Mutation as an origin of genetic variability in Helicobacter pylori

The availability of two complete Helicobacter pylori genome sequences and recent studies of its population genetics have provided a detailed picture of genetic diversity in this important human gastric pathogen. It is believed that, in addition to genetic recombination, de novo mutation could have a role in generating the high level of genetic variation in H. pylori.     

Joining forces: first application of a rapamycin‐induced dimerizable Cre system for conditional null mutant analysis in Leishmania

Reverse genetics in Leishmania spp has gained importance beyond basic research as efforts increase to discover and validate new drug targets. Often, the most promising targets are essential for viability of the parasites, defying a genetic analysis by current gene replacement strategies. Duncan et al. demonstrate the applicability of DiCre recombination in Leishmania for induced replacement of the kinase CRK3 gene in promastigotes. DiCre gene replacement leads to the rapid loss of the gene and allows monitoring the phenotypic effects of the loss of function, eliminating the need for prolonged cultivation and selection. Implementation of the DiCre approach will allow functional genetics of the most important of Leishmania genes and is likely to boost genetic research and drug target discovery.     

Alu Repeats in the Human Genome

Highly repetitive DNA sequences account for more than 50% of the human genome. The L1 and Alu families harbor the most common mammalian long and short interspersed elements. An Alu element is a dimer of similar, but not identical, fragments of total size about 300 bp, and originates from the 7SL RNA gene. Each element contains a bipartite promoter for RNA polymerase III, a poly(A) tract located between the monomers, a 3"-terminal poly(A) tract, and numerous CpG islands, and is flanked by short direct repeats. Alu repeats constitute more than 10% of the human genome and are capable of retroposition. Possibly, these elements played an important part in genome evolution. Insertion of an Alu element into a functionally important genome region or other Alu-dependent alterations of gene functions cause various hereditary disorders and are probably associated with carcinogenesis. In total, 14 Alu families differing in diagnostic mutations are known. Some of these, which are present in the human genome, are polymorphic and relatively recently have been inserted into new loci. Alu copies transposed during ethnic divergence of the human population are useful markers for evolutionary genetic studies.     

Online Mendelian Inheritance in Man (OMIM), a knowledgebase of human genes and genetic disorders

Online Mendelian Inheritance in Man (OMIM™) is a comprehensive, authoritative and timely knowledgebase of human genes and genetic disorders compiled to support research and education in human genomics and the practice of clinical genetics. Started by Dr Victor A. McKusick as the definitive reference Mendelian Inheritance in Man, OMIM (www.ncbi.nlm.nih.gov/omim) is now distributed electronically by the National Center for Biotechnology Information (NCBI), where it is integrated with the Entrez suite of databases. Derived from the biomedical literature, OMIM is written and edited at Johns Hopkins University with input from scientists and physicians around the world. Each OMIM entry has a full-text summary of a genetically determined phenotype and/or gene and has numerous links to other genetic databases such as DNA and protein sequence, PubMed references, general and locus-specific mutation databases, approved gene nomenclature, and the highly detailed mapviewer, as well as patient support groups and many others. OMIM is an easy and straightforward portal to the burgeoning information in human genetics.     

Microsatellite variation and the differentiation of modern humans

This study presents an analysis of 20 tetranucleotide microsatellites in 16 worldwide human populations representing the major geographic groups. Global Fst values for the 20 microsatellites are indicators of their relative validity as tools in human population genetics. Four different measures of genetic distance (Fst, D_SW, δμ ² and Rst) have been tested and compared with each other. Neighbor-joining trees have been constructed for all the measures of genetic distance and populations. Measures of genetic distance such as Fst, which does not consider different mutational relationships among alleles and has a known relationship to differentiation by drift, and to some extent D_SW, reflect what is known of human evolution, while mutation-based distances such as Rst and δμ ² give very different results from those recognized from other sources (genetic or archaeological). When the genetic relationship between human populations is analyzed through allelic frequencies for microsatellites, the choice of distance may be a key issue in the picture obtained of genetic relationships between human populations. The results of the present study suggest that genetic drift played the main role in generating the present distributions of microsatellite alleles and their variation among human populations; the role of mutation must have been less important owing to the time constraint imposed by the small timescale in which most human differentiation has occurred. Moreover, the results support the theory of a recent origin of modern humans, although the existence of strong bottlenecks in the origin of the various human groups seems unlikely. Received: 20 March 1996     

Isolation of microsatellite markers in the tiger mosquito Aedes albopictus (Skuse)

Among the numerous molecular markers available in population genetics, microsatellites are one of the most powerful tools developed in recent years. This paper describes the isolation of six polymorphic microsatellite loci in the tiger mosquito Aedes albopictus using an enriched genomic library technique. Such loci should be an efficient tool in population genetic studies for this mosquito species.     

A QTL on chromosome 3q23 influences processing speed in humans

Processing speed is a psychological construct that refers to the speed with which an individual can perform any cognitive operation. Processing speed correlates strongly with general cognitive ability, declines sharply with age and is impaired across a number of neurological and psychiatric disorders. Thus, identifying genes that influence processing speed will likely improve understanding of the genetics of intelligence, biological aging and the etiologies of numerous disorders. Previous genetics studies of processing speed have relied on simple phenotypes (eg, mean reaction time) derived from single tasks. This strategy assumes, erroneously, that processing speed is a unitary construct. In the present study, we aimed to characterize the genetic architecture of processing speed by using a multidimensional model applied to a battery of cognitive tasks. Linkage and QTL‐specific association analyses were performed on the factors from this model. The randomly ascertained sample comprised 1291 Mexican‐American individuals from extended pedigrees. We found that performance on all three distinct processing‐speed factors (Psychomotor Speed; Sequencing and Shifting and Verbal Fluency) were moderately and significantly heritable. We identified a genome‐wide significant quantitative trait locus (QTL) on chromosome 3q23 for Psychomotor Speed (LOD = 4.83). Within this locus, we identified a plausible and interesting candidate gene for Psychomotor Speed (Z = 2.90, P = 1.86 × 10^?03).     

Relative importance of tree genetics and microhabitat on macrofungal biodiversity on coarse woody debris

Understanding the contribution of genetic variation within foundation species to community-level pattern and diversity represents the cornerstone of the developing field of community genetics. We assessed the relative importance of intraspecific genetic variation, spatial variation within a forest and microhabitat variation on a macrofungal decay community developing on logs of the Australian forest tree, Eucalyptus globulus. Uniform logs were harvested from trees from eight geographic races of E. globulus growing in a 15-year-old genetic trial. Logs were placed as designed grids within a native E. globulus forest and after 3 years of natural colonisation the presence of 62 macrofungal taxa were recorded from eight microhabitats on each log. The key factor found to drive macrofungal distribution and biodiversity on structurally uniform coarse woody debris was log-microhabitat, explaining 42% of the total variation in richness. Differences between log-microhabitats appeared to be due to variation in aspect, substrate (bark vs wood) and area/time of exposure to colonisation. This findings demonstrates the importance of considering fine-scale (within substrate) variation in the conservation and management of macrofungal biodiversity, an area that has received little previous attention. While a number of recent studies have demonstrated that the genetics of foundation tree species can influence dependent communities, this was not found to be the case for the early log decay community associated with E. globulus. Despite genetic variation in wood and bark properties existing within this species, there was no significant effect of tree genetics on macrofungal community richness or composition. This finding highlights the variation that may exist among guilds of organisms in their response to genetic variation within foundation species, an important consideration in a promising new area of research.     

Architecture of the X Chromosome,Expression of LIM Kinase 1, and Recombination in the agnostic Mutants of Drosophila: A Model for Human Williams Syndrome

As the Human Genome and Drosophila Genome Projects were completed, it became clear that functions of human disease-associated genes may be elucidated by studying the phenotypic expression of mutations affecting their structural or functional homologs in Drosophila.Genomic diseases were identified as a new class of human disorders. Their cause is recombination, which takes place at gene-flanking duplicons to generate chromosome aberrations such as deletions, duplications, inversions, and translocations. The resulting imbalance of the dosage of developmentally important genes arises at a frequency of 10^-3 (higher than the mutation rate of individual genes) and leads to syndromes with multiple manifestations, including cognitive defects. Genomic DNA fragments were cloned from the Drosophila melanogaster agnostic locus, whose mutations impair learning ability and memory. As a result, the locus was exactly localized in X-chromosome region 11AB containing the LIM kinase 1 (LIMK1) gene (CG1848), which is conserved among many species. Hemizygosity for the LIMK1 gene, which is caused by recombination at neighboring extended repeats, underlies cognitive disorders in human Williams syndrome. LIMK1 is a component of the integrin signaling cascade, which regulates the functions of the actin cytoskeleton, synaptogenesis, and morphogenesis in the developing brain. Immunofluorescence analysis revealed LIMK1 in all subdomains of the central complex and the visual system of Drosophila melanogaster.Like in the human genome, theD. melanogaster region is flanked by numerous repeats, which were detected by molecular genetic methods and analysis of ectopic chromosome pairing. The repeats determined a higher rate of spontaneous and induced recombination, including unequal crossing over, in theagnostic gene region. Hence, the agnostic locus was considered as the first D. melanogaster model suitable for studying the genetic defect associated with Williams syndrome in human.     

Genetics of mosquitoes

Beginning in the mid-1950s, much progress has been made in studying various aspects of the genetics of mosquitoes, particularly involving several species of three principal genera,Aedes, Culex andAnopheles, that transmit important human diseases. Here I discuss selected areas of research involving formal genetics; genome structure, organization and evolution at the interspecific and intraspecific level; and evolutionary genetics of theAedes scutellaris group. Information and insights gained from in-depth analyses of these areas, particularly transmission genetics, cytogenetics and genetics of chromosomal rearrangements, and of mutagen-induced sexual sterility, have proved invaluable for the development of the theory and evaluation of feasibility of genetic control of natural populations. As a result, mosquitoes represent some of the best studied taxa at various levels of genetic organization. Recent developments in molecular genetics offer exciting possibilities for extension of these concepts.     

Application of Molecular Biology and Genetics in Endocrinology

ObjectiveTo review the growing impact of molecular biology and genetics on clinical endocrinology.MethodsMedical literature, databases, and Web sites describing genetics and genomic medicine with relevance for clinical endocrinology were reviewed.ResultsMany monogenic disorders can now be explained at the molecular level and the diagnosis can be established through mutational analysis. The ability to establish a molecular diagnosis is relevant for carrier detection and genetic counseling. In contrast to the significant advances in monogenic disorders, the current knowledge about the genetic components contributing to the pathogenesis of complex disorders is still relatively modest and is a major focus of current research efforts. Molecular biology already has an important impact on therapy in endocrine disorders. A broad spectrum of recombinant peptides and proteins are used in daily practice, eg, insulin and insulin analogues. Moreover, the increasingly detailed understanding of the molecular pathogenesis of cancer is leading to the development of novel and more specific inhibitors. While genetic testing has many advantages, it is important that physicians and patients are aware of potential limitations. They include, among others, technical limitations and allelic and nonallelic heterogeneity. These limitations need to be discussed in detail with patients and relatives, and it is often useful to involve a genetic counselor before obtaining informed consent by the individuals undergoing testing.ConclusionMolecular biology and genetics play an increasingly important role for the diagnosis and therapy of endocrine disorders. Challenges for the future include the elucidation of the genetic components contributing to complex disorders, eg, diabetes mellitus type 2, and the development of cheaper and comprehensive DNA sequencing technologies. Lastly, it is important that there is continuing attention directed towards the ethical, social, and legal aspects surrounding genetic medicine. (Endocr Pract, 2007;13: 534-541)     

Insights on ADAMTS proteases and ADAMTS-like proteins from mammalian genetics

The mammalian ADAMTS superfamily comprises 19 secreted metalloproteinases and 7 ADAMTS-like proteins, each the product of a distinct gene. Thus far, all appear to be relevant to extracellular matrix function or to cell–matrix interactions. Most ADAMTS functions first emerged from analysis of spontaneous human and animal mutations and genetically engineered animals. The clinical manifestations of Mendelian disorders resulting from mutations in ADAMTS2, ADAMTS10, ADAMTS13, ADAMTS17, ADAMTSL2 and ADAMTSL4 identified essential roles for each gene, but also suggested potential cooperative functions of ADAMTS proteins. These observations were extended by analysis of spontaneous animal mutations, such as in bovine ADAMTS2, canine ADAMTS10, ADAMTS17 and ADAMTSL2 and mouse ADAMTS20. These human and animal disorders are recessive and their manifestations appear to result from a loss-of-function mechanism. Genome-wide analyses have determined an association of some ADAMTS loci such as ADAMTS9 and ADAMTS7, with specific traits and acquired disorders. Analysis of genetically engineered rodent mutations, now achieved for over half the superfamily, has provided novel biological insights and animal models for the respective human genetic disorders and suggested potential candidate genes for related human phenotypes. Engineered mouse mutants have been interbred to generate combinatorial mutants, uncovering cooperative functions of ADAMTS proteins in morphogenesis. Specific genetic models have provided crucial insights on mechanisms of osteoarthritis (OA), a common adult-onset degenerative condition. Engineered mutants will facilitate interpretation of exome variants identified in isolated birth defects and rare genetic conditions, as well as in genome-wide screens for trait and disease associations. Mammalian forward and reverse genetics, together with genome-wide analysis, together constitute a powerful force for revealing the functions of ADAMTS proteins in physiological pathways and health disorders. Their continuing use, together with genome-editing technology and the ability to generate stem cells from mutants, presents numerous opportunities for advancing basic knowledge, human disease pathways and therapy.     

Sunflower genetic,genomic and ecological resources

Long a major focus of genetic research and breeding, sunflowers (Helianthus) are emerging as an increasingly important experimental system for ecological and evolutionary studies. Here, we review the various attributes of wild and domesticated sunflowers that make them valuable for ecological experimentation and describe the numerous publicly available resources that have enabled rapid advances in ecological and evolutionary genetics. Resources include seed collections available from germplasm centres at the USDA and INRA, genomic and EST sequences, mapping populations, genetic markers, genetic and physical maps and other forward‐ and reverse‐genetic tools. We also discuss some of the key evolutionary, genetic and ecological questions being addressed in sunflowers, as well as gaps in our knowledge and promising areas for future research.     

A genetic component of extinction risk in mammals

Genetic factors may play an important role in species extinction but their actual effect remains poorly understood, particularly because of a strong and potentially masking effect expected from ecological traits. We investigated the role of genetics in mammal extinction taking both ecological and genetic factors into account. As a proxy for the role of genetics we used the ratio of the rates of nonsynonymous (amino acid changing) to synonymous (leaving the amino acid unchanged) nucleotide substitutions, K_a / K_s. Because most nonsynonymous substitutions are likely to be slightly deleterious and thus selected against, this ratio is a measure of the inefficiency of selection: if large (but less than 1), it implies a low efficiency of selection against nonsynonymous mutations. As a result, nonsynonymous mutations may accumulate and thus contribute to extinction. As a proxy for the role of ecology we used body mass W, with which most extinction‐related ecological traits strongly correlate. As a measure of extinction risk we used species’ affiliation with the five levels of extinction threat according to the IUCN Red List of Threatened Species. We calculated K_a / K_s for mitochondrial protein‐coding genes of 211 mammalian species, each of which was characterized by body mass and the level of threat. Using logistic regression analysis, we then constructed a set of logistic regression models of extinction risk on ln(K_a / K_s) and lnW. We found that K_a / K_s and body mass are responsible for a 38% and a 62% increase in extinction risk, respectively. Given that the standard error of these values is 13%, the contribution of genetic factors to extinction risk in mammals is estimated to be one‐quarter to one‐half of the total of ecological and genetic effects. We conclude that the effect of genetics on extinction is significant, though it is almost certainly smaller than the effect of ecological traits. Synthesis Mutation provides the material for evolution. However, most mutations that play a role in evolution are slightly deleterious and thus may contribute to extinction. We assess the role of mitochondrial DNA mutations in mammalian extinction risk and find it to be one‐quarter to one‐half of the total of mutation and body mass effects, where body mass represents an integral measure of extinction‐related ecological traits. Genetic factors may be all the more important, because ecological traits associated with large body mass would both promote and protect from extinction, while mutation accumulation caused by low effective population size seems to have no counterbalance.     

The contribution of evening primrose (<Emphasis Type="Italic">Oenothera biennis</Emphasis>) to a modern synthesis of evolutionary ecology

In this review, I consider the contribution that common evening primrose (Oenothera biennis) has made towards integrating the ecology, evolution and genetics of species interactions. Oenothera biennis was among the earliest plant models in genetics and cytogenetics and it played an important role in the modern synthesis of evolutionary biology. More recently, population and ecological genetics approaches have provided insight into the patterns of genetic variation within and between populations, and how a combination of abiotic and biotic factors maintain and select on heritable variation within O. biennis populations. From an ecological perspective, field experiments show that genetic variation and evolution within populations can have cascading effects throughout communities. Plant genotype affects the preference and performance of individual arthropod populations, as well as the composition, biomass, total abundance and diversity of arthropod species on plants. A combination of experiments and simulation models show that natural selection on specific plant traits can drive rapid ecological changes in these same community variables. At the patch level, increasing genotypic diversity leads to a greater abundance and diversity of omnivorous and predaceous arthropods, which is also associated with increased biomass and fecundity of plants in genetically diverse patches. Finally, in questioning whether a community genetics perspective is needed in biology, I review several multifactorial experiments which show that plant genotype often explains as much variation in community variables as other ecological factors typically identified as most important in ecology. As a whole, research in the O. biennis system has contributed to a more complete understanding of the dynamic interplay between ecology, evolution and genetics.     

Molecular mapping of obesity genes

Advances in molecular genetics have made it possible to clone mutant genes from mammals. This capability should facilitate efforts to determine the genetic factors that control food intake and body composition. In order to identify these genetic factors, we have been making use of mouse mutations that cause obesity. The basic premise of this approach is to take advantage of the mouse as a genetic system for the analysis of genetically complex disorders and to then apply that information to the study of human disease. This paper reviews: (1) current concepts concerning the control of body weight in man and other mammals; (2) the biologic characteristics of the mouse obesity mutations; (3) our progress in the use of positional cloning techniques to clone the mouse obese (ob) and diabetes (db) genes; (4) an approach to polygenic obesity in mice; and (5) the possible relevance of the mouse obesity mutations to human obesity.     

The distribution,diversity, and conservation status of Cycas in China

As ancient gymnosperm and woody plants, cycads have survived through dramatic tectonic activities, climate fluctuation, and environmental variations making them of great significance in studying the origin and evolution of flora biodiversity. However, they are among the most threatened plant groups in the world. The principal aim of this review is to outline the distribution, diversity, and conservation status of Cycas in China and provide suggestions for conservation practices. In this review, we describe the taxonomy, distribution, and conservation status of Cycas in China. By comparing Chinese Cycas species with its relatives worldwide, we then discuss the current genetic diversity, genetic differentiation of Cycas, and try to disentangle the potential effects of Quaternary climate changes and topographical events on Cycas. We review conservation practices from both researchers and practitioners for these rare and endangered species. High genetic diversity at the species level and strong genetic differentiation within Cycas have been observed. Most Cycas species in southwest China have experienced population retreats in contrast to the coastal Cycas's expansion during the Quaternary glaciation. Additionally, human activities and habitat fragmentation have pushed these endangered taxa to the brink of extinction. Although numerous efforts have been made to mitigate threats to Cycas survival, implementation and compliance monitoring in protection zones are currently inadequate. We outline six proposals to strengthen conservation measures for Cycas in China and anticipate that these measures will provide guidelines for further research on population genetics as well as conservation biology of not only cycads but also other endangered species worldwide.     

Marker-assisted congenic screening (MACS): A database tool for the efficient production and characterization of congenic lines

Over the past decades, genetic studies in rodent models of human multifactorial disorders have led to the detection of numerous chromosomal regions associated with disease phenotypes. Owing to the complex control of these phenotypes and the size of the disease loci, identifying the underlying genes requires further analyses in new original models, including chromosome substitution (consomic) and congenic lines, derived to evaluate the phenotypic effects of disease susceptibility loci and fine-map the disease genes. We have developed a relational database (MACS) specifically designed for the genetic marker-assisted production of large series of rodent consomic and congenic lines (speed congenics), the organization of their genetic and phenotypic characterizations, and the acquisition and archiving of both genetic and phenotypic data. This database, originally optimized for the production of rat congenics, can also be applied to mouse mapping projects. MACS represents an essential system for significantly improving efficiency and accuracy in investigations of multiple consomic and congenic lines simultaneously derived for different disease loci, and ultimately cloning genes underlying complex phenotypes.     

First development and characterization of 27 novel microsatellite markers in the dobsonfly Neoneuromus ignobilis (Megaloptera: Corydalidae) at genome-scale level

The dobsonfly species Neoneuromus ignobilis Navás (Megaloptera: Corydalidae) is endemic to but widely distributed from eastern and southeastern Asia, being an important insect indicator for freshwater biomonitoring. At present, there is no report on the development of microsatellites of Megaloptera. Here, we developed 27 novel microsatellite markers of N. ignobilis from 850,920 candidate microsatellites with the stringent screening criteria considering the amplification success rate, the presence or absence of stutter peaks, the peak intensity, the polymorphism of the loci, the heterozygosity, and the number of alleles. The allele number of 27 microsatellite markers ranges from 3 to 12 with an average value of 6.19 per locus. The observed heterozygosity (H_O) and expected heterozygosity (H_E) revealed a range from 0.000 to 0.947 and 0.000 to 0.842, respectively. We constructed three panels (MP panel, most polymorphic; SS panel, most stringent strategy; ALL panel, total 27 microsatellite markers) and compared the analyses on population genetic diversity and structure. The result showed that the MP panel can significantly improve the analyses of individual assignment and genetic diversity. Accordingly, we advocate selecting the most polymorphic microsatellite marker for analyzing population genetics based on microsatellite data. The present work represents the first study on the microsatellite development of Megaloptera.