Victims and survivors: Stable isotopes used to identify migrants from the Great Irish Famine to 19th century London

Historical evidence documents mass migration from Ireland to London during the period of the Great Irish Famine of 1845–52. The rural Irish were reliant on a restricted diet based on potatoes but maize, a C₄ plant, was imported from the United States of America in 1846–47 to mitigate against Famine. In London, Irish migrants joined a population with a more varied diet. To investigate and characterize their diet, carbon and nitrogen isotope ratios were obtained from bone collagen of 119 and hair keratin of six individuals from Lukin Street cemetery, Tower Hamlets (1843–54), and bone collagen of 20 individuals from the cemetery at Kilkenny Union Workhouse in Ireland (1847–51). A comparison of the results with other contemporaneous English populations suggests that Londoners may have elevated δ¹⁵N compared with their contemporaries in other cities. In comparison, the Irish group have lower δ¹⁵N. Hair analysis combined with bone collagen allows the reconstruction of perimortem dietary changes. Three children aged 5–15 years from Kilkenny have bone collagen δ¹³C values that indicate consumption of maize (C₄). As maize was only imported into Ireland in quantity from late 1846 and 1847, these results demonstrate relatively rapid bone collagen turnover in children and highlight the importance of age‐related bone turnover rates, and the impact the age of the individual can have on studies of short‐term dietary change or recent migration. Stable light isotope data in this study are consistent with the epigraphic and documentary evidence for the presence of migrants within the London cemetery. Am J Phys Anthropol, 2013. © 2012 Wiley Periodicals, Inc.     

Epistasis in iron metabolism: complex interactions between Cp, Mon1a, and Slc40a1 loci and tissue iron in mice

Disorders of iron metabolism are among the most common acquired and constitutive diseases. Hemochromatosis has a solid genetic basis and in Northern European populations it is usually associated with homozygosity for the C282Y mutation in the HFE protein. However, the penetrance of this mutation is incomplete and the clinical presentation is highly variable. The rare and common variants identified so far as genetic modifiers of HFE-related hemochromatosis are unable to account for the phenotypic heterogeneity of this disorder. There are wide variations in the basal iron status of common inbred mouse strains, and this diversity may reflect the genetic background of the phenotypic diversity under pathological conditions. We therefore examined the genetic basis of iron homeostasis using quantitative trait loci mapping applied to the HcB-15 recombinant congenic strains for tissue and serum iron indices. Two highly significant QTL containing either the N374S Mon1a mutation or the Ferroportin locus were found to be major determinants in spleen and liver iron loading. Interestingly, when considering possible epistatic interactions, the effects of Mon1a on macrophage iron export are conditioned by the genotype at the Slc40a1 locus. Only mice that are C57BL/10ScSnA homozygous at both loci display a lower spleen iron burden. Furthermore, the liver-iron lowering effect of the N374S Mon1a mutation is observed only in mice that display a nonsense mutation in the Ceruloplasmin (Cp) gene. This study highlights the existence of genetic interactions between Cp, Mon1a, and the Slc40a1 locus in iron metabolism, suggesting that epistasis may be a crucial determinant of the variable biological and clinical presentations in iron disorders.     

Kinetic Characterization of 100 Glycoside Hydrolase Mutants Enables the Discovery of Structural Features Correlated with Kinetic Constants

The use of computational modeling algorithms to guide the design of novel enzyme catalysts is a rapidly growing field. Force-field based methods have now been used to engineer both enzyme specificity and activity. However, the proportion of designed mutants with the intended function is often less than ten percent. One potential reason for this is that current force-field based approaches are trained on indirect measures of function rather than direct correlation to experimentally-determined functional effects of mutations. We hypothesize that this is partially due to the lack of data sets for which a large panel of enzyme variants has been produced, purified, and kinetically characterized. Here we report the k_cat and K_M values of 100 purified mutants of a glycoside hydrolase enzyme. We demonstrate the utility of this data set by using machine learning to train a new algorithm that enables prediction of each kinetic parameter based on readily-modeled structural features. The generated dataset and analyses carried out in this study not only provide insight into how this enzyme functions, they also provide a clear path forward for the improvement of computational enzyme redesign algorithms.     

Effects of avermectin residues in cattle dung on yellow dung fly Scathophaga stercoraria (Diptera: Scathophagidae) populations in grazed pastures

The effects of avermectin exposure on natural populations of the yellow dung fly, Scathophaga stercoraria Linnaeus, were investigated at the field scale on farms in south-west Scotland. Pastures forming the focus of the study were grazed with either untreated cattle or cattle receiving standard, manufacturer-recommended treatment regimes of an avermectin product. Flies were sampled between April and July in 2002 and 2003 using dung-baited pitfall traps. Abundance and wing asymmetry in S. stercoraria populations were examined in relation to a range of environmental and management variables (including avermectin exposure, pasture management intensity, weather and season). Data used for abundance analyses were collected in fields where treated cattle had been dosed with either doramectin or ivermectin, while the data for the asymmetry analyses were from a subset of fields where treated cattle had been dosed with doramectin only. While abundance of S. stercoraria varied significantly between years and with season, there was no difference in their abundance between fields grazed by avermectin-treated or untreated cattle. Asymmetry was significantly higher in fly populations in fields grazed by doramectin-treated cattle, suggesting that exposure to doramectin during development could have imposed some degree of environmental stress. While these results suggest that exposure to doramectin residues in dung on grazed pastures may have sublethal effects on the insects developing in that dung, there was no evident avermectin effect on the abundance of adult S. stercoraria occurring in the pastures.     

Stocking may increase mitochondrial DNA diversity but fails to halt the decline of endangered Atlantic salmon populations

Over the last 50 years, Spanish Atlantic salmon (Salmo salar) populations have been in decline. In order to bolster these populations, rivers were stocked with fish of northern European origin during the period 1974–1996, probably also introducing the furunculosis-inducing pathogen, Aeromonas salmonicida. Here we assess the relative importance of processes influencing mitochondrial (mt)DNA variability in these populations from 1948 to 2002. Genetic material collected over this period from four rivers in northern Spain (Cantabria) was used to detect variability at the mtDNA ND1 gene. Before stocking, a single haplotype was found at high frequency (0.980). Following stocking, haplotype diversity (h) increased in all rivers (mean h before stocking was 0.041, and 0.245 afterwards). These increases were due principally to the dramatic increase in frequency of a previously very low frequency haplotype, reported at higher frequencies in northern European populations proximate to those used to stock Cantabrian rivers. Genetic structuring increased after stocking: among-river differentiation was low before stocking (1950s/1960s Φ _ST = –0.00296–0.00284), increasing considerably at the height of stocking (1980s Φ _ST = 0.18932) and decreasing post-stocking (1990s/2002 Φ _ST = 0.04934–0.03852). Gene flow from stocked fish therefore seems to have had a substantial role in increasing mtDNA variability. Additionally, we found significant differentiation between individuals that had probably died from infectious disease and apparently healthy, angled fish, suggesting a possible role for pathogen-driven selection of mtDNA variation. Our results suggest that stocking with non-native fish may increase genetic diversity in the short term, but may not reverse population declines.     

Detecting population expansion and decline using microsatellites

This article considers a demographic model where a population varies in size either linearly or exponentially. The genealogical history of microsatellite data sampled from this population can be described using coalescent theory. A method is presented whereby the posterior probability distribution of the genealogical and demographic parameters can be estimated using Markov chain Monte Carlo simulations. The likelihood surface for the demographic parameters is complicated and its general features are described. The method is then applied to published microsatellite data from two populations. Data from the northern hairy-nosed wombat show strong evidence of decline. Data from European humans show weak evidence of expansion.     

Molecular mechanisms of iron homeostasis

Iron metabolism in mammals requires a complex and tightly regulated molecular network. The classical view of iron metabolism has been challenged over the past ten years by the discovery of several new proteins, mostly Fe (II) iron transporters, enzymes with ferro-oxydase (hephaestin or ceruloplasmin) or ferri-reductase (Dcytb) activity or regulatory proteins like HFE and hepcidin. Furthermore, a new transferrin receptor has been identified, mostly expressed in the liver, and the ability of the megalin-cubilin complex to internalise the urinary Fe (III)-transferrin complex in renal tubular cells has been highlighted. Intestinal iron absorption by mature duodenal enterocytes requires Fe (III) iron reduction by Dcytb and Fe (II) iron transport through apical membranes by the iron transporter Nramp2/DMT1. This is followed by iron transfer to the baso-lateral side, export by ferroportin and oxidation into Fe (III) by hephaestin prior to binding to plasma transferrin. Macrophages play also an important role in iron delivery to plasma transferrin through phagocytosis of senescent red blood cell, heme catabolism and recycling of iron. Iron egress from macrophages is probably also mediated by ferroportin and patients with heterozygous ferroportin mutations develop progressive iron overload in liver macrophages. Iron homeostasis at the level of the organism is based on a tight control of intestinal iron absorption and efficient recycling of iron by macrophages. Signalling between iron stores in the liver and both duodenal enterocytes and macrophages is mediated by hepcidin, a circulating peptide synthesized by the liver and secreted into the plasma. Hepcidin expression is stimulated in response to iron overload or inflammation, and down regulated by anemia and hypoxia. Hepcidin deficiency leads to iron overload and hepcidin overexpression to anemia. Hepcidin synthesis in response to iron overload seems to be controlled by the HFE molecule. Patients with hereditary hemochromatosis due to HFE mutation have impaired hepcidin synthesis and forced expression of an hepcidin transgene in HFE deficient mice prevents iron overload. These results open new therapeutic perspectives, especially with the possibility to use hepcidin or antagonists for the treatment of iron overload disorders.