Linkage of the gene for equine combined immunodeficiency disease to microsatellite markers HTG8 and HTG4; synteny and FISH mapping to ECA9

Equine combined immunodeficiency disease (CID) is caused by homozygosity for an autosomal recessive gene. To identify linked markers for the disease, we studied a family segregating for the equine CID gene. A stallion and 19 of his CID-affected offspring were tested for marker segregation at 23 microsatellite DNA loci. His CID-affected offspring inherited only one of his two alleles at the HTG8 and HTG4 loci, namely HTG8–186 and HTG4–124 , respectively. Lod scores for linkage to the CID gene using a Θ of 0·01were 5·34 for HTG8 and 2·37 for HTG4. The apparent genotypes also suggested linkage disequilibrium between the HTG8–186 allele and the gene for CID. The gene for the DNA protein kinase catalytic subunit ( DNA-PK ) was recently suggested as a candidate gene for equine CID. A defect of this gene causes a disease in mice that is similar to equine CID. Therefore, we investigated whether this gene might be associated with the microsatellite markers. Analysis of a somatic cell hybrid panel demonstrated synteny of DNA-PK with HTG4 and HTG8 (Kentucky Synteny Group 3). Fluorescence in situ hybridization (FISH) studies demonstrated that DNA-PK is located on horse chromosome ECA9p12. This work supports the hypothesis of DNA-PK as the probable cause of equine CID.     

Repeated horizontal gene transfer of GALactose metabolism genes violates Dollo’s law of irreversible loss

Dollo’s law posits that evolutionary losses are irreversible, thereby narrowing the potential paths of evolutionary change. While phenotypic reversals to ancestral states have been observed, little is known about their underlying genetic causes. The genomes of budding yeasts have been shaped by extensive reductive evolution, such as reduced genome sizes and the losses of metabolic capabilities. However, the extent and mechanisms of trait reacquisition after gene loss in yeasts have not been thoroughly studied. Here, through phylogenomic analyses, we reconstructed the evolutionary history of the yeast galactose utilization pathway and observed widespread and repeated losses of the ability to utilize galactose, which occurred concurrently with the losses of GALactose (GAL) utilization genes. Unexpectedly, we detected multiple galactose-utilizing lineages that were deeply embedded within clades that underwent ancient losses of galactose utilization. We show that at least two, and possibly three, lineages reacquired the GAL pathway via yeast-to-yeast horizontal gene transfer. Our results show how trait reacquisition can occur tens of millions of years after an initial loss via horizontal gene transfer from distant relatives. These findings demonstrate that the losses of complex traits and even whole pathways are not always evolutionary dead-ends, highlighting how reversals to ancestral states can occur.     

Heterokaryon formation and parasexual recombination between vegetatively incompatible lineages in a population of the chestnut blight fungus, Cryphonectria parasitica

Heterokaryosis was recently reported in the chestnut blight fungus, Cryphonectria parasitica, in which individuals contain nuclei that are isogenic except at the mating-type locus (MAT). MAT heterokaryons were found in several natural populations, including a putatively clonal population in West Salem, Wisconsin, providing an opportunity to address the question of how heterokaryons arise. We represented relationships among RFLP fingerprint haplotypes as networks in which loop formation is considered evidence of recombination. From 1990 to 1995, this population was clonal, as indicated by a simple haplotype network without loops, and the correlation of vegetative compatibility (vc) types and mating types with haplotype lineages. By 1999, we observed loops in the haplotype network involving isolates of two vc types (WS-2 and WS-3). Isolates with haplotypes in the loops were either MAT heterokaryons, carried the opposite mating type from other isolates of the same vc type, and/or had two alleles at two or more codominant SCAR (sequence-characterized amplified region) loci. Segregation of markers and recombination were evident among single-spore isolates from one heterokaryon; these single-spore isolates had novel fingerprint haplotypes, also within the loops. In contrast, vc type WS-1, which comprises 85% of the population, was represented by a simple network with no loops, indicating a clonal lineage varying only by mutation. Almost all isolates of WS-1 had the same mating type; the exceptions were five isolates that were MAT heterokaryons. These results are consistent with the hypothesis that heterokaryons formed between vegetatively incompatible individuals, and recombination occurred by a parasexual process.     

CR1-mediated ATP Release by Human Red Blood Cells Promotes CR1 Clustering and Modulates the Immune Transfer Process

Humans and other higher primates are unique among mammals in using complement receptor 1 (CR1, CD35) on red blood cells (RBC) to ligate complement-tagged inflammatory particles (immune complexes, apoptotic/necrotic debris, and microbes) in the circulation for quiet transport to the sinusoids of spleen and liver where resident macrophages remove the particles, but allow the RBC to return unharmed to the circulation. This process is called immune-adherence clearance. In this study we found using luminometric- and fluorescence-based methods that ligation of CR1 on human RBC promotes ATP release. Our data show that CR1-mediated ATP release does not depend on Ca²⁺ or enzymes previously shown to mediate an increase in membrane deformability promoted by CR1 ligation. Furthermore, ATP release following CR1 ligation increases the mobility of the lipid fraction of RBC membranes, which in turn facilitates CR1 clustering, and thereby enhances the binding avidity of complement-opsonized particles to the RBC CR1. Finally, we have found that RBC-derived ATP has a stimulatory effect on phagocytosis of immune-adherent immune complexes.     

Evolved psychology in a novel environment

The human “environment of evolutionary adaptedness” can only be inferred indirectly. In contrast, the behavior of some nonhuman animals can be compared among “natural” and various altered environments. As an example, male immigration tactics in unprovisioned versus provisioned macaque (Macaca) populations are compared using Tooby and Cosmides’s (1992) framework for evolutionary functional analysis. In unprovisioned populations, social groups contain few males, and immigrant male takeovers of alpha rank occur frequently. In provisioned populations, groups contain many males, and males almost invariably enter social groups at very low rank and rise in rank only as more dominant males emigrate or die. Male conformity to the “seniority rule” is hypothesized to represent the behavioral output of an evolved decision-making algorithm (psychological mechanism) that takes into account (1) the net payoff of each rank in the dominance hierarchy and (2) the power of male group size as a predictor of the likelihood of successful immigrant takeover. Joseph H. Manson is Assistant Professor of Anthropology at the University of California, Los Angeles. His research interests are social relationships in nonhuman primates and humans, with particular emphases on mate choice, courtship tactics, intrasexual competition, and (currently) mother-infant relationships and infant handling. He has conducted fieldwork on rhesus macaques at Cayo Santiago and white-faced capuchins in Costa Rica.     

A model of stress and strain in the interosseous ligament of the forearm based on fiber network theory

Fiber network theory was developed to describe cloth, a thin material with strength in the fiber directions. The interosseous ligament (IOL) of the forearm is a broad, thin ligament with highly aligned fibers. The objectives of this study were to develop a model of the stress and strain distributions in the IOL, based on fiber network theory, to compare the strains from the model with the experimentally measured strains, and to evaluate the force distribution across the ligament fibers from the model. The geometries of the radius, ulna, and IOL were reconstructed from CT scans. Position and orientation of IOL insertion sites and force in the IOL were measured during a forearm compression experiment in pronation, neutral rotation, and supination. An optical image-based technique was used to directly measure strain in two regions of the IOL in neutral rotation. For the network model, the IOL was represented as a parametric ruled three-dimensional surface, with rulings along local fiber directions. Fiber strains were calculated from the deformation field, and fiber stresses were calculated from the strains using average IOL tensile properties from a previous study. The in situ strain in the IOL was assumed uniform and was calculated so that the net force predicted by the network model in neutral rotation matched the experimental result. The net force in the IOL was comparable to experimental results in supination and pronation. The model predicted higher stress and strain in fibers near the elbow in neutral rotation, and higher stresses in fibers near the wrist in supination. Strains in neutral forearm rotation followed the same trends as those measured experimentally. In this study, a model of stress and strain in the IOL utilizing fiber network theory was successfully implemented. The model illustrates variations in the stress and strain distribution in the IOL. This model can be used to show surgeons how different fibers are taut in different forearm rotation positions-this information is important for understanding the biomechanical role of the IOL and for planning an IOL reconstruction.     

Prion protein interacts with BACE1 protein and differentially regulates its activity toward wild type and Swedish mutant amyloid precursor protein

In Alzheimer disease amyloid-β (Aβ) peptides derived from the amyloid precursor protein (APP) accumulate in the brain. Cleavage of APP by the β-secretase BACE1 is the rate-limiting step in the production of Aβ. We have reported previously that the cellular prion protein (PrP(C)) inhibited the action of BACE1 toward human wild type APP (APP(WT)) in cellular models and that the levels of endogenous murine Aβ were significantly increased in PrP(C)-null mouse brain. Here we investigated the molecular and cellular mechanisms underlying this observation. PrP(C) interacted directly with the prodomain of the immature Golgi-localized form of BACE1. This interaction decreased BACE1 at the cell surface and in endosomes where it preferentially cleaves APP(WT) but increased it in the Golgi where it preferentially cleaves APP with the Swedish mutation (APP(Swe)). In transgenic mice expressing human APP with the Swedish and Indiana familial mutations (APP(Swe,Ind)), PrP(C) deletion had no influence on APP proteolytic processing, Aβ plaque deposition, or levels of soluble Aβ or Aβ oligomers. In cells, although PrP(C) inhibited the action of BACE1 on APP(WT), it did not inhibit BACE1 activity toward APP(Swe). The differential subcellular location of the BACE1 cleavage of APP(Swe) relative to APP(WT) provides an explanation for the failure of PrP(C) deletion to affect Aβ accumulation in APP(Swe,Ind) mice. Thus, although PrP(C) exerts no control on cleavage of APP(Swe) by BACE1, it has a profound influence on the cleavage of APP(WT), suggesting that PrP(C) may be a key protective player against sporadic Alzheimer disease.