under stabilizing selection.

Animals↗
PubMed2003

Consequences of children's exposure to community violence.

Much has been learned over the past decade about the way children respond to experiences of violence in their community. The goal of this paper is to review what is known about the effects of community violence on children's development. In addition to main effects, factors that mediate these effects, as well as factors that moderate children's response to community violence are discussed. Special attention is paid to developmental differences in children's responses to community violence and the factors that may promote resilient functioning.

Blood Pressure↗
PubMed2003

The structure and early evolution of recently arisen gene duplicates in the Caenorhabditis elegans genome.

The significance of gene duplication in provisioning raw materials for the evolution of genomic diversity is widely recognized, but the early evolutionary dynamics of duplicate genes remain obscure. To elucidate the structural characteristics of newly arisen gene duplicates at infancy and their subsequent evolutionary properties, we analyzed gene pairs with < or =10% divergence at synonymous sites within the genome of Caenorhabditis elegans. Structural heterogeneity between duplicate copies is present very early in their evolutionary history and is maintained over longer evolutionary timescales, suggesting that duplications across gene boundaries in conjunction with shuffling events have at least as much potential to contribute to long-term evolution as do fully redundant (complete) duplicates. The median duplication span of 1.4 kb falls short of the average gene length in C. elegans (2.5 kb), suggesting that partial gene duplications are frequent. Most gene duplicates reside close to the parent copy at inception, often as tandem inverted loci, and appear to disperse in the genome as they age, as a result of reduced survivorship of duplicates located in proximity to the ancestral copy. We propose that illegitimate recombination events leading to inverted duplications play a disproportionately large role in gene duplication within this genome in comparison with other mechanisms.

Animals↗
PubMed2003

Rapid fitness recovery in mutationally degraded lines of Caenorhabditis elegans.

Deleterious mutation accumulation has been implicated in many biological phenomena and as a potentially significant threat to human health and the persistence of small populations. The vast majority of mutations with effects on fitness are known to be deleterious in a given environment, and their accumulation results in mean population fitness decline. However, whether populations are capable of recovering from negative effects of prolonged genetic bottlenecks via beneficial or compensatory mutation accumulation has not previously been tested. To address this question, long-term mutation-accumulation lines of the nematode Caenorhabditis elegans, previously propagated as single individuals each generation, were maintained in large population sizes under competitive conditions. Fitness assays of these lines and comparison to parallel mutation-accumulation lines and the ancestral control show that, while the process of fitness restoration was incomplete for some lines, full recovery of mean fitness was achieved in fewer than 80 generations. Several lines of evidence indicate that this fitness restoration was at least partially driven by compensatory mutation accumulation rather than a result of a generic form of laboratory adaptation. This surprising result has broad implications for the influence of the mutational process on many issues in evolutionary and conservation biology.

Analysis of Variance↗
PubMed2003

Toward a realistic model of mutations affecting fitness.

Analysis of a recent mutation accumulation (MA) experiment has led to the suggestion that as many as one-half of spontaneous mutations in Arabidopsis are advantageous for fitness. We evaluate this in the light of data from other MA experiments, along with molecular evidence, that suggest the vast majority of new mutations are deleterious.

Animals↗
PubMed2003

The evolutionary demography of duplicate genes.

Although gene duplication has generally been viewed as a necessary source of material for the origin of evolutionary novelties, the rates of origin, loss, and preservation of gene duplicates are not well understood. Applying steady-state demographic techniques to the age distributions of duplicate genes censused in seven completely sequenced genomes, we estimate the average rate of duplication of a eukaryotic gene to be on the order of 0.01/ gene/million years, which is of the same order of magnitude as the mutation rate per nucleotide site. However, the average half-life of duplicate genes is relatively small, on the order of 4.0 million years. Significant interspecific variation in these rates appears to be responsible for differences in species-specific genome sizes that arise as a consequence of a quasi-equilibrium birth-death process. Most duplicated genes experience a brief period of relaxed selection early in their history and a minority exhibit the signature of directional selection, but those that survive more than a few million years eventually experience strong purifying selection. Thus, although most theoretical work on the gene-duplication process has focused on issues related to adaptive evolution, the origin of a new function appears to be a very rare fate for a duplicate gene. A more significant role of the duplication process may be the generation of microchromosomal rearrangements through reciprocal silencing of alternative copies, which can lead to the passive origin of post-zygotic reproductive barriers in descendant lineages of incipient species.

Animals↗
PubMed2002

Intron evolution as a population-genetic process.

Debate over the mechanisms responsible for the phylogenetic and genomic distribution of introns has proceeded largely without consideration of the population-genetic forces influencing the establishment and retention of novel genetic elements. However, a simple model incorporating random genetic drift and weak mutation pressure against intron-containing alleles yields predictions consistent with a diversity of observations: (i) the rarity of introns in unicellular organisms with large population sizes, and their expansion after the origin of multicellular organisms with reduced population sizes; (ii) the relationship between intron abundance and the stringency of splice-site requirements; (iii) the tendency for introns to be more numerous and longer in regions of low recombination; and (iv) the bias toward phase-0 introns. This study provides a second example of a mechanism whereby genomic complexity originates passively as a "pathological" response to small population size, and raises difficulties for the idea that ancient introns played a major role in the origin of genes by exon shuffling.

Alleles↗
PubMed2002

Repeated brief seizures induce progressive hippocampal neuron loss and memory deficits.

The long-term effects of repeated brief seizures on spatial memory and hippocampal neuronal populations were assessed in kindled rats. Rats that experienced a range of 3 afterdischarges to 134 secondary generalized tonic-clonic (Class V) seizures evoked by stimulation of the olfactory bulb were evaluated in a radial arm maze task that is a measure of spatial memory and is disrupted by hippocampal damage. After completion of the memory task and a minimum of approximately 3 months after the last evoked seizure, stereological methods were used to assess neuronal populations at septal and temporal locations of the hippocampus and dentate gyrus. Repeated brief seizures induced a long-lasting deficit in spatial memory performance that was detected after a cumulative total of approximately 6 partial and 30 secondary generalized seizures. The memory deficit progressively increased as a function of the number of seizures, and was not observed in age-matched, electrode-implanted, unstimulated, but otherwise similarly handled paired controls. Neuronal loss was detected in the temporal hilus of the dentate gyrus, CA1, and CA3 of the hippocampus after 69 or more secondary generalized tonic-clonic seizures, and was associated with the progressive memory dysfunction. Repeated brief seizures induced progressive, permanent functional and structural abnormalities in the hippocampus, which included spatial memory deficits accompanied by gradually evolving neuronal loss in a pattern resembling human hippocampal sclerosis. These experimental results support the view that hippocampal sclerosis and associated memory dysfunction are induced by repeated seizures, and imply that seizure control could prevent adverse long-term consequences of seizures on hippocampal dependent functions.

Animals↗
PubMed2002

The evolution of spliceosomal introns.

Although the widespread proliferation of introns in eukaryotic protein-coding genes remains one of the most poorly understood aspects of genomic architecture, major advances have emerged recently from large-scale genome sequencing projects and functional analyses of mRNA-processing events. Evidence supports the idea that spliceosomal introns were not only present in the stem eukaryote but diverged into at least two distinct classes very early in eukaryotic evolution. Some rough estimates of intron turnover rates are provided, and a testable hypothesis for the origin of new introns is proposed. In light of recent findings on the molecular natural history of splicing, various aspects of the phylogenetic and physical distributions of introns can now be interpreted in a theoretical framework that jointly considers the population-genetic roles of mutation, random genetic drift, and natural selection.

Animals↗