A model for nematodiasis in New Zealand lambs.

A strategic model is described for the epidemiology of mixed nematode infections in New Zealand lambs. The model successfully reproduces known patterns of parasite epidemiology and production loss in lambs under currently implemented control strategies. The variation in model output during sensitivity analysis was within acceptable limits defined by field data. Model output was most sensitive to variation in parameters affecting survival and migration of the free-living stages and host resistance to infection, suggesting that these factors are most influential in regulating parasite populations. It is intended to use the model to focus research on key aspects of nematode epidemiology and control and, following the incorporation of appropriate genetic mechanisms, anthelmintic resistance.     

Pedigree-based and phylogenetic methods support surprising patterns of mutation rate and spectrum in the gray mouse lemur

Mutations are the raw material on which evolution acts, and knowledge of their frequency and genomic distribution is crucial for understanding how evolution operates at both long and short timescales. At present, the rate and spectrum of de novo mutations have been directly characterized in relatively few lineages. Our study provides the first direct mutation-rate estimate for a strepsirrhine (i.e., the lemurs and lorises), which comprises nearly half of the primate clade. Using high-coverage linked-read sequencing for a focal quartet of gray mouse lemurs (Microcebus murinus), we estimated the mutation rate to be among the highest calculated for a mammal at 1.52 × 10^–8 (95% credible interval: 1.28 × 10⁻⁸–1.78 × 10⁻⁸) mutations/site/generation. Further, we found an unexpectedly low count of paternal mutations, and only a modest overrepresentation of mutations at CpG sites. Despite the surprising nature of these results, we found both the rate and spectrum to be robust to the manipulation of a wide range of computational filtering criteria. We also sequenced a technical replicate to estimate a false-negative and false-positive rate for our data and show that any point estimate of a de novo mutation rate should be considered with a large degree of uncertainty. For validation, we conducted an independent analysis of context-dependent substitution types for gray mouse lemur and five additional primate species for which de novo mutation rates have also been estimated. These comparisons revealed general consistency of the mutation spectrum between the pedigree-based and the substitution-rate analyses for all species compared.Subject terms: Evolution, Molecular evolution     

一种新的可用于干细胞移植的新西兰白兔青光眼视神经损伤模型

青光眼是一种致盲且不可逆神经退行性疾病,目前还没有能够彻底解决其视野缺失的治疗方法。神经干细胞研究的兴起为该病的治疗带来了可能,且迫切需要一种适用于干细胞移植研究的青光眼造模方法。该实验对新西兰白兔球结膜下注射地塞米松给药,2.5mg/次,一周3次,持续8周。眼底照相显示造模眼眼球屈光间质保持清晰,视乳头凹陷明显扩大、血管呈屈膝状;病理切片显示造模眼视神经明显损伤;海德堡视网膜断层扫描仪(Heidelberg retina tomography,HRT)定量分析显示造模眼盘沿面积减小(1.10±0.88)mm2、杯/盘比增大0.17±0.13,视网膜神经纤维层平均厚度降低(0.44±0.31)mm等青光眼性质病理改变,且均达到极显著水平(P<0.001)。建模成功后,于角膜缘后4mm向造模眼玻璃体注入猕猴神经干细胞,植入5个月后摘取眼球切片,通过荧光显微镜观察到存活的移植细胞。该实验建立了一种简单可靠、重复性强且适用于神经干细胞移植研究的慢性青光眼造模方法。     

Haldane and the mutation rate

Based on a talk given at the Haldane Centenary Symposium held on 6 November 1992 at Ahmedabad as part of the 58th Annual Meeting of the Indian Academy of Sciences.     

Identification of a mutation causing mucopolysaccharidosis type IIIA in New Zealand Huntaway dogs

Mucopolysaccharidosis type IIIA (MPS IIIA) is an autosomal recessive disease that occurs due to a deficiency of heparan sulfate sulfamidase (SGSH). The deficiency of SGSH results in the lysosomal accumulation and urinary excretion of the glycosaminoglycan heparan sulfate. The clinical severity of MPS IIIA is predominantly characterized by severe central nervous system degeneration. Naturally occurring MPS IIIA has recently been described in New Zealand Huntaway dogs, with similar disease progression and biochemical characteristics observed in severely affected MPS IIIA patients. Here, we identify the disease-causing mutation in the MPS IIIA Huntaway dog as 708-709insC. The frequency of the 708-709insC mutation in a sample group of 203 New Zealand Huntaway dogs was determined to be 3.8%. The identification of the 708-709insC mutation will permit the identification of heterozygous carriers as an initial step toward establishing a breeding colony of MPS IIIA dogs for the study of various therapeutic strategies targeted to the central nervous system.     

A model for the correlation of mutation rate with GC content and the origin of GC-rich isochores

Based on the biochemical kinetics of DNA replication and mutagenesis, including misincorporation and correction, a model has been developed for studying the relationships among the mutation rate (u), the G + C content of the sequence (f), and the G + C proportion in the nucleotide precursor pool (N). Also a measure for the next-nucleotide effect, called the maximum capacity of the next-nucleotide effect (MC), has been proposed. Under the normal physiological conditions of mammalian germ cells, our results indicate: (1) the equilibrium G + C content in a sequence is approximately equal to the G + C proportion in the nucleotide precursor pool, i.e., f ≈ N, which is independent of the next-nucleotide effect; (2) an inverted-V-shaped distribution of mutation rates with respect to G + C contents is predicted, when the next-nucleotide effect is week, i.e., MC ≈ 1; (3) the distribution becomes flatter (i.e., inverted-U-shaped) as MC increases, but the peak at 50% GC is still observed when MC < 2; and (4) the peak disappears when MC > 2.8, that is, when the next-nucleotide effect becomes strong. Our results suggest that changes in the relative concentrations of nucleotide precursors can cause variations among genes both in mutation rate and in G + C content and that compositional isochores (DNA segments with a homogeneous G + C content) can arise in a genome due to differences in replication times of DNA segments. Correspondence to: W.-H. Li     

Tolerance defects in New Zealand Black and New Zealand Black X New Zealand White F1 mice

The susceptibility of autoimmune NZB and (NZB X NZW)F1 mice to the induction of tolerance by monomeric BSA was compared with several normal mouse strains. Unresponsiveness in T and B lymphocyte compartments was probed by challenging with DNP8BSA and measuring anti-DNP and anti-BSA antibodies separately. Tolerance induced by monomeric BSA was carrier specific, and there was no evidence of epitope-specific suppression. Normal NZW, NFS, and B10.D2 mice were easily rendered tolerant with monomeric BSA and did not produce anti-DNP or anti-BSA antibodies after challenge with DNP8BSA. By contrast, the lack of anti-DNP antibody response in similarly treated NZB mice was dependent on the dose of monomeric BSA, indicating that the helper T cells were partially resistant to tolerance induction. NZB mice treated with a high dose of monomeric BSA produced anti-BSA, but not anti-DNP, antibodies after immunization. Thus, the anti-carrier B cells in NZB mice may have been primed by monomeric BSA. The presence of the xid gene on the NZB background rendered the mice susceptible to induction of tolerance, suggesting that the tolerance defect in NZB mice involves the B cell compartment. This abnormal antibody response was a dominant trait: (NZB X NFS)F1 and (NZB X B10.D2)F1 mice had the same characteristics as NZB mice. These F1 hybrids do not develop autoimmune disease, indicating that resistance to experimental tolerance induction expressed at a B cell level may not be sufficient for disease development. In contrast to NZB and other NZB F1 hybrids, (NZB X NZW)F1 hybrids treated with monomeric BSA and challenged with DNP8BSA responded to both DNP and BSA. The contribution of a B cell defect to the tolerance abnormality of (NZB X NZW)F1 mice was examined by analyzing the effect of the xid gene on the progeny of (NZB.xid X NZW)F1 mice. Unlike the effect of the xid gene on NZB mice, both phenotypically normal heterozygous female and phenotypically xid hemizygous male mice produced anti-DNP and anti-BSA antibodies after tolerance induction and immunization, demonstrating that a major helper T cell abnormality was present in (NZB X NZW)F1 mice. The (NZW X B10.D2)F1 hybrid was rendered tolerant by this procedure, indicating that the helper T cell defect (NZB X NZW)F1 mice may have resulted from gene complementation with the NZB mice contributing partial resistance of T helper cells to tolerance induction.(ABSTRACT TRUNCATED AT 400 WORDS)     

Clone selection and the mutation rate

A statistical model for mutation and selection is formulated for organisms that reproduce by division. The mutation rate that optimizes the probability of clone survival is approximated using the theory of branching processes. However, it is shown by example that this optimizing mutation rate need not be the most advantageous mutation rate. The principle that selection favors those modifying features that optimize the probability of clone survival is thereby shown to be of limited applicability.     

Decline in capture rate of stoats at high mouse densities in New Zealand

We present two statistical models documenting variations in density indices of stoats and of mice in New Zealand southern beech (Nothofagus spp.) forests. They confirm previous, simpler correlations showing that the summer capture rate of stoats increases with spring mouse density index up to about 20–25 mouse captures per 100 trap-nights (C/100TN). However, at much higher mouse densities (60–80 C/100TN), observed in the Grebe and Borland Valleys in southern Fiordland in 1979/80 and again in 1999/2000, fewer stoats were caught than expected. These models quantify a serious decline in capture rate of stoats during periods of high mouse abundance over the range 25-80 C/100TN. At such times, management strategies aiming to protect threatened birds by intensive lethal trapping of stoats during the nesting seasons may be least effective just when they are most needed.     

Mammalian DNA replication: mutation biases and the mutation rate

Experimental studies have shown that the fidelity of DNA replication can be affected by the concentrations of free deoxyribonucleotides present in the cell. Replication of mammalian chromosomes is achieved using pools of newly-synthesized deoxyribonucleotides which fluctuate during the cell cycle. Since regions of mammalian chromosomes are replicated sequentially, there is the potential for differences among mammalian loci in both the relative and absolute frequencies of the various transitional and transversional mutations which may occur. Where these mutations are effectively neutral, at silent sites in genes and in non-coding sequences, this may result in different rates of evolution and in different base compositions, as have been observed in data from mammalian genes. A simple model of the DNA replication process is developed to describe how the mutation rate could be affected by the G + C contents of the deoxyribonucleotide pools and of the replicating DNA. Mutation rates are predicted to vary from locus to locus; only in the particular case of identical G + C contents in the DNA locus and the deoxyribonucleotide pools, and no proofreading, will the mutation rate be uniform over all loci.     

A two-hit trigger for siRNA biogenesis in plants

In Arabidopsis, microRNA-directed cleavage can define one end of RNAs that then generate phased siRNAs. However, most miRNA-targeted RNAs do not spawn siRNAs, suggesting the existence of additional determinants within those that do. We find that in moss, phased siRNAs arise from regions flanked by dual miR390 cleavage sites. AtTAS3, an siRNA locus important for development and conserved among higher plants, also has dual miR390 complementary sites. Both sites bind miR390 in vitro and are functionally required in Arabidopsis, but cleavage is undetectable at the 5' site--demonstrating that noncleavable sites can be functional in plants. Phased siRNAs also emanate from the bounded regions of every Arabidopsis gene with two known microRNA/siRNA complementary sites, but only rarely from genes with single sites. Therefore, two "hits,"--often, but not always, two cleavage events--constitute a conserved trigger for siRNA biogenesis, a finding with implications for recognition and silencing of aberrant RNA.     

Hyper IgE in New Zealand black mice due to a dominant-negative CD23 mutation

Immunoglobulin E (IgE) plays a critical role in both resistance to parasitic infection and allergy to environmental antigens. The IgE response is in turn regulated by the B-cell co-receptor CD23, and CD23-deficient mice show exaggerated IgE responses and airway hyper-responsiveness. In this report, we show that New Zealand black (NZB) mice express a variant CD23 allele, with mutations in both the C-lectin-binding domain and stalk region, which fails to bind IgE at high affinity and has reduced expression on the cell surface. Expression of the variant CD23 chain interferes with trimerisation of the receptor and has a dominant-negative effect leading to reduced IgE binding in crosses between NZB and other strains. Genetic mapping shows that the variant CD23 leads to an exaggerated primary IgE response, which is independent of other strain-specific effects. These results suggest that NZB mice or mice carrying the variant allele will be useful models for studying both allergy and quantitative traits associated with atopy. The exaggerated IgE response provides an explanation for the natural resistance of NZB mice to parasitic infection by Leishmania.     

Multiple factors determine the rate of increase of an invading non-native tree in New Zealand

We reconstructed the invasion of a non-native tree (hawthorn, Crataegus monogyna) into fire-induced grassland in montane South Island, New Zealand. Using the relationship between height and age to reconstruct the rate of increase of the population, we identified three distinct invasion phases. We hypothesised that these related to the abundance of woody vegetation and therefore of non-native blackbirds (Turdus merula), the primary disperser of hawthorn in this environment. From the 1930s to 1959, increase was relatively slow, with hawthorn spread probably constrained due to browsing of seedlings by European rabbits (Oryctolagus cuniculus) and the low abundance of a native N-fixing shrub (matagouri, Discaria toumatou) providing few perches and nesting sites for blackbirds and safe sites for hawthorn establishment. Subsequently, from 1959 to 1976, hawthorn showed greater than six fold acceleration in its rate of population increase, resulting largely from intensive rabbit control, less frequent fires, and aerial topdressing of phosphate fertilizer promoting the growth of matagouri scrub. In addition, maturing hawthorn trees provided additional food and nesting sites for blackbirds. Hawthorn population increase slowed again from 1976, possibly because most suitable habitat in the immediate vicinity of the population neared saturation. From this case study we have constructed a general hypothesis for the factors determining the rate of invasion of matagouri—grassland habitats by bird-dispersed non-native woody plants in montane New Zealand.     

Radiolysis of lac repressor by gamma-rays and heavy ions: a two-hit model for protein inactivation

Upon gamma-ray or argon ion irradiation of the lac repressor protein, its peptide chain is cleaved and the protein loses its lac operator-binding activity, as shown respectively by polyacrylamide gel electrophoresis and retardation gel electrophoresis. We developed phenomenological models that satisfactorily account for the experimental results: the peptide chain cleavage model considers that the average number of chain breaks per protomer is proportional to the irradiation dose and that the distribution of the number of breaks per protomer obeys Poisson's law. The repressor inactivation model takes into account the quaternary structure (a dimer of dimer) and the organization of the repressor in domains (two DNA binding sites, one per dimer). A protomer is inactivated by at least two different radiation-induced damages. A dimer is inactivated when at least one of the two protomers is inactivated. A tetramer is inactivated when both dimers are inactivated. From the combination of both models, we can deduce that chain cleavage cannot account for the protein inactivation, which should mainly result from oxidation of amino acid side chains. Indeed, particularly oxidizable and accessible amino acids (Tyr, His) are involved in the DNA binding process.     

Mitochondrial DNA sequences support allozyme evidence for cryptic radiation of New Zealand Peripatoides (Onychophora)

A combination of single-strand conformation polymorphism analysis (SSCP) and sequencing were used to survey cytochrome oxidase I (COI) mitochondrial DNA (mtDNA) diversity among New Zealand ovoviviparous Onychophora. Most of the sites and individuals had previously been analysed using allozyme electrophoresis. A total of 157 peripatus collected at 54 sites throughout New Zealand were screened yielding 62 different haplotypes. Comparison of 540-bp COI sequences from Peripatoides revealed mean among-clade genetic distances of up to 11. 4% using Kimura 2-parameter (K2P) analysis or 17.5% using general time-reversible (GTR + I + Gamma) analysis. Phylogenetic analysis revealed eight well-supported clades that were consistent with the allozyme analysis. Five of the six cryptic peripatus species distinguished by allozymes were confirmed by mtDNA analysis. The sixth taxon appeared to be paraphyletic, but genetic and geographical evidence suggested recent speciation. Two additional taxa were evident from the mtDNA data but neither occurred within the areas surveyed using allozymes. Among the peripatus surveyed with both mtDNA and allozymes, only one clear instance of recent introgression was evident, even though several taxa occurred in sympatry. This suggests well-developed mate recognition despite minimal morphological variation and low overall genetic diversity.     

Seedling growth rate and survival do not predict invasiveness in naturalized woody plants in New Zealand

We tested if plant species invasiveness (measured as rate of geographic spread in New Zealand) was positively associated with seedling relative growth rate (RGR) and survival, among 33 naturalized woody plant species in four families (Fabaceae, Mimosaceae, Pinaceae, Rosaceae). Eight disturbance and fertilization treatments were applied to seedlings in pots to mimic conditions the species are likely to encounter in the wild. We tested if seedlings of more invasive species have higher RGR and greater survival under these conditions. We also tested whether more invasive species had wider tolerance of the conditions to which they were subjected. There were no significant relationships between seedling RGR or survival and invasiveness for any of the treatments. Measures of tolerance (a species' relative performance across all treatments), based on both RGR and survival, also failed to explain differences in invasiveness. Our findings contrast with those from a recent study by Grotkopp et al. (2002) showing a positive correlation between seedling RGR and invasiveness in Pinus species, even though our study included 12 Pinus species. The findings of the two studies may differ because they focus on different stages in the invasion process. Our study tested whether RGR (and survival) was associated with the rate of spread of invasive species following naturalization, whereas Grotkopp et al. primarily tested whether RGR was associated with the probability of naturalization. We caution that relationships between RGR and measures of invasiveness are likely to be confounded with human introduction effort. Among pines, species with high RGR are more likely to have been widely cultivated, for purposes such as timber production, providing more opportunities for naturalization and spread. Associations between RGR, invasiveness and human introduction effort need to be partitioned out before we can reliably infer causal relationships.     

Historical records of passerine introductions to New Zealand fail to support the propagule pressure hypothesis

Blackburn et al. (Biodiver Conserv 20:2189–2199, 2011) claim that a reanalysis of passerine introductions to New Zealand supports the propagule pressure hypothesis. The conclusions of Blackburn et al. (2011) are invalid for three reasons: First, the historical record is so flawed that there is no sound basis for identifying the mechanisms behind extinction following introduction, or whether species were successful because they were introduced in large numbers or were introduced in large numbers because earlier releases succeeded. Second, the GLIMMIX analysis of Blackburn et al. (2011) is biased in favor of the propagule pressure hypothesis. Third, the population viability analysis presented by Blackburn et al. (2011) is based on unjustified and questionable assumptions. It is likely that the outcome of passerine bird introductions to New Zealand depended on species characteristics, site characteristics, and human decisions more than on a simple summing of the numbers introduced.     

Fleshy-fruitedness in the New Zealand flora

Aim It has been claimed that the New Zealand flora has an unusually high frequency of fleshy-fruitedness. This paper tests whether fleshy-fruitedness is indeed more common in New Zealand than in other temperate floras, then examines the distribution of fleshy-fruitedness among taxa and floristic elements to determine whether the flora conforms to predictions for a continental island with a relictual floristic element. Lastly, I test the extent to which fleshy-fruitedness has influenced colonization success and subsequent speciation within New Zealand. Methods Information on fruit characteristics for all indigenous seed plants was extracted from the Flora of New Zealand series and analysed with χ² tests. Results Contrary to previous claims fleshy-fruitedness was not unusually common in the New Zealand flora as a whole, when compared with other temperate floras. It is only more common in alpine communities and among trees. I also found no evidence for selective immigration; fleshy-fruited New Zealand genera were not more likely, than dry-fruited genera, to also occur in Australia. Furthermore there is no evidence that the New Zealand environment has favoured fleshy-fruited taxa; there has been no autochthonous evolution of fleshy-fruitedness in New Zealand, fleshy-fruitedness has had no significant effect on speciation within New Zealand, and endemic genera are no more likely to be fleshy-fruited than nonendemic genera. Fleshy-fruitedness in New Zealand is, however, strongly related to floristic elements of the flora. New Zealand is a continental island and therefore, theoretically, those elements of the flora dating from a time when the landmass was less isolated, should show a more balanced representation of dispersal modes. Contrary to this, fleshy-fruitedness is more common among species in Gondwanan taxa or in taxa with pollen records dating to before the Miocene. Main conclusions Fleshy-fruitedness in New Zealand conforms to neither the expectations for an isolated landmasses, namely a disharmonic range of dispersal modes, nor expectations for a continental island. I suggest that this pattern may be a product of selective survival of highly vagile taxa in the low-lying archipelago that was New Zealand during the late Cretaceous to mid-Cenozoic, followed by an invasion by taxa with a broader range of dispersal modes facilitated by the establishment of the circumpolar current.