HLA class II alleles and measles virus-specific cytokine immune response following two doses of measles vaccine

Measles virus-specific T cells and the production of cytokines play a critical role in the immune response following measles immunization. To understand the genetic factors that influence variation in IFN- and IL-4 responses following measles immunization and to provide insight into the factors influencing both cellular and humoral immunity to measles, we assessed associations between human leukocyte antigen (HLA) class II genes and measles-specific Th1 and Th2-type cytokine responses in peripheral blood lymphocytes from 339 children previously vaccinated with two doses of measles-mumps-rubella vaccine (MMR-II). Median values for measles-specific IFN- and IL-4 secretion levels were 40.73 and 9.71 pg/ml, respectively. The global tests suggested associations between measles-specific IFN- response and alleles of the DRB1 and DQB1 loci (P=0.07 and P=0.02, respectively). Specifically, DRB1*0301, *0901, and *1501 alleles were significantly associated with IFN- secretion. The alleles that suggested evidence of an HLA association with IL-4 secretion were DRB1*0103, *0701, and *1101. Th1 cytokine responses and DQB1 allele associations revealed that the alleles with the strongest association with IFN- secretion were DQB1*0201, *0303, *0402, and *0602. Specific alleles with a suggestive association with low measles-specific Th2 cytokine responses were DQB1*0202 and *0503. In addition, DPB1*0101, *0201, and *0601 alleles provided suggestive evidence of an HLA association with measles-induced IFN- response, while DPB1*0501 was associated with an IL-4 response. These data suggest that IFN- and IL-4 cytokine responses to measles may be genetically restricted in part by HLA class II genes, which in turn can restrict the cellular immune response to measles vaccine.     

Genetic variability and phylogeography of the invasive zebra mussel, Dreissena polymorpha (Pallas)

The zebra mussel, Dreissena polymorpha (Pallas), a bivalve species originally native to the Black and Caspian seas, has invaded Ireland in the last decade. Five microsatellite loci were used to investigate genetic diversity and population structure in 10 populations across Europe (Ireland, UK, the Netherlands and Romania) and the Great Lakes (Lake Ontario and Lake St Clair). Levels of allelic diversity and mean expected heterozygosity were high for all populations (mean number of alleles/locus and H(E) were 10-15.2 and 0.79-0.89, respectively). High levels of polymorphism observed in Irish populations suggest that the Irish founder population(s) were large and/or several introductions took place after foundation. Significant deficits of heterozygotes were recorded for all populations, and null alleles were the most probable factor contributing to these deficits. Pairwise comparisons using Fisher exact tests and F(ST) values revealed little genetic differentiation between Irish populations. The UK sample was not significantly differentiated from the Irish samples, most probably reflecting an English origin for Irish zebra mussels. No significant differentiation was detected between the two Great Lakes populations. Our data support a northwest rather than a central or east European source for North American zebra mussels.     

Estimating pollen flow using SSR markers and paternity exclusion: accounting for mistyping

Highly informative genetic markers, such as simple sequence repeats (SSRs), can be used to directly measure pollen flow by parentage analysis. However, mistyping (i.e. false inference of genotypes caused by the occurrence of null alleles, mutations, and detection errors) can lead to substantial biases in the estimates obtained. Using computer simulations, we evaluated a direct method for estimating pollen immigration using SSR markers and a paternity exclusion approach. This method accounts for mistyping and does not rely on assumptions about the distribution of male reproductive success. If ignored, even minor rates of mistyping (1.5%) resulted in overestimating pollen immigration by up to 150%. When we required at least two mismatching loci before excluding candidate fathers from paternity, the resulting pollen immigration estimates had small biases for rates of mistyping up to 4.5%. Requiring at least three mismatches for exclusion was needed to minimize the upward biases of pollen immigration caused by rates of mistyping up to 10.5%. The minimum number of highly variable SSR loci needed to minimize cryptic gene flow and obtain reliable estimates of pollen immigration varied from five to seven for a sampling scheme applicable to most conifers (i.e. when paternal haplotypes can be unambiguously determined). Between five and nine highly variable SSR loci were needed for a more general sampling scheme that is applicable to all diploid seed plants. With moderately variable SSR markers, consistently accurate estimates of pollen immigration could be obtained only for rates of mistyping up to 4.5%. We developed the POLLEN FLOW (PFL) computer program which can be used to obtain unbiased and precise estimates of pollen immigration under a wide range of conditions, including population sizes as large as 600 parents and mistyping rates as high as 10.5%.     

Conditional likelihood score functions for mixed models in linkage analysis

In this paper, we develop a general strategy for linkage analysis, applicable for arbitrary pedigree structures and genetic models with one major gene, polygenes and shared environmental effects. Extending work of Whittemore (1996), McPeek (1999) and Hossjer (2003d), the efficient score statistic is computed from a conditional likelihood of marker data given phenotypes. The resulting semiparametric linkage analysis is very similar to nonparametric linkage based on affected individuals. The efficient score S depends not only on identical-by-descent sharing and phenotypes, but also on a few parameters chosen by the user. We focus on (1) weak penetrance models, where the major gene has a small effect and (2) rare disease models, where the major gene has a possibly strong effect but the disease causing allele is rare. We illustrate our results for a large class of genetic models with a multivariate Gaussian liability. This class incorporates one major gene, polygenes and shared environmental effects in the liability, and allows e.g. binary, Gaussian, Poisson distributed and life-length phenotypes. A detailed simulation study is conducted for Gaussian phenotypes. The performance of the two optimal score functions S(wpairs) and S(normdom) are investigated. The conclusion is that (i) inclusion of polygenic effects into the score function increases overall performance for a wide range of genetic models and (ii) score functions based on the rare disease assumption are slightly more powerful.     

Non-Mendelian transmission of alleles at microsatellite loci: an example in Ixodes ricinus, the vector of Lyme disease

Microsatellite loci are usually considered to be neutral co-dominant and Mendelian markers. We undertook to study the inheritance of five microsatellite loci in the European Lyme disease vector, the tick Ixodes ricinus. Only two loci appeared fully Mendelian while the three others displayed non-Mendelian patterns that highly frequent null alleles could not fully explain. At one locus, IR27, some phenomenon seems to hinder the PCR amplification of one allele, depending on its origin (maternal imprinting) and/or its size (short allele dominance). DNA methylation, which appeared to be a possible explanation of this amplification bias, was rejected by a specific test comparing the amplification efficiency that did not differ between unmethylated and experimentally methylated DNA. The role of allele size in heterozygous individuals was then revealed from the data available on field collected ticks and consistent with the results of a theoretical approach. These observations highlight the need for prudence while inferring reproductive systems (selfing rates), parentage or even allelic frequencies from microsatellite markers, in particular for parasitic organisms for which molecular approaches often represent the only way for population biology inferences.     

Analysis of microsatellite variation in Pinus radiata reveals effects of genetic drift but no recent bottlenecks

Most conifer species occur in large continuous populations, but radiata pine, Pinus radiata, occurs only in five disjunctive natural populations in California and Mexico. The Mexican island populations were presumably colonized from the mainland millions of years ago. According to Axelrod (1981), the mainland populations are relicts of an earlier much wider distribution, reduced some 8,000 years ago, whereas according to Millar (1997, 2000), the patchy metapopulation-like structure is typical of the long-term population demography of the species. We used 19 highly polymorphic microsatellite loci to describe population structure and to search for signs of the dynamics of population demography over space and time. Frequencies of null alleles at microsatellite loci were estimated using an approach based on the probability of identity by descent. Microsatellite genetic diversities were high in all populations [expected heterozygosity (H(e)) = 0.68-0.77], but the island populations had significantly lower estimates. Variation between loci in genetic differentiation (F(ST)) was high, but no locus deviated statistically significantly from the rest at an experiment wide level of 0.05. Thus, all loci were included in subsequent analysis. The average differentiation was measured as F(ST) = 0.14 (SD 0.012), comparable with earlier allozyme results. The island populations were more diverged from the other populations and from an inferred common ancestral gene pool than the mainland ones. All populations showed a deficiency of expected heterozygosity given the number of alleles, the mainland populations more so than the island ones. The results thus do not support a recent important contraction in the mainland range of radiata pine.     

Major histocompatibility alleles associated with local resistance to malaria in a passerine

Malaria parasites are a major cause of human mortality in tropical countries and a potential threat for wildlife, as witnessed by the malaria-induced extinction of naive Hawaiian avifauna. Identifying resistance mechanisms is therefore crucial both for human health and wildlife conservation. Patterns of malaria resistance are known to be highly polygenic in both humans and mice, with marked contributions attributed to major histocompatibility (Mhc) genes. Here we show that specific Mhc variants are linked to both increased resistance and susceptibility to malaria infection in a wild passerine species, the house sparrow (Passer domesticus). In addition, links between host immunogenetics and resistance to malaria involved population-specific alleles, suggesting local adaptation in this host-parasite interaction. This is the first evidence for a population-specific genetic control of resistance to malaria in a wild species.     

Genetic variation of isolated and peripheral populations of Pinus sylvestris (L.) from glacial refugia

Analysis of variation at 10 polymorphic isoenzyme loci in 51 European populations of Pinus sylvestris both from its main continuous range and from isolated, marginal populations out of the continuous range, revealed differences in genetic structure. The highest genetic richness, measured as mean number of alleles per locus, was recorded for populations from the Iberian Peninsula, followed by those from Scotland and the Balkans. Marginal, isolated populations were characterized by much greater interpopulation variation than populations from the continuous range of the species. The highest mean observed heterozygosity was recorded for the Iberian populations. The highest gene flow was observed among populations in the continuous range of the species. The populations could be classified into five groups based on genetic similarities. Populations from the continuous range formed one group, those from Spain two groups, pines from Scotland one group and those from the Balkans one group. One population from Scotland was found to be most distinct from the other Scottish pines and was found to be grouped with the Balkan populations. The occurrence and frequencies of rare alleles in the populations showed a characteristic pattern, suggesting that populations from the Iberian Peninsula probably did not participate in the colonization of Europe by Pinus sylvestris after the last glaciation. In contrast, the migration of populations from the Balkan refugium into Central and Western Europe had a significant effect on the contemporary gene pools of populations of Pinus sylvestris in its continuous range.     

European phylogeography of the epiphytic lichen fungus Lobaria pulmonaria and its green algal symbiont

In lichen symbiosis, fungal and algal partners form close associations, often codispersed by vegetative propagules. Due to the particular interdependence, processes such as colonization, dispersal or genetic drift are expected to result in congruent patterns of genetic structure in the symbionts. To study the population structure of an obligate symbiotic system in Europe, we genotyped the fungal and algal symbionts of the epiphytic lichen Lobaria pulmonaria at eight and seven microsatellite loci, respectively, and analysed about 4300 L. pulmonaria thalli from 142 populations from the species' European distribution range. Based on a centroid approach, which localizes centres of genetic differentiation with a high frequency of geographically restricted alleles, we identified the South Italy–Balkan region as the primary glacial refugial area of the lichen symbiosis. Procrustean rotation analysis and a distance congruence test between the fungal and algal population graphs indicated general concordance between the phylogeographies of the symbionts. The incongruent patterns found in areas of postglacial recolonization may show the presence of an additional refugial area for the fungal symbiont, and the impact that horizontal photobiont transmission and different mutation rates of the symbionts have on their genotypic associations at a continental scale.     

A framework for estimating the fixation time of an advantageous allele in stepping-stone models

Determining how population subdivision increases the fixation time of an advantageous allele is an important problem in evolutionary genetics as this influences many processes. Here, I lay out a framework for calculating the fixation time of a positively selected allele in a subdivided population, as a function of the number of demes present, the migration rate between them and the manner in which they are connected. Using this framework, it becomes clear that a beneficial allele's fixation time is significantly reduced through migration continuously introducing copies of the allele into a newly colonized subpopulation, increasing its frequency within these demes. The effect that migration has on allele frequency needs to be explicitly taken into account to produce a realistic estimate of fixation time. This behaviour is most prominent when demes are arranged on a two-dimensional torus, in comparison with populations where demes are arranged in a circle. This is because each subpopulation is connected to several neighbours over a torus, so that there are multiple paths that an allele can take in order to fix. As a consequence, some demes experience a greater influx and efflux of migrants than others. Analytical results are found to be very accurate when compared to stochastic simulations, and are generally robust if there are a large number of demes, or if the allele is weakly selected for.