Analysing the effect of candidate genes on complex traits: an application in multiple sclerosis

The conventional approach of candidate gene studies in complex diseases is to look at the effect of one gene at a time. However, as the outcome of chronic diseases is influenced by a large number of alleles, simultaneous analysis is needed. We demonstrate the application of multivariate regression and cluster analysis to a multiple sclerosis (MS) dataset with genotypes for 489 patients at 11 candidate genes selected on their involvement in the immune response. Using multivariate regression, we observed that different sets of genes were associated with different disease characteristics that reflect different aspects of disease. Out of 15 polymorphisms, we identified one that contributed to the severity of disease. In addition, the set of 15 polymorphisms was predictive for yearly increase in lesion volume as seen on T1-weighted MRI (p=0.044). From this set, no individual polymorphisms could be identified after adjustment for multiple hypotheses testing. By means of a cluster analysis, we aimed to identify subgroups of patients with different pathogenic subtypes of MS on the basis of their genetic profile. We constructed genetic profiles from the genotypes at the 11 candidate genes. The approach proved to be feasible. We observed three clusters in the sample of patients. In this study, we observed no significant differences in the usual clinical and MRI outcome measures between the different clusters. However, a number of consistent trends indicated that this clustering might be related to the course of disease. With a larger number of genes regulating the course of disease, we may be able to identify clinically relevant clusters. The analyses are easily implemented and will be applicable to candidate gene studies of complex traits in general.     

The Coevolution of Genes and Genetic Codes: Crick’s Frozen Accident Revisited

The standard genetic code is the nearly universal system for the translation of genes into proteins. The code exhibits two salient structural characteristics: it possesses a distinct organization that makes it extremely robust to errors in replication and translation, and it is highly redundant. The origin of these properties has intrigued researchers since the code was first discovered. One suggestion, which is the subject of this review, is that the code’s organization is the outcome of the coevolution of genes and genetic codes. In 1968, Francis Crick explored the possible implications of coevolution at different stages of code evolution. Although he argues that coevolution was likely to influence the evolution of the code, he concludes that it falls short of explaining the organization of the code we see today. The recent application of mathematical modeling to study the effects of errors on the course of coevolution, suggests a different conclusion. It shows that coevolution readily generates genetic codes that are highly redundant and similar in their error-correcting organization to the standard code. We review this recent work and suggest that further affirmation of the role of coevolution can be attained by investigating the extent to which the outcome of coevolution is robust to other influences that were present during the evolution of the code. Electronic Supplementary Material Electronic Supplementary material is available for this article at and accessible for authorised users. [Reviewing Editor: Dr. Martin Kreitman]     

Representation in the genome and in other inheritance systems

There is ongoing controversy as to whether the genome is a representing system (Sterelny K., Smith K.C. and Dickson M. 1996. Biol. Philos. 11: 377–403; Griffiths P.E. 2001. Philos. Sci. 68: 394–412). Although it is widely recognised that DNA carries information, both correlating with and coding for various outcomes, neither of these implies that the genome has semantic properties like correctness or satisfaction conditions (Godfrey-Smith P. 2002. In: Wolenski J. and Kajania-Placek K. (eds), In the Scope of Logic, Methodology, and the Philosophy of Sciences, Vol. II. Kluwer, Dordrecht, pp. 387–400). Here a modified version of teleosemantics is applied to the genome to show that it does indeed have semantic properties – there is representation in the genome. The account differs in three respects from previous attempts to apply teleosemantics to genes. It emphasises the role of the consumer of representations (in addition to their mode of production). It rejects the standard assumption that genetic representation can be used to explain the course of an organism’s development. And it identifies the explanatory role played by representational properties of the genome. A striking consequence of this account is that other inheritance systems could also be representational. Thus, a version of the parity thesis is accepted (Griffiths P.E. 2001. Philos. Sci. 68: 394–412). However, the criteria for being an inheritance system are demanding, so semantic properties are not ubiquitous.     

Sparse cerebellar innervation can morph the dynamics of a model oculomotor neural integrator

The oculomotor integrator is a brainstem neural network that converts velocity signals into the position commands necessary for eye-movement control. The cerebellum can independently adjust the amplitude of eye-movement commands and the temporal characteristics of neural integration, but the percentage of integrator neurons that receive cerebellar input is very small. Adaptive dynamic systems models, configured using the genetic algorithm, show how sparse cerebellar inputs could morph the dynamics of the oculomotor integrator and independently adjust its overall response amplitude and time course. Dynamic morphing involves an interplay of opposites, in which some model Purkinje cells exert positive feedback on the network, while others exert negative feedback. Positive feedback can be increased to prolong the integrator time course at virtually any level of negative feedback. The more these two influences oppose each other, the larger become the response amplitudes of the individual units and of the overall integrator network. Action Editor: Jonathan D. Victor     

基因工程课程双语教学的探索与实践

基因工程处于生命科学的最前沿, 其内容国际前沿性强, 发展和更新迅速。基于培养适应全球化发展的复合型本科生的需要, 福建师范大学生命科学学院生物工程专业自2006年对《基因工程》课程进行双语教学模式的探索。本文根据几年来基因工程双语教学的实践, 介绍了该课程双语教学的体会, 包括教学内容与双语教材选择、教学手段与方式改革以及网络资源的利用等, 并探讨了存在的问题和对策。     

Genetic polymorphism in varietal identification and genetic improvement

Summary New sources of genetic polymorphisms promise significant additions to the number of useful genetic markers in agricultural plants and animals, and prompt this review of potential applications of polymorphic genetic markers in plant and animal breeding. Two major areas of application can be distinguished. The first is based on the utilization of genetic markers to determine genetic relationships. These applications include varietal identification, protection of breeder's rights, and parentage determination. The second area of application is based on the use of genetic markers to identify and map loci affecting quantitative traits, and to monitor these loci during introgression or selection programs. A variety of breeding applications based on these possibilities can be envisaged for Selfers, particularly for those species having a relatively small genome size. These applications include: (i) screening genetic resources for useful quantitative trait alleles, and introgression of chromosome segments containing these alleles from resource strain to commercial variety; (ii) development of improved pure lines out of a cross between two existing commercial varieties; and (iii) development of crosses showing increased hybrid vigor. Breeding applications in segregating populations are more limited, particularly in species with a relatively large genome size. Potential applications, however, include: (i) preliminary selection of young males in dairy cattle on the basis of evaluated chromosomes of their proven sire; (ii) genetic analysis of resource strains characterized by high values for a particular quantitative trait, and introgression of chromosome segments carrying alleles contributing to the high values from resource strain to recipient strain.Contribution from The Agricultural Research Organization, The Volcani Center, Bet Dagan, Israel, No. 767-E, 1983 Series     

Avian mitochondrial DNA sequence divergence across a headwater stream of the Rio Tapajós, a major Amazonian river

Populations of ten Amazonian bird species were sampled on opposite banks of the Rio Teles Pires, a headwater stream of the Rio Tapajós, in the Alta Floresta region, northern Mato Grosso, Brazil. The river is 100–300 m wide in this region. We found a range of genetic differentiation from none to relatively high levels; six of the ten species studied exhibit what appear to be genetic breaks at the river. With one exception, the antbird Hylophylax poecilinota, there is no morphologically recognized differentiation correlating with genetic differentiation. From the perspective of traditional morphology-based taxonomy, the Rio Teles Pires is not a faunal barrier. Rather, contact zones between members of species and subspecies pairs appear more or less randomly distributed in this region, some being located at varying distances to the east, others at varying distances to the west of the Rio Teles Pires, with few following the course of this river itself.

Errors in genetic theory equations

Summary This study addresses the consequences of eliminating terms such as x² and x³ from genetic equations when the variable x is known to be small. This paper indicates logically that to assign such terms a value of 0.0 requires knowing the magnitude of the coefficients for each of these terms as well as the magnitude of all other terms in a given expression. Since most genetic expressions of interest involve several unknowns, the elimination of these terms appears difficult to justify in most situations. The effects of the elimination of a single term from an expression in a classical plant breeding paper were investigated as a simple exemplifying case. In the example, the simplified equation for change in population mean with selection sometimes greatly overestimated the response to selection and in some cases also altered conclusions as to best procedure. Though simplified equations are usually much more tractable and interpretable, the bias which is introduced into the research results and the potential for propagation of such biases in subsequent studies indicates that no term can be uncritically ignored in a genetic equation. The obvious alternatives are (1) do not simplify by eliminating terms, (2) perform a complete error analysis, or (3) restrict the range of values for variables so that terms can be justifiably eliminated in the error analysis.Cooperative investigations of the Alfalfa Production Research Unit, United States Department of Agriculture, Agricultural Research Service, and the Nevada Agricultural Experiment Station, Reno, NV     

Maximizing microbial degradation of perchlorate using a genetic algorithm: Media optimization

Microbial communities are under constant influence of physical and chemical components in ecosystems. Shifts in conditions such as pH, temperature or carbon source concentration can translate into shifts in overall ecosystem functioning. These conditions can be manipulated in a laboratory setup using evolutionary computation methods such as genetic algorithms (GAs). In work described here, a GA methodology was successfully applied to define sets of environmental conditions for microbial enrichments and pure cultures to achieve maximum rates of perchlorate degradation. Over the course of 11 generations of optimization using a GA, we saw a statistically significant 16.45 and 16.76-fold increases in average perchlorate degradation rates by Dechlorosoma sp. strain KJ and Dechloromonas sp. strain Miss R, respectively. For two bacterial consortia, Pl6 and Cw3, 5.79 and 5.75-fold increases in average perchlorate degradation were noted. Comparison of zero-order kinetic rate constants for environmental conditions in GA-determined first and last generations of all bacterial cultures additionally showed marked increases.     

Genetic diversity of French common wheat germplasm based on gliadin alleles

 Analysis of gliadin electrophoretic (APAGE) patterns made it possible to identify 79 alleles at six Gli-1 and Gli-2 loci (from 9 to 18 per locus) and 173 gliadin genotypes in the 187 French common wheat cultivars considered. Six new alleles were registered in the catalogue of gliadin alleles. The genetic diversity of French common wheats was found to be high (H=0.714) and had not changed much during the last 25–50 years. Analysis of genetic distances showed some gradual changes in French wheat germplasm over the course of time. Genetic distances between French and several European wheat germplasm were analysed; genotypes of European wheats were found to relate very distantly to Canadian genotypes. The considerable differentiation of wheat genotypes from different countries and cereal companies might be caused by breeders’ personal preferences and by hidden natural selection specific to each local environment. In French cultivars, genetic variation in earliness, and in the North/South habit of the cultivars studied, correlated significantly with allelic variation at Gli-B1, Gli-A2 and Gli-D2 for earliness, and at Gli-D2 for the North/ South habit. Early and late cultivars are grown mainly in Southern and Northern France, respectively (r ²=0.30). Cultivars having either the 1B/1R translocation or allele Gli-D2g are, on average, later and more resistant to cold; they hence are grown in the North of France. Alternatively, cultivars with the allele Gli-D2m are earlier and cold-sensitive, and are grown in the South of France. Received: 5 February 1997 / Accepted: 19 September 1997     

Population demography and genetic characteristics of the Pacific Oyster Crassostrea gigas in Japan

The Pacific oyster Crassostrea gigas is a commercially important bivalve distributed along the northwest Pacific coast. Here C. gigas in Japan was investigated using mtDNA and microsatellite markers to elucidate its genetic structure and phylogeny. On the basis of mtDNA all populations showed high genetic diversity with limited genetic differentiation among populations. The pattern of MtDNA diversity suggested that C. gigas had experienced population expansion about 112 Kya, prior to the last glacial maximum (LGM), which accorded well with other marine organisms. For microsatellites, a Bayesian-based assignment test demonstrated that C. gigas is nearly panmictic. However, on the basis of estimates of F_ST, Kumano populations differed significantly from other populations, a recent occurrence based on low R_ST. Irrespective of geographical distance, genetic similarity was observed in the main aquaculture regions with large-scale transportation of cultured spat. Unlike in the Yellow Sea, a genetic bottleneck was not detected in Japanese populations. These results imply, contrary to the prevailing view, that C. gigas in Japan was demographically stable during the LGM. Gene flow by larval dispersal seems to be regionally restricted to localities of congenital areas by ocean currents, while genetic homogenization by cultivated oysters might have occurred in aquaculture areas.     

Genetic traits

Recognizing that all traits are the result of an interaction between genes and environment, I offer a set of criteria for nevertheless making sense of our practice of singling out certain traits as genetic ones, in effect making a distinction between causes and mere conditions. The central criterion is that a trait is genetic if it is genetic differences that make the differences in that trait variable in a given population. A second criterion requires that genetic traits be individuated in a way that matches what some genetic factors cause specifically. Clarifying our causal and classificatory language here can help us to avoid confusions of both theoretical and practical significance.     

太湖猪遗传多样性和系统发生关系的RAPD分析

报道了对太湖猪７个类群,红灯笼猪,约克夏种猪及太湖地区野猪共５７个个体随机扩增多态ＤＮＡ（ＲＡＰＤ）分析的结果,重建了太湖猪的系统发生树。实验从４０个引物中选用重复性较好的１３个引物对所有个体进行了随机扩增,共获得１９８个ＲＡＰＤ标记,单个引物获得的标记数在３－１６间。     

The meaning of genetic variation within and between subpopulations

Summary Argumentation is presented which indicates that the additive decomposition of the total genetic variation of a population into variation within and between (among) its subpopulations suffers from conceptual inconsistency. While the measurement of variation between subpopulations can be shown to be identical to the measurement of subpopulation differentiation, the notion of variation within subpopulations, when viewed as a single measurement, cannot be derived as an independent and cogent concept. Rather, it appears to be merely technically defined as the arithmetic difference between the total variation and the variation between subpopulations, and this difference happens to be non-negative for concave measures of variation such as the (statistical) variance or certain measures of genetic diversity. In order to overcome the conceptual inconsistency, variation between subpopulations could be regarded as subpopulation differentiation and the notion of variation within subpopulations could be replaced by measurements of the degree to which the variation in the total population is represented within the subpopulations. A complementary situation with respect to total variation is thus realized once more, and appropriate measures can be directly derived from existing ones.     

濒危植物矮沙冬青的等位酶多样性及居群分化

采用超薄平板微型聚丙烯酰胺等电聚焦技术,对珍稀濒危植物矮沙冬青(Ammopiptanthus nanus)6个自然居群的等位酶遗传多样性进行了初步研究。8个酶系统、l9个酶位点的检测结果表明,矮沙冬青具有较低的遗传变异水平。物种水平上的遗传多样性参数为：P=21．05％,A=1．21,Ht=0．040;居群水平上的平均遗传多样性为：P=14．04％,A=1．14(0．04),Ht=0．036(0．018),比长寿命多年生木本的狭域分布种和特有种的多样性水平都低。F-统计量分析显示,矮沙冬青在居群水平(F15=0．129)和总居群水平(FIT=0．202)上都表现为杂合子缺乏;Fsr=0．085表明居群问遗传分化较小,这与居群间较高的遗传一致度(I=0．997)的结果一致。据研究结果推测矮沙冬青进化历史上经历过遗传瓶颈,是造成遗传多样性水平偏低的重要原因。基于研究结果,提出应当重点保护遗传变异相对丰富的何依儿佣克尔(KE)居群,并且可将其作为引种的种源地。     

Genetic diversity of natural populations of Larix principis-rupprechtii in Shanxi Province,China

Prince Rupprecht's Larch (Larix principis-rupprechtii Mayr.) is one of dominant components of middle and high elevation forests in North China. Shanxi Province is well known as “the Hometown of Prince Rupprecht's Larch” in China. In this study, six natural populations of this species across Shanxi were selected to investigate the genetic variation of the species using amplified fragment length polymorphism (AFLP) markers. Results showed that in comparison with some other species of Larix, higher genetic diversity was revealed at the species level for L. principis-rupprechtii (percentage of polymorphic loci PPL = 71.9%, Nei's gene diversity H_E = 0.225, Shannon information index I = 0.341). Most of genetic variation existed within populations (80.5%), while the genetic differentiation among populations was significant (p < 0.001) and higher (G_st = 0.194) than most other species of Larix. The differentiation can be attributed to the limited gene flow (N_m = 1.035) among populations, which could be due to the spatial isolation and habitat fragmentation. The six populations can be divided into three groups based on the Nei's genetic distances between populations (from 0.033 to 0.076). There was no significant correlation (r = 0.268, p > 0.05) between genetic distance and geographic distance among populations. The measures for in-situ or ex-situ conservation should be taken to preserve the genetic diversity of this species.     

The use of replicated progenies in marker-based mapping of QTL's

Summary Seven types of progeny are described which can be used in detection of linkage between marker loci and quantitative trait loci (QTL) in a cross between two inbred lines. Three types of progeny: recombinant inbred lines (RI); doubled haploid lines (DH); and S₁ lines can be used to detect linked main effects, d. DH and RI lines can be used to detect smaller effects than S₁ lines. However, S₁ lines can also be used to detect within-population dominance effects, h. The smallest d detectible is in the range of 1/2 to 1/12 the size of the corresponding LSD_(0.05) for the quantitative trait, using 100 lines and 6 replicates. The smallest h detectible is 3–4 times this size. Four types of progeny can be used to detect differences in the dominance behavior of alleles within the population relative to an allele in another inbred line (P₄: DH lines x P₄; RI lines x P₄; either F₂ x P₄ or S₁ lines x P₄; and progeny generated by crossing (F₁ x P₃) x P₄. Dominance differences in the range of 1 1/4 to 1/6 the size of the corresponding LSD_(0.05) are routinely detectible using 100 lines and 6 replicates. Increasing the numbers of progeny evaluated or the number of replicates allows for the detection of relatively smaller linked effects.Contribution of United AgriSeeds, Inc.     

Natural hybridization within seed sources of shortleaf pine (Pinus echinata Mill.) and loblolly pine (Pinus taeda L.)

Shortleaf and loblolly pine trees (n = 93 and 102, respectively) from 22 seed sources of the Southwide Southern Pine Seed Source Study plantings or equivalent origin were evaluated for amplified fragment length polymorphism (AFLP) variation. These sampled trees represent shortleaf pine and loblolly pine, as they existed across their native geographic ranges before intensive forest management. Using 17 primer pairs, a total of 96 AFLPs between shortleaf pine and loblolly pine were produced and scored on the sample trees and two control-pollinated F1 interspecies hybrids and their parents. In addition, the well known isocitrate dehydrogenase (IDH) isozyme marker was scored for all trees. IDH detected two putative hybrids among the loblolly pine samples and two among the shortleaf pine samples, while either 13 or 12 putative hybrids were detected using all AFLP markers and IDH and either NewHybrids or Structure software, respectively. Results of this study show that later generation hybrids can be reliably identified using AFLP markers and confirmed that IDH is not a definitive marker for detecting hybrids; that is, at least in some seed sources, the alternative species’ IDH allele resides in the source species. Based on all the markers, hybridization frequency varied geographically, ranging from 30% in an Arkansas seed source to 0% in several other seed sources. The hybridization level was higher in populations west of the Mississippi River than in populations east of the river; the shortleaf pine hybridization rates were 16.3% and 2.4% and the loblolly pine rates were 4.5% and 3.3%, west and east of the river, respectively. The results suggest that hybridization between these two species is significant but varies by seed source and species, and the potential for the unintended creation of hybrids should be considered in forest management decisions regarding both natural and artificial regeneration.     

Effects of genomic imprinting on quantitative traits

Standard Mendelian genetic processes incorporate several symmetries, one of which is that the level of expression of a gene inherited from an organism’s mother is identical to the level should that gene have been inherited paternally. For a small number of loci in a variety of taxa, this symmetry does not hold; such genes are said to be “genomically imprinted” (or simply “imprinted”). The best known examples of imprinted loci come from mammals and angiosperms, although there are also cases from several insects and some data suggesting that imprinting exists in zebra fish. Imprinting means that reciprocal heterozygotes need not be, on average, phenotypically identical. When this difference is incorporated into the standard quantitative-genetic model for two alleles at a single locus, a number of standard expressions are altered in fundamental ways. Most importantly, in contrast to the case with euMendelian expression, the additive and dominance deviations are correlated. It would clearly be of interest to be able to separate imprinting effects from maternal genetic effects, but when the latter are added to the model, the well-known generalized least-squares approach to deriving breeding values cannot be applied. Distinguishing these two types of parent-of-origin effects is not a simple problem and requires further research.     

Theory and application of open-pollination and polycross in forage grass breeding

Summary Progeny testing and selection of forage grasses by means of growing half-sib (HS) families from openpollination and polycross have been considered from theoretical and practical points of view. Special attention has been paid to the genetic variation within half-sib families, which is expected to be large as compared to the genetic variation between families. Based on observations of individual plants within plots, the environmental component of the variation is expected to be large and nonestimatable. The results of an experiment in meadow fescue (Festuca pratensis Huds.) are presented. In this experiment, randomly selected individual plants within HS families were cloned and laid out in randomized blocks. For the characters observed (earliness and raw matter yield) no significant variance component for dominance was found. The highly significant additive component estimated for earliness, as well as for yield, after each of three cuts and in total were about three times as large within as between families, as expected from the theoretical considerations. The estimated response to selection was much higher for a combination of between- and within-family selection as compared to free clone or family mean selection alone. It is suggested that a program for progeny testing and selection in a base population of perennial forage grasses should start with an experiment in which a large number of randomly selected parental clones and a fixed number of clones from each of the half-sib families derived from the mother genotypes are grown simultaneously. The selected clones within superior families could later on be further cloned, placed in a polycross field, and the new HS-families could be sown in ordinary field trials at various locations for further selection.