International Commission for Protection against Environmental Mutagens and Carcinogens. ICPEMC working paper 5/1: Perspectives in mutation epidemiology. 1. Incidence and prevalence of genetic disease (excluding chromosomal aberrations) in human populations

Detailed knowledge of the birth frequency or the cumulative incidence over all ages of genetic diseases in human populations is a prerequisite for assessing the magnitude of possible genetic hazards caused by environmental mutagens. However, both theoretical and practical difficulties are involved in precisely measuring the total frequency of these diseases. Two sets of data from large-scale population studies, one from Northern Ireland and the other from British Columbia, are compared with each other and with the results from ad hoc surveys for individual monogenic disorders. With due allowance for differences in approach, examination indicates that the data from the large-scale population studies are inadequate. However, it could provide a crude estimate of the total frequency of genetic diseases and a fairly reliable estimate of the individual frequency of certain genetic disorders with early onset that are familiar and readily diagnosed. In addition to environmental mutagens, there are a number of factors associated with current human activity that may change the incidence of genetic diseases. In order to monitor the human population for environmental mutagens, the change in frequency of sporadic cases of those genetic diseases that arose from fresh mutation and that can be easily detected as early as possible should be followed closely. The mechanism of data collection currently being employed in some countries for childhood cancers, certain congenital malformations, and inborn errors of metabolism could be extended to include the so-called sentinel phenotypes. The rationale and feasibility of using retinoblastoma and Wilms' tumor (nephroblastoma) as examples of such population monitoring are described.     

杜鹃红山茶遗传多样性的ISSR分析

运用ISSR分子标记技术,利用筛选的10条ISSR引物,对珍稀濒危植物杜鹃红山茶(Camellia changii Ye)2个亚种群60个单株的遗传多样性进行了研究。结果表明:物种水平上的多态位点百分率(PPB)为55.29%,Nei’s基因多样性指数(H)及Shannon多态性信息指数(I)分别为0.2191和0.3215。种群间的遗传分化系数(GST)仅为0.0922。研究结果揭示了杜鹃红山茶的遗传多样性较低,亚种群间遗传分化较小。小种群和人为活动干扰是杜鹃红山茶现存种群的主要限制因素。影响杜鹃红山茶种群发展的其它因素亟需进一步研究。     

复杂疾病全基因组关联研究进展——遗传统计分析

2005年, Science杂志首次报道了有关人类年龄相关性黄斑变性的全基因组关联研究, 此后有关肥胖、2型糖尿病、冠心病、阿尔茨海默病等一系列复杂疾病的全基因组关联研究被陆续报道, 这一阶段被称为人类全基因组关联研究的第一次浪潮。文章分别介绍了全基因组关联研究统计分析的方法、软件和应用实例; 比较了关联分析中多重检验的P值调整方法, 包括Bonferroni、递减的Bonferroni校正法、模拟运算法和控制错误发现率的方法; 还讨论了人群混杂对关联分析结果可能产生的影响及原理, 以及全基因组关联研究中控制人群混杂的方法的研究进展和应用实例。在全基因组关联研究的第一次浪潮中, 应用经典的遗传统计方法发现了许多基因-表型之间的关联并且能够对这些关联做出解释, 其中包括许多基因组中的未知基因和染色体区域。然而, 全基因组关联研究的继续发展需要进一步阐述基因组内基因之间相互作用、基因-基因之间的复杂作用网络与环境因素的相互作用在复杂疾病发生中的作用, 现有的统计分析方法肯定不能满足需要, 开发更为高级的统计分析方法势在必行。最后, 文章还给出了全基因组关联研究统计分析软件的相关网站信息。     

Inter- and intramouse heterogeneity of radiation response for a growing paired organ

An intensive search for predictive markers of individual radiation response of apparently normal tissues in cancer patients is in progress at the genetic and epigenetic levels. However, the relative impact of variability at these levels is not clear. Experimental results obtained in inbred rodents, which have significantly reduced genetic heterogeneity relative to a population of human patients, may help to clarify this issue. We investigated a paired-organ mouse system in a strain of inbred mice to evaluate the intermouse variability of normal tissue radiation response, singled out from measurement errors and stochastic effects. The legs of 5-day-old C3H mice were homogeneously gamma-irradiated with a range of single doses. The lengths of the right and left tibiae were measured in 30 kVp X-ray images taken at the time of irradiation and at 84 days postirradiation. The dose-effect curves were smooth and well defined, with bone growth retardation evident at approximately 14 Gy and higher, and were marginally gender-dependent. The intramouse (left compared to right) variability of the tibia length on day 89, which characterized stochastic effects, was not distinguishable from the measurement error for doses less than 16-18 Gy and slightly exceeded measurement errors only at the largest doses of 20-22 Gy. The corresponding intermouse variability was greater than the measurement error and stochastic effects at all doses used. Interestingly, the total variability, judged by the gamma(50) values of approximately 7 we obtained, was similar to that reported for severe late reactions in human normal tissue. If the variations of response determined by epigenetic events in human patients free of known factors associated with altered radiation sensitivity are comparable to those observed in this mouse model, our results imply a relatively low power of genetic approaches alone to predict individual side effects in radiotherapy.     

Phylogeography of the marbled crab Pachygrapsus marmoratus (Decapoda,Grapsidae) along part of the African Mediterranean coast reveals genetic homogeneity across the Siculo-Tunisian Strait versus heterogeneity across the Gibraltar Strait

We investigate the influence of previously postulated biogeographic barriers in the Mediterranean Sea on the population genetic structure of a highly dispersive and continuously distributed coastal species. In particular, we examine nuclear and mitochondrial genetic variation in the marbled crab, Pachygrapsus marmoratus, across part of the African Mediterranean coast in order to assess the influence of the Siculo-Tunisian Strait on its population genetic structure. Four polymorphic microsatellite loci were genotyped for 110 individuals, collected from eight locations covering parts of the Algerian, Tunisian and Libyan coasts. In addition, mtDNA corresponding to the Cox1 gene was sequenced for 80 samples. The corresponding results show contrasting patterns of genetic differentiation. While mtDNA results revealed a homogeneous haplotype composition in our study area, microsatellite data depicted genetic differentiation among populations, but not associated with any geographic barrier. This pattern, already recorded for this species from different geographic regions, may hint at the involvement of a complex series of abiotic and biotic factors in determining genetic structure. Demographic history reconstruction, inferred from mtDNA data, supports demographic and spatial expansion for the North African metapopulation dating back to the Mid-Pleistocene and following an historical bottleneck. Comparison of these African mitochondrial sequences with new sequences from a Turkish population and previously published sequences revealed a weak but significant separation of Atlantic and Mediterranean populations across the Gibraltar Strait, which was not recorded in previous studies of this grapsid species.     

Efficient control of population structure in model organism association mapping

Genomewide association mapping in model organisms such as inbred mouse strains is a promising approach for the identification of risk factors related to human diseases. However, genetic association studies in inbred model organisms are confronted by the problem of complex population structure among strains. This induces inflated false positive rates, which cannot be corrected using standard approaches applied in human association studies such as genomic control or structured association. Recent studies demonstrated that mixed models successfully correct for the genetic relatedness in association mapping in maize and Arabidopsis panel data sets. However, the currently available mixed-model methods suffer from computational inefficiency. In this article, we propose a new method, efficient mixed-model association (EMMA), which corrects for population structure and genetic relatedness in model organism association mapping. Our method takes advantage of the specific nature of the optimization problem in applying mixed models for association mapping, which allows us to substantially increase the computational speed and reliability of the results. We applied EMMA to in silico whole-genome association mapping of inbred mouse strains involving hundreds of thousands of SNPs, in addition to Arabidopsis and maize data sets. We also performed extensive simulation studies to estimate the statistical power of EMMA under various SNP effects, varying degrees of population structure, and differing numbers of multiple measurements per strain. Despite the limited power of inbred mouse association mapping due to the limited number of available inbred strains, we are able to identify significantly associated SNPs, which fall into known QTL or genes identified through previous studies while avoiding an inflation of false positives. An R package implementation and webserver of our EMMA method are publicly available.     

Analysis of the Alu insertion polymorphism in urban and rural populations of Siberia]

Polymorphic Alu-repeat loci of human genome are commonly used as effective genetic markers in population and evolution studies. In this work, the data on genetic structure of two Russian populations from Siberia obtained via analysis of five polymorphic Alu repeats are presented. The urban population was characterized by a slightly higher level of genetic diversity compared to the rural population. The value of genetic differentiation coefficient for the populations studied was 0.57%, pointing to the absence of genetic subdivision within the urban and rural populations. Phylogenetic analysis of these populations, together with literature data, shows that, with respect to the markers examined, the gene pool structure of Russian population is similar to that of other Caucasoid populations.     

Population structure and inbreeding from pedigree analysis of purebred dogs

Dogs are of increasing interest as models for human diseases, and many canine population-association studies are beginning to emerge. The choice of breeds for such studies should be informed by a knowledge of factors such as inbreeding, genetic diversity, and population structure, which are likely to depend on breed-specific selective breeding patterns. To address the lack of such studies we have exploited one of the world's most extensive resources for canine population-genetics studies: the United Kingdom (UK) Kennel Club registration database. We chose 10 representative breeds and analyzed their pedigrees since electronic records were established around 1970, corresponding to about eight generations before present. We find extremely inbred dogs in each breed except the greyhound and estimate an inbreeding effective population size between 40 and 80 for all but 2 breeds. For all but 3 breeds, >90% of unique genetic variants are lost over six generations, indicating a dramatic effect of breeding patterns on genetic diversity. We introduce a novel index Psi for measuring population structure directly from the pedigree and use it to identify subpopulations in several breeds. As well as informing the design of canine population genetics studies, our results have implications for breeding practices to enhance canine welfare.     

Bayesian Inference of Shared Recombination Hotspots Between Humans and Chimpanzees

Recombination generates variation and facilitates evolution. Recombination (or lack thereof) also contributes to human genetic disease. Methods for mapping genes influencing complex genetic diseases via association rely on linkage disequilibrium (LD) in human populations, which is influenced by rates of recombination across the genome. Comparative population genomic analyses of recombination using related primate species can identify factors influencing rates of recombination in humans. Such studies can indicate how variable hotspots for recombination may be both among individuals (or populations) and over evolutionary timescales. Previous studies have suggested that locations of recombination hotspots are not conserved between humans and chimpanzees. We made use of the data sets from recent resequencing projects and applied a Bayesian method for identifying hotspots and estimating recombination rates. We also reanalyzed SNP data sets for regions with known hotspots in humans using samples from the human and chimpanzee. The Bayes factors (BF) of shared recombination hotspots between human and chimpanzee across regions were obtained. Based on the analysis of the aligned regions of human chromosome 21, locations where the two species show evidence of shared recombination hotspots (with high BFs) were identified. Interestingly, previous comparative studies of human and chimpanzee that focused on the known human recombination hotspots within the β-globin and HLA regions did not find overlapping of hotspots. Our results show high BFs of shared hotspots at locations within both regions, and the estimated locations of shared hotspots overlap with the locations of human recombination hotspots obtained from sperm-typing studies.     

Use of DNA fingerprinting for human population genetic studies

DNA fingerprinting techniques have been used in population genetic studies on many different kinds of organisms. Here, we present new applications for multilocus DNA fingerprint probes in population studies and demonstrate the applicability of DNA fingerprinting to human population genetics, using M13 phage DNA as a probe. The new approach, which is based on a factor method of numerical coding of non-quantitative data (factor correspondence analysis-FCA), shows good agreement between population position, as indicated by the three principal factors, and ethnogenetic proximity.     

The relative efficacy of functional and developmental cranial modules for reconstructing global human population history

This study tests the relative efficacy of human cranial modules, defined on the basis of developmental and functional criteria, for reconstructing neutral genetic population history. Specifically, two hypotheses were tested: 1) The "basicranial hypothesis" predicts that the endochondrally ossifying basicranium will be more reliable for reconstructing population history than intramembranously ossifying regions of the human cranium. This is based on the assumption that early ossification of the basicranium and its distinct functional constraints produce a cranial structure that is relatively immune to non-neutral evolutionary forces. 2) The "single function hypothesis" predicts that cranial regions associated with a single (sensory) function are less reliable indicators of neutral genetic history. Here the prediction is based on the logic that complex, multi-functional, integrated cranial regions are less likely toexhibit homoplasy and, therefore, provide a more accurate morphological proxy for genetic relationships. The congruence between craniometric affinity matrices and neutral genetic population matrices based on autosomal microsatellite and classical markers was assessed using a series of Mantel and Dow-Cheverud tests. The results did not support the predictions of the "basicranial hypothesis," as the endochondrally ossifying basicranium was not significantly more congruent with the genetic data than intramembraneously ossifying modules. Moreover, although the results provided some support for the "single function hypothesis," defining cranial modules on the basis of anatomical or functional complexity did not provide a consistent means of predicting their phylogenetic efficacy. These results have important implications for building an accurate inference model of cranial evolution in the human fossil record.     

Ecological correlates of population genetic structure: a comparative approach using a vertebrate metacommunity

Identifying ecological factors associated with population genetic differentiation is important for understanding microevolutionary processes and guiding the management of threatened populations. We identified ecological correlates of several population genetic parameters for three interacting species (two garter snakes and an anuran) that occupy a common landscape. Using multiple regression analysis, we found that species interactions were more important in explaining variation in population genetic parameters than habitat and nearest-neighbour characteristics. Effective population size was best explained by census size, while migration was associated with differences in species abundance. In contrast, genetic distance was poorly explained by the ecological correlates that we tested, but geographical distance was prominent in models for all species. We found substantially different population dynamics for the prey species relative to the two predators, characterized by larger effective sizes, lower gene flow and a state of migration-drift equilibrium. We also identified an escarpment formed by a series of block faults that serves as a barrier to dispersal for the predators. Our results suggest that successful landscape-level management should incorporate genetic and ecological data for all relevant species, because even closely associated species can exhibit very different population genetic dynamics on the same landscape.     

Nutrigenomics research for personalized nutrition and medicine

Current nutritional and genetic epidemiological methods yield 'risk factors' on the basis of population studies. Risk factors, however, are statistical estimates of the percentage reduction in disease in the population if the risk were to be avoided or the gene variant were not present. These measures are often assumed to apply to individuals who are likely to differ in genetic make-up, lifestyle, and dietary patterns than to the individuals in the study population. Developing individual risk factors in light of the genetic diversity of human populations, the complexity of foods, culture and lifestyle, and the variety of metabolic processes that lead to health or disease is a significant challenge for personalizing dietary advice for healthy or individuals with chronic disease.     

Tuberculosis as a complex trait: impact of genetic epidemiological study design

Several studies have suggested a role for human genetic risk factors in the susceptibility to developing tuberculosis (TB). However, results of these studies have been inconsistent, and one potential reason for these inconsistencies is variation in aspects of study design. Specifically, phenotype definitions and population genetic factors have varied dramatically. Since TB is a complex trait, there are many challenges in designing studies to assess appropriately human genetic risk factors for the development of TB as opposed to the acquisition of latent M. tuberculosis infection. In this review we summarize these important study design differences, with illustrations from the TB genetics literature. We cite specific examples of studies of the NRAMP1 (SLC11A1) gene and present Fisher??s combined p values for different stratifications of these studies to further illustrate the impact of study design differences. Finally, we provide suggestions for the design of future genetic epidemiological studies of TB.     

The protective role of selenium on genetic damage and on cancer

Collectively, results from epidemiologic studies, laboratory bioassays, and human clinical intervention trials clearly support a protective role of selenium against cancer development. Several hypotheses have been proposed to explain these observations. Increased genomic instability, either inherent or induced by exogenous agents (mutagens or carcinogens), has been considered as a primary event leading to neoplastic transformation. This report deals specifically with the evidence for a role of selenium in the inhibition of carcinogen-induced covalent DNA adduct formation and retardation of oxidative damage to DNA, lipids and proteins, and for modulating cellular and molecular events that are critical in cell growth inhibition and in the multi-step carcinogenesis process. At present, the bulk of our knowledge on the role of selenium on genetic stability is based primarily on animal data and from studies conducted in in vitro systems. Studies performed in vitro showed that the dose and form of selenium compounds are critical factors with regard to cellular responses. Inorganic (at doses up to 10microM) and organic selenium compounds (at doses equal to or greater than 10microM) elicit distinctly different cellular responses. The recommended daily allowance (RDA) is 50-70 microgramSe per day for healthy adults; with 40 microgramSe as minimum requirement. Less than 11 microgramSe will definitely put people at risk of deficiency that would be expected to cause genetic damage. Daily doses of 100-200 microgramSe inhibited genetic damage and cancer development in humans. About 400 microgramSe per day is considered an upper limit. Clearly, doses above the RDA are needed to inhibit genetic damage and cancer. However, it has been hypothesized that the intake of excessive doses of selenium may cause oxidative damage, leading to genomic instability. The use of a cocktail consisting of selenium, and other vitamins and minerals appears to be a promising approach to inhibit genetic damage and the development of cancer. It is the author's recommendation that development of mechanism-based hypotheses that can be tested in pilot studies in different populations prior to a large-scale clinical trial in humans, is of paramount importance in order to better understand the role of selenium on genetic stability and cancer.     

Native American Admixture in the Quebec Founder Population

For years, studies of founder populations and genetic isolates represented the mainstream of genetic mapping in the effort to target genetic defects causing Mendelian disorders. The genetic homogeneity of such populations as well as relatively homogeneous environmental exposures were also seen as primary advantages in studies of genetic susceptibility loci that underlie complex diseases. European colonization of the St-Lawrence Valley by a small number of settlers, mainly from France, resulted in a founder effect reflected by the appearance of a number of population-specific disease-causing mutations in Quebec. The purported genetic homogeneity of this population was recently challenged by genealogical and genetic analyses. We studied one of the contributing factors to genetic heterogeneity, early Native American admixture that was never investigated in this population before. Consistent admixture estimates, in the order of one per cent, were obtained from genome-wide autosomal data using the ADMIXTURE and HAPMIX software, as well as with the fastIBD software evaluating the degree of the identity-by-descent between Quebec individuals and Native American populations. These genomic results correlated well with the genealogical estimates. Correlations are imperfect most likely because of incomplete records of Native founders’ origin in genealogical data. Although the overall degree of admixture is modest, it contributed to the enrichment of the population diversity and to its demographic stratification. Because admixture greatly varies among regions of Quebec and among individuals, it could have significantly affected the homogeneity of the population, which is of importance in mapping studies, especially when rare genetic susceptibility variants are in play.     

Collection of pedigree data for genetic analysis in isolate populations

Pedigree data are useful for a wealth of research purposes in human population biology and genetics. The collection of extended pedigrees represents the most powerful sampling design for quantitative genetic and linkage studies of both normal and disease-related quantitative traits. In this paper we outline an approach for collecting pedigree data in stable isolate populations. As an example, the pedigree for the Jirel population, which was obtained using the methods presented, is described. The Jirel pedigree contains 2,000 study participants and more than 62,000 pairwise relationships that are informative for genetic analysis. Once such pedigrees are genetically characterized by a genome scan for a given trait, they become an invaluable resource for future genetic studies of any quantitative trait.     

Population genomics: diversity and virulence in the Neisseria

Advances in high-throughput nucleotide sequencing and bioinformatics make the study of genomes at the population level feasible. Preliminary population genomic studies have explored the relationships among three closely related bacteria, Neisseria meningitidis, Neisseria gonorrhoeae and Neisseria lactamica, which exhibit very different phenotypes with respect to human colonisation. The data obtained have been especially valuable in the establishing of the role of horizontal genetic exchange in bacterial speciation and shaping population structure. In the meningococcus, they have been used to define invasive genetic types, search for virulence factors and potential vaccine components and investigate the effects of vaccines on population structure. These are generic approaches and their application to the Neisseria provides a foretaste for their application to the wider bacterial world.     

Genetic effects on variation in red-blood-cell folate in adults: implications for the familial aggregation of neural tube defects.

Recent studies have implicated folic acid as an important determinant of normal human growth, development, and function. Insufficient folate levels appear to be a risk factor for neural tube defects (NTD), as well as for several chronic diseases of adulthood. However, relatively little is known about the factors that influence folate status in the general population. To estimate the relative contribution of genetic and nongenetic factors to variation in folate, we have evaluated red blood cell (RBC) folate levels in 440 pairs of MZ twins and in 331 pairs of DZ twins. The data were best described by a model in which 46% of the variance in RBC folate was attributable to additive genetic effects, 16% of the variance was due to measured phenotypic covariates, and 38% of the variance was due to random environmental effects. Moreover, the correlations for RBC folate in MZ co-twins (r = .46) and in repeat measures from the same individual (r = .51) were very similar, indicating that virtually all repeatable variation in RBC folate is attributable to genetic factors. On the basis of these results, it would seem reasonable to initiate a search for the specific genes that influence RBC folate levels in the general population. Such genes ultimately may be used to identify individuals at increased risk for NTD and other folate-related diseases.