Plasmids of lactococci - genetic accessories or genetic necessities?

Lactococci are one of the most exploited microorganisms used in the manufacture of food. These intensively used cultures are generally characterized by having a rich plasmid complement. It could be argued that it is the plasmid complement of commercially utilized cultures that gives them their technical superiority and individuality. Consequently, it is timely to reflect on the desirable characteristics encoded on lactococcal plasmids. It is argued that plasmids play a key role in the evolution of modern starter strains and are a lot more than just selfish replicosomes but more essential necessities of intensively used commercial starters. Moreover, the study of plasmid biology provides a genetic blueprint that has proved essential for the generation of molecular tools for the genetic improvement of Lactococcus lactis.     

What is genetic quality?

Mate choice is favored by indirect selection if choosy females mate with males of high genetic quality. We believe, however, that testing hypotheses about indirect selection has been constrained by how we conceptualize and therefore empirically measure male genetic quality. Here, we argue that genetic quality is the breeding value of an individual for total fitness. We can therefore learn little about genetic quality from measures of only a few fitness components. We explain breeding value for total fitness, drawing on concepts from life-history theory and quantitative genetics, and suggest how approaches incorporating these insights might result in empirical progress.     

Early detection of genetic hemochromatosis: should all young adults be offered the genetic test?

Genetic hemochromatosis (GH) is a late-onset, autosomal recessive disorder. The majority of those at risk from iron overload and its clinical consequences may be detected by a simple genetic test. Furthermore, treatment by phlebotomy, if instituted early, removes excess iron and prevents the complications of iron overload which include arthralgia, diabetes, and cirrhosis of the liver. GH seems to be an obvious candidate for inclusion in national screening programs. However, important questions remain concerning the proportion of individuals with the high-risk genotype who eventually show clinical manifestations of iron overload and the significance of heterozygosity for haemochromatosis in terms of morbidity. Until these questions are resolved, the introduction of widespread genetic screening cannot be justified.     

Origin of genetic variation: regulation of genetic recombination in the higher organisms — a theory

Summary Recent studies in the fungi, particularly Neurospora and Schizophyllum, have revealed a number of genetic features which, viewed in conjunction with earlier observations on other organisms, form a pattern, or model, which appears to be basic to the control of recombination in all eukaryotes, including higher organisms. It is assumed that the control is exercised on mechanisms that produce new alleles through recombination, as understood in broad terms and including such a likely phenomenon as gene conversion, which may or may not involve crossing-over, as well as equal and unequal crossing-over. The recombination may thus occur between alleles in either the homozygous or heterozygous condition. In the model, regulatory genes and breeding behaviour are integrated into one self-regulatory system controlling the production of new genetic variation.The model is based on the following five general features, largely substantiated by the results in Neurospora and Schizophyllum: 1) The frequency of recombination in a particular chromosomal region is controlled by specific regulatory genes (rec). 2) There may be a number of such specific, regulatory genes responsible for recombination in a given region. 3) A rec. locus may influence recombination in more than one region. 4) The regulatory genes have no specific physical relationship with the region(s) they control, and are usually located at random in the genome. 5) Of the allelic forms of the regulatory genes it is always the dominant gene which suppresses recombination and the recessive gene which increases recombination. The rec system is epistatic to other genetic elements jointly involved in the overall control of recombination in a specific region. It is suggested that usually the control of recombination in a given region is exercised, cumulatively, by the balance of the dominant and recessive genes of the specific rec loci in the organism. Outbreeding, with the associated high heterozygosity of the regulatory rec loci, virtually switches off recombination, producing few new variations. Inbreeding produces homozygosity of these loci, resulting in certain individuals which will have a considerable number of their regulatory loci in the homozygous recessive condition and in which recombination will be switched on, producing new variation at a high frequency. Inbreeding is thus an integrated, evolutionary system of considerable importance, and is not a degenerate dead end, as many investigators have previously thought.The model has another compensatory function in evolution. In major loci, or in an operon, where there are structural genes and closely linked operator genes, as exemplified by the S locus, there are indications that the present model is concerned with the regulation of both structural and operator genes. The consequences of the model in the two classes of genes, however, are in direct contrast to each other: High heterozygosity which is instrumental in switching off recombination, and which is therefore helpful in maintaining stability in the structural gene, is conducive to functional variation of the operator gene; and high homozygosity, which is instrumental in switching on recombination, and which is therefore helpful in producing variation in the structural gene, is conducive to the stability of the operator gene.This model of the control of genetic variation in a specific chromosomal region is significant in development as well as in evolution, and throws light on a number of hitherto intractable problems peculiar to the higher organisms. For example, the model is helpful in explaining: 1) the origin of new self-incompatibility alleles in the flowering plants; 2) the impressive speciation in the waif flora (and fauna) of the oceanic islands; 3) the presence of high genetic variability in inbreeding species of plants; 4) environmentally-induced heritable variation in certain plants; and 5) the genetic mechanism of antibody diversity in animals.     

Do bottlenecks increase additive genetic variance?

Because of anthropogenic factors many populations have been at least temporarily reduced to a very small population size. Such reductions could potentially decrease genetic variation and increase the probability of extinction. Analysis of molecular markers has shown a decrease in genetic variation but in many cases this has not reduced the ability of the population to recover from the bottleneck. This apparent paradox is resolved by a consideration of how population bottlenecks can affect additive genetic variance, the relevant measure of ability to respond to selective factors. A bottleneck has the potential to increase additive genetic variance in a population. This may result in an increase in fitness, particularly in populations of conservation concern that are small and lack genetic variation. Here we present a meta-analysis of experimental tests of this prediction using models designed to fit data that is strictly additive and data that has non-additive components. This analysis shows that additive genetic variance in a dataset dominated by morphological traits increases, on average, after a bottleneck event when the inbreeding coefficient is less than 0.3, but neither of the theoretical models alone can adequately explain this result. Because of our inability at present to predict the results of a population bottleneck in a specific case and the probability of extinction associated with small population size we caution against using bottlenecks to increase genetic variance, and thus the fitness, of endangered populations.     

Why are some genetic diseases common?

Various processes (selection, mutation, migration and genetic dirft) are known to determine the frequency of genetic disease in human populations, but so far it has proved almost impossible to decide to what extent each is responsible for the presence of a particular genetic disease. The techniques of gene and haplotype analysis offer new hope in addressing this issue, and we review relevant studies of three haemoglobinopathies: sickle cell anaemia, and and thalassaemia. We show how for each disease it is possible to recognize a pattern of regionally specific mutations, found in association with one or a few haplotypes, that is best explained as the result of selection; other patterns are due to population migration and genetic drift. However, we caution that such conclusions can be drawn in special circumstances only. In the case of the haemoglobinopathies it is possible because a selective agent (malaria) was already suspected, and the investigations could be carried out in relatively genetically homogenous populations whose migratory histories are known. Moreover, some data reviewed here suggest that gene conversion and the haplotype composition of a population may affect the frequency of a mutation, making interpretation of gene frequencies difficult on the basis of standard population genetics theory. Hence attempts to use the same approaches with other genetic diseases are likely to be frustrated by a lack of suitably untrammelled populations and by difficulties accounting for poorly understood genetic processes. We conclude that although this combination of molecular and population genetics is successful when applied to the study of haemoglobinopathies, it may not be so easy to apply it to the study of other genetic diseases.     

Does genetic modification violate intrinsic value?

The ‘Genetic engineering and the intrinsic value and integrity of animals and plants’ meeting, was organised by IfGene and held in Edinburgh, Scotland 18–21 September 2002.     

Is cystic fibrosis genetic medicine's canary?

In 1989 the gene that causes cystic fibrosis (CF) was identified in a search accompanied by intense anticipation that the gene, once discovered, would lead rapidly to gene therapy. Many hoped that the disease would effectively disappear. Those affected were going to inhale vectors packed with functioning genes, which would go immediately to work in the lungs. It was a bewitching image, repeatedly invoked in both scientific and popular texts. Gene therapy clinical trials were carried out with a range of strategies and occasionally success seemed close, but by 1996 the idea that gene therapy for CF would quickly provide a cure was being abandoned by the communities engaged with treatment and research. While conventional wisdom holds that the death of Jesse Gelsinger in an unrelated gene therapy trial in 1999 produced new skepticism about gene therapy, the CF story suggests a different trajectory, and some different lessons. This article considers the rise and fall of gene therapy for CF and suggests that CF may provide a particularly compelling case study of a failed genomic technology, perhaps even of a medical "canary." The story of CF might be a kind of warning to us that genetic medicine may create as many problems as it solves, and that moving forward constructively with these techniques and practices requires many kinds of right information, not just about biology, but also about values, priorities, market forces, uncertainty, and consumer choice.     

Is skeletal mechanotransduction under genetic control?

Studies of twins have established that peak bone mass is about 70% heritable. The skeletal response to exercise contributes to peak bone mass, as mechanical loading increases skeletal mass during growth and development. It is possible that the skeletal responsiveness to mechanical loading is under genetic control, so that some individuals will build stronger bones with exercise. This appears to be the case in mice. Long bones in mice of the C3H/He strain are largely unresponsive to mechanical loading. Ironically, this strain of mice has very high bone density. Perhaps the genes that regulate BMD are not the same as those that regulate mechanical loading response. Studies of recombinant inbred and congenic strains derived from C3H mice will help to identify genes influencing bone size, density and responsiveness to mechanical loading.     

What factors shape genetic diversity in cetaceans?

Understanding what factors drive patterns of genetic diversity is a central aspect of many biological questions, ranging from the inference of historical demography to assessing the evolutionary potential of a species. However, as a larger number of datasets have become available, it is becoming clear that the relationship between the characteristics of a species and its genetic diversity is more complex than previously assumed. This may be particularly true for cetaceans, due to their relatively long lifespans, long generation times, complex social structures, and extensive ranges. In this study, we used microsatellite and mitochondrial DNA data from a systematic literature review to produce estimates of diversity for both markers across 42 cetacean species. Factors relating to demography, distribution, classification, biology, and behavior were then tested using phylogenetic methods and linear models to assess their relative influence on the genetic diversity of both marker types. The results show that while relative nuclear diversity is correlated with population size, mitochondrial diversity is not. This is particularly relevant given the widespread use of mitochondrial DNA to infer historical demography. Instead, mitochondrial diversity was mostly influenced by the range and social structure of the species. In addition to population size, habitat type (neritic vs. oceanic) had a significant correlation with relative nuclear diversity. Combined, these results show that many often‐unconsidered factors are likely influencing patterns of genetic diversity in cetaceans, with implications regarding how to interpret, and what can be inferred from, existing patterns of diversity.     

Novel genetic analysis in Beh?et's disease

Behçet''s disease (BD) is characterized by oral and genital ulceration and is complicated by eye, skin, joint and central nervous system lesions. It has long been understood that BD has a strong genetic component, but to date the identified genes account for only around 30% of the risk for developing the disease, and the work has mostly been based on candidate gene analysis. In a recent report, Fei and coworkers presented the results of the first genome-wide analysis of patients with BD. These findings suggest new pathways for investigation in this complex disease.Error, like straws, upon the surface flowHe who would search for pearls must dive belowJohn Dryden, 1678Fei and coworkers [1] identified novel single nucleotide polymorphisms (SNPs) in five genes (KIAA1529, CPVL, LOC100129342, UBASH3B and UBAC2) that encode proteins with both known and unknown functions. Moreover, subset analysis showed links between some of the SNPs and particular manifestations of Behçet''s disease (BD).KIAA1529 and LOC100129342 have no known function, but the latter SNP on chromosome 1p34 confirms a locus previously identified in a multiplex family study [2]. UBASH3B and UBAC2 encode ubiquitin-associated proteins. The ubiquitin system is best described in targeting misfolded or damaged proteins for proteosomal degradation, but it is also involved in several other cellular processes, including regulation of nuclear factor-κB function and autophagy. Such processes are involved in cells of both innate and adaptive immune responses, which is of interest with respect to the ongoing debate on whether BD is an autoinflammatory or an autoimmune disorder [3]. Dysfunction of the ubiquitin pathway has been implicated in cancer, neurodegenerative diseases and type 2 diabetes [4,5].Carboxypeptidase vitellogenic-like protein is upregulated in monocytes on conversion to macrophages, in which it co-localizes to the secreted proteins tumour necrosis factor and the chemokine CCL3 (C-C chemokine ligand 3). It has been implicated in the processing/transport of peptides for loading onto major histocompatibility complex (MHC) class I molecules [6]. The strongest genetic association with BD is human leucocyte antigen (HLA)-B*5101 and HLA-B*5108, an MHC class I molecule. Microsatellite analysis confirms HLA-{"type":"entrez-nucleotide","attrs":{"text":"B85101","term_id":"2926233","term_text":"B85101"}}B85101/5108 as the most likely causative gene in BD, but SNPs in other genes in close proximity on chromosome 6 – MICA, MICB and TNF – have also been reported [7]. Moreover, the mechanism of action of HLA-B*5101/5108 in BD has not been elucidated. Alteration in the process of peptide production by the CVLP SNP could have important implications in the expression or maintenance of MHC class I molecules on the cell surface and be linked to the pathogenesis of the disease.In subset analysis the UBASH3B SNP was more common in patients with ocular and vascular manifestations, whereas the KIAA1529 SNP was more common in patients without such involvement. The authors correctly stated that the numbers with each manifestation make such an analysis very preliminary, but several other SNPs have been linked to ocular disease specifically, so these findings are not unexpected [8]. It should be noted, however, that eye and vascular disease can take many forms in BD, and more detailed analysis will be required when greater numbers are tested for these SNPs.There are certain caveats to the findings. Genome-wide analysis (GWAS) is normally performed on a large number of samples, which is not easy for a rare condition such as BD. The authors addressed this point by performing the initial analysis on pooled samples and then, having identified potential SNPs, validating the findings in each sample individually. However, it is important for these results to be validated in other cohorts of BD patients. There are extensive data describing ethnic differences in SNPs studied by candidate analysis, and the association of these newly identified SNPs in BD patients from different geographical areas will be important. Similarly, in several studies males have been shown to have a worse prognosis, and the association of these SNPs with sex should be examined. Other GWAS are ongoing or planned in Japanese, European and Turkish patients with BD, and comparison with the current study will be of great interest. Finally, and most importantly, the functional relevance of these SNPs will need to be investigated and – if found – tested in different cell types such as lymphoid, myeloid, epithelial and endothelial cells that are involved in BD.BD is a complex disease. Different patients will experience different symptoms, and there is a clear geographical distribution of the disease. The candidate gene approach has been useful in identifying susceptibility and severity genes in BD, but the ability to undertake GWAS has led to the identification of several new SNPs in many human diseases, increasing our understanding of the pathogenic mechanisms involved. Fei and coworkers [1] are to be commended for such a study in BD.     

Developmental neurobiology: A genetic Cheshire cat?

In the wake of evidence that essential neurogenic processes might involve aspects of DNA rearrangement, recent discoveries about the unusual arrangement of genes encoding neuronal adhesion molecules known as protocadherins are very intriguing. But is this just a coincidence?     

Unequal genetic redundancies in Arabidopsis--a neglected phenomenon?

Genetic redundancy is a common phenomenon in Arabidopsis and is thought to be responsible for the absence of phenotypes in the majority of single loss-of-function mutants. In this review, we highlight an increasing number of examples in which redundancy between homologous genes is limited or absent despite functional equivalence of the respective proteins. In particular, we focus on cases of unequal redundancy, where the absence of a mutant phenotype in loss-of-function mutants of one gene contrasts with a strong phenotype in mutants of its homolog. In the double mutants, this phenotype is strongly enhanced. Possible explanations for such scenarios are discussed. We propose that the study of unequally redundant gene pairs offers a unique opportunity to understand global patterns of functional genome evolution.     

Stable propagation of ‘selfish’ genetic elements

Extrachromosomal or chromosomally integrated genetic elements are common among prokaryotic and eukaryotic cells. These elements exhibit a variety of ‘selfish’ strategies to ensure their replication and propagation during the growth of their host cells. To establish long-term persistence, they have to moderate the degree of selfishness so as not to imperil the fitness of their hosts. Earlier genetic and biochemical studies together with more recent cell biological investigations have revealed details of the partitioning mechanisms employed by low copy bacterial plasmids. At least some bacterial chromosomes also appear to rely on similar mechanisms for their own segregation. The 2 μm plasmid ofSaccharomyces cerevisiae and related yeast plasmids provide models for optimized eukaryotic selfish DNA elements. Selfish DNA elements exploit the genetic endowments of their hosts without imposing an undue metabolic burden on them. The partitioning systems of these plasmids appear to make use of a molecular trick by which the plasmids feed into the segregation pathway established for the host chromosomes.     

Investigation of lymphotoxin α genetic variants in migraine

Migraine is a common neurological disease with a genetic basis affecting approximately 12% of the population. Pain during a migraine attack is associated with activation of the trigeminal nerve system, which carries pain signals from the meninges and the blood vessels infusing the meninges to the trigeminal nucleus in the brain stem. The release of inflammatory mediators following cortical spreading depression (CSD) may further promote and sustain the activation and sensitization of meningeal nociceptors, inducing the persistent throbbing headache characterised in migraine. Lymphotoxin α (LTA) is a cytokine secreted by lymphocytes and is a member of the tumour necrosis factor (TNF) family. Genetic variation with the TNF and LTA genes may contribute to threshold brain excitability, propagation of neuronal hyperexcitability and thus initiation and maintenance of a migraine attack. Three LTA variants rs2009658, rs2844482 and rs2229094 were identified in a recent pGWAS study conducted in the Norfolk Island population as being potentially implicated in migraine with nominally significant p values of p = 0.0093, p = 0.0088 and p = 0.033 respectively. To determine whether these SNPs played a role in migraine in a general outbred population these SNPs were gentoyped in a large case control Australian Caucasian population and tested for association with migraine. All three SNPs showed no association in our cohort (p > 0.05). Validation of GWAS data in independent case-controls cohorts is essential to establish risk validity within specific population groups. The importance of cytokines in modulating neural inflammation and pain threshold in addition to other studies showing associations between TNF-α and SNPs in the LTA gene with migraine, suggests that LTA could be an important factor contributing to migraine. Although the present study did not support a role for the tested LTA variants in migraine, investigation of other variants within the LTA gene is still warranted.     

Dwindling genetic diversity in European ground squirrels?

The European ground squirrel (Spermophilus citellus) is endangered and in decline. Populations are increasingly fragmented, and only a coordinated conservation effort at the European level may guarantee its long-term survival. To obtain a general population genetic picture on a larger geographic scale, we screened 117 individuals from seven local populations in Hungary, Romania, and Austria for allelic variation at eleven microsatellite loci. We found a high (23.4%) proportion of private alleles, and a moderate to somewhat elevated level (15.27%) of partitioning of genetic diversity among populations, compared to that found in many other terrestrial mammals. Genetic variability was significantly higher than in earlier studied Czech populations that are considered genetically depleted, but significantly lower than in undisturbed populations of S. suslicus and S. brunneus, that are similar to the European ground squirrel in their ecological requirements, reproductive biology, and social organization. Genetic diversity was also lower than in most presumably “undisturbed” populations of other Sciurid species. This, together with the observed level and pattern of genetic differentiation among populations, such as no significant increase of genetic differentiation with geographic distance and similar variance of genetic differentiation between populations independent of geographic distance, indicated the prevalence of relatively strong drift effects for all populations. A Bayesian STRUCTURE analysis and a factorial correspondence analysis concordantly revealed a fairly complex genetic composition of local populations, but no major geographic trend in the pattern of the genetic composition. Overall, the results suggest disintegration of local colonies that might earlier have been more connected genetically. The STRUCTURE analysis also suggested anthropogenic translocations among single Hungarian populations. Our data on genetic diversity and its distribution do not object to such conservation measures. Translocation of individuals particularly from nearby populations may increase the chances of survival of small and isolated populations and counteract inbreeding at low densities.