Learning directed acyclic graphs from large-scale genomics data

In this paper, we consider the problem of learning the genetic interaction map, i.e., the topology of a directed acyclic graph (DAG) of genetic interactions from noisy double-knockout (DK) data. Based on a set of well-established biological interaction models, we detect and classify the interactions between genes. We propose a novel linear integer optimization program called the Genetic-Interactions-Detector (GENIE) to identify the complex biological dependencies among genes and to compute the DAG topology that matches the DK measurements best. Furthermore, we extend the GENIE program by incorporating genetic interaction profile (GI-profile) data to further enhance the detection performance. In addition, we propose a sequential scalability technique for large sets of genes under study, in order to provide statistically significant results for real measurement data. Finally, we show via numeric simulations that the GENIE program and the GI-profile data extended GENIE (GI-GENIE) program clearly outperform the conventional techniques and present real data results for our proposed sequential scalability technique.     

Inferring Regulatory Networks from Expression Data Using Tree-Based Methods

One of the pressing open problems of computational systems biology is the elucidation of the topology of genetic regulatory networks (GRNs) using high throughput genomic data, in particular microarray gene expression data. The Dialogue for Reverse Engineering Assessments and Methods (DREAM) challenge aims to evaluate the success of GRN inference algorithms on benchmarks of simulated data. In this article, we present GENIE3, a new algorithm for the inference of GRNs that was best performer in the DREAM4 In Silico Multifactorial challenge. GENIE3 decomposes the prediction of a regulatory network between p genes into p different regression problems. In each of the regression problems, the expression pattern of one of the genes (target gene) is predicted from the expression patterns of all the other genes (input genes), using tree-based ensemble methods Random Forests or Extra-Trees. The importance of an input gene in the prediction of the target gene expression pattern is taken as an indication of a putative regulatory link. Putative regulatory links are then aggregated over all genes to provide a ranking of interactions from which the whole network is reconstructed. In addition to performing well on the DREAM4 In Silico Multifactorial challenge simulated data, we show that GENIE3 compares favorably with existing algorithms to decipher the genetic regulatory network of Escherichia coli. It doesn''t make any assumption about the nature of gene regulation, can deal with combinatorial and non-linear interactions, produces directed GRNs, and is fast and scalable. In conclusion, we propose a new algorithm for GRN inference that performs well on both synthetic and real gene expression data. The algorithm, based on feature selection with tree-based ensemble methods, is simple and generic, making it adaptable to other types of genomic data and interactions.     

Application of nuclear analytical techniques using long-life sealed-tube neutron generators

The new range of sealed-tube neutron generators developed by SODERN appears to be appropriate for the industrial environment. The main characteristics are the high emission stability during the very long lifetime of the tube, flexible pulsed mode capability, safety in operation with no radiation in “off” state, and the easy, transportation of equipment. Some applications of the neutron generators, called GENIE, are considered: high-sensitivity measurement of transuranic elements in nuclear waste drums, bulk material analysis for process control, and determination of the airborne pollutants for environmental monitoring.

     

Older age should not be a barrier to testing for somatic variants in homologous recombination DNA repair-related genes in patients with high-grade serous ovarian carcinoma

BackgroundSomatic pathogenic variants (PVs) in homologous recombination DNA repair (HR)-related genes found in high-grade serous ovarian carcinomas (HGSC) are not well-characterised in older patients (≥70 years). This may reflect low testing rates in older patients.MethodsData from 1210 HGSC patients in AACR Project GENIE and 324 patients in an independent dataset INOVATe were analysed. Cases where somatic variants could be distinguished from germline variants were included, and analysis was restricted to those with a somatic TP53 variant, to ensure cases were HGSC.ResultsOf 1210 patients in GENIE, 27% (n = 325) were aged ≥70 years at testing. Patients with somatic-only PVs in BRCA2 were older compared with BRCA1 (median 71 vs 60 years, p = 0.002). Median age for 21 patients with somatic-only PVs in 11 other HR-related genes ranged from 40 to 67 years. In older patients, 7% (n = 22) had somatic BRCA1/2 PVs, and 1% (n = 2) had PVs other HR-related genes; this rate was not significantly different to younger patients (<70 years), 7% (n = 62) BRCA1/2 and 2% (n = 19) other HR-related genes (p = 0.36). The overall frequency of somatic BRCA1/2 PVs was similar in INOVATe (n = 25; 7.7%) and somatic-only BRCA2 PVs were again found in older patients compared with BRCA1 (median age: at testing, 70 vs 63 years; at diagnosis, 68 vs 60 years).ConclusionsThe overall frequency of somatic-only PVs in HR-related genes was similar in older and younger patients with HGSC, highlighting the importance of somatic testing irrespective of age. Limiting somatic testing by age may exclude patients who could benefit from maintenance poly(ADP-ribose) polymerase (PARP) inhibitors.     

Two complementary perspectives on inter-individual genetic distance

This paper examines population structure through the prism of pairwise genetic distances. Two complementary perspectives, framed as two simple questions, are explored: Q1: What is the probability that a random pair of individuals from the same local population is more genetically dissimilar than a random pair from two distinct populations? Q2: On average, how genetically different are two individuals from the same local population, in comparison with two individuals chosen from any two distinct populations? Models are developed to provide quantitative answers for the two questions, given allele frequencies across any number of markers from two diploid populations. The probability from Q1 is shown to drop to zero with increasing number of genetic markers even for very closely-related populations and rare alleles. The average genetic dissimilarity of two individuals from distinct populations diverges from the average dissimilarity of two individuals from the same population by a percentage dependent on estimates of population differentiation. This perspective also suggests a measure of population distance based on the intuitive notion of pairwise genetic distance, along with a simple method of estimation. Results from recent empirical research on inter-individual genetic distance in human populations are analyzed in the context of the theoretical framework.     

Relationships between Human Population Density and Burned Area at Continental and Global Scales

We explore the large spatial variation in the relationship between population density and burned area, using continental-scale Geographically Weighted Regression (GWR) based on 13 years of satellite-derived burned area maps from the global fire emissions database (GFED) and the human population density from the gridded population of the world (GPW 2005). Significant relationships are observed over 51.5% of the global land area, and the area affected varies from continent to continent: population density has a significant impact on fire over most of Asia and Africa but is important in explaining fire over < 22% of Europe and Australia. Increasing population density is associated with both increased and decreased in fire. The nature of the relationship depends on land-use: increasing population density is associated with increased burned are in rangelands but with decreased burned area in croplands. Overall, the relationship between population density and burned area is non-monotonic: burned area initially increases with population density and then decreases when population density exceeds a threshold. These thresholds vary regionally. Our study contributes to improved understanding of how human activities relate to burned area, and should contribute to a better estimate of atmospheric emissions from biomass burning.     

THE HOUSE SPARROW PASSER DOMESTICUS: POPULATION PROBLEMS

Two problems of House Sparrow populations are examined: the influence of habitat on numbers and the variation in a population of House Sparrows throughout the year. Available data on censuses in Great Britain enable the population to be estimated as 10 millions; censuses from several parts of the bird's range suggest that House Sparrow numbers are correlated with the human population, the ratio being 1: 5. The seasonal variation in composition of a population is estimated from observations over five years on House Sparrows breeding on a group of seventeen houses together with breeding and mortality data obtained from British Trust for Ornithology records. The population reaches a maximum at the end of July when it is slightly less than double that at the beginning of the breeding season. It is considered that numbers are controlled by food supply and the colonial behaviour of the bird.     

TRAP及SSCP检测草鱼微卫星序列多态性

目的：在草鱼不同种群遗传结构比较中,应用一些来自鲤鱼的微卫星引物扩增草鱼的相关序列缺少多态性,该研究通过应用几种方法提高这些序列在遗传学研究中的价值。方法：运用TRAP随机引物与鲤鱼的微卫星引物组合,扩增出多态性好、重复性强的产物;同时采用SSCP技术对那些没有长度多态的微卫星序列进一步分析,寻找这些序列存在一些核苷酸位点的多态性。结果：TRAP可以检查到多态性好、重复性强的产物;SSCP发现一部分没有长度多态性的微卫星序列存在核苷酸位点多态性并且可以清楚分辨不同的基因型。结论：结果表明TRAP及SSCP在种群遗传学研究有良好的应用前景。     

RET rearrangements in non-small cell lung cancer: Evolving treatment landscape and future challenges

The Rearranged during Transfection (RET) oncogene has been extensively investigated in solid malignancies, particularly thyroid cancer and non-small cell lung cancer (NSCLC), and represents an attractive therapeutic target. RET rearrangements occur in 1–2% of lung adenocarcinomas, where they function as potent oncogenic drivers. Importantly, tumors harboring RET fusions are particularly sensitive to RET tyrosine kinase inhibitors. Results of the LIBRETTO-001 and ARROW clinical trials led to the approval of novel potent and selective RET inhibitors, selpercatinib and pralsetinib, able to overcome the limits of previously used multikinase inhibitors. Herein, we review the most relevant evidences about the role of RET signaling in NSCLC. In addition, we interrogated the Project GENIE database to investigate common clinical and molecular features of RET-fusion positive NSCLC. This analysis revealed that RET rearrangements occurred more frequently in younger and light smoker patients and were associated with a lower tumor mutational burden, compared to RET-fusion negative tumors. Moreover, we assessed and described the differences between RET genomic alterations in NSCLC and thyroid cancers. Finally, we summarized how the treatment landscape of RET-rearranged NSCLC has changed in the last few years, which are the available data about the recognized mechanisms of resistance to RET inhibitors and the challenges for future development of novel therapeutic strategies, aiming to improve management of patients with RET-fusion positive NSCLC.     

Population distributions of minimum inhibitory concentration--increasing accuracy and utility

AIMS: To generate continuous minimum inhibitory concentration (MIC) data that describes the discrete nature of experimentally derived population MIC data. METHODS AND RESULTS: A logistic model was fitted to experimentally derived MIC population cumulative distributions from clinical isolates of Haemophilus influenzae, Moraxella catarrhalis, Streptococcus pneumoniae and Staphylococcus aureus (European Committee on Antimicrobial Susceptibility Testing, BSAC and MYSTIC population susceptibility databases). From the model continuous distributions of population susceptibility were generated. The experimentally observed population distributions based on discrete MIC could be reproduced from this underlying continuous distribution. Monte Carlo (MC) simulation was used to confirm findings. Where the discrete experimental data contained few or no isolates with MIC greater or less than the antimicrobial concentration range tested, the true mean MIC was a factor of 0.707 times that normally reported and may be of little clinical significance. Where data contained isolates beyond the range of concentration used, the true MIC was dependent on the SD and the number of isolates and could be clinically significant. Subpopulations of differing susceptibilities could be modelled successfully using a modified logistic equation: this allows a more accurate examination of the data from these databases. CONCLUSIONS: The mean MIC and SD of population data currently reported are incorrect as the method of obtaining such parameters relies on normally distributed data which current MIC population data are not. SIGNIFICANCE AND IMPACT OF THE STUDY: Obtaining the distribution parameters from the underlying continuous distribution of MIC can be carried out using a simple logistic equation. MC simulation using these values allows easy visualization of the discrete data. The analyses of subpopulations within the data should increase the usefulness of horizontal studies.     

甘肃鼢鼠不同地理种群的形态变异分析

甘肃鼢鼠(Myospalax cansus)隶属于啮齿目(Rodentia)、鼹形鼠科(Spalacidae)、鼢鼠亚科(Myospalacinae)、鼢鼠属(Myospalax)(Norris et al.,2004),主要分布于我国西北地区的黄土高原,为陕西、甘肃、宁夏及青海东部地区农田和草原的主要害鼠之一,对林业幼苗也有一定的损伤,同时亦是水土保持的主要破坏因素之一(江廷安等,1996).作为地下掘土类食草动物,由于地下积水和空气不流通,甘肃鼢鼠经受着食物匮乏等的环境压力,很可能促使甘肃鼢鼠身体结构向有利于适应洞道系统的方向变化,导致种群分化.     

中国北方汉族人群sTnT基因单核苷酸多态性分析

目的：研究中国北方汉族人群sTnT基因的单核苷酸多态性（SNP）,观察其在北方汉族人群中的分布。方法：用PCR-RFLP的方法对204名中国北方汉族人群sTnT基因的SNP进行分析,确定其等位基因频率。结果：美国国立生物技术信息中心报告的外显子11上的27916722 A／C未在本项研究人群中检测到。27930097 C／G和的27920978 C／F的等位基因频率与美国国立生物技术信息中心（NCBI）报道均有显著性差异。结论：sTnT基因SNP分布具有种族差异性。     

Invasion dynamics and attractor inheritance

 We study the dynamics of a population of residents that is being invaded by an initially rare mutant. We show that under relatively mild conditions the sum of the mutant and resident population sizes stays arbitrarily close to the initial attractor of the monomorphic resident population whenever the mutant has a strategy sufficiently similar to that of the resident. For stochastic systems we show that the probability density of the sum of the mutant and resident population sizes stays arbitrarily close to the stationary probability density of the monomorphic resident population. Attractor switching, evolutionary suicide as well as most cases of ``the resident strikes back' in systems with multiple attractors are possible only near a bifurcation point in the strategy space where the resident attractor undergoes a discontinuous change. Away from such points, when the mutant takes over the population from the resident and hence becomes the new resident itself, the population stays on the same attractor. In other words, the new resident ``inherits' the attractor from its predecessor, the former resident. Received: 10 December 2000 / Revised version: 14 September 2001 / Published online: 17 May 2002     

Genetic diversity of longtail macaques (Macaca fascicularis) on the island of Mauritius: an assessment of nuclear and mitochondrial DNA polymorphisms

BACKGROUND: Individuals from an introduced population of longtail macaques on Mauritius have been extensively used in recent research. This population has low MHC gene diversity, and is thus regarded as a valuable resource for research. METHODS: We investigated the genetic diversity of this population using multiple molecular markers located in mitochondrial DNA and microsatellite DNA loci on the autosomes and the Y chromosome. We tested samples from 82 individuals taken from seven study sites. RESULTS AND CONCLUSIONS: We found this population to be panmictic, with a low degree of genetic variability. On the basis of an mtDNA phylogeny, we inferred that these macaques' ancestors originated from Java in Asia. Weak gametic disequilibrium was observed, suggesting decay of non-random associations between genomic genes at the time of founding. The results suggest that macaques bred in Mauritius are valuable as model animals for biomedical research because of their genetic homogeneity.     

唐家河大熊猫种群生存力分析

唐家河大熊猫是一个包括3个亚种群的异质种群,借助于游涡模型（vortex 8.21),对唐家河大熊猫未来100a内的种群动态动物了模拟,并分析了不同因子对该种群命运的影响,结果表明,在不考虑近亲繁殖,灾害等因素的情况下,该种群100a内在总体上保持稳定,并略有增长,但种群基因杂合率下降,累积绝灭率增加,尤以薄衣沟亚种群为最,提高环境容纳量,补充外来个体等措施能在不同程度上有利于该种群的长期存活,而近亲繁殖,灾害等因素则大大加速了种群的灭绝步伐,另外,成功的迁移扩散有利于异质种群的稳定与发展,否则对数量稀少的大熊猫种群有害无益,最后提出了针对性的保护与管理建议。     

Estimates of African, European and Native American ancestry in Afro-Caribbean men on the island of Tobago

BACKGROUND/AIMS: The Tobago Afro-Caribbean population is a valuable resource for studying the genetics of diseases that show significant differences in prevalence between populations of African descent and populations of other ancestries. Empirical confirmation of low European and Native American admixture may help in clarifying the ethnic variation in risk for such diseases. We hypothesize that the degree of European and Native American admixture in the Tobago population is low. METHODS: Admixture was estimated in a random sample of 220 men, from a population-based prostate cancer screening survey of 3,082 Tobago males, aged 40 to 79 years. We used a set of six autosomal markers with large allele frequency differences between the major ethnic populations involved in the admixture process, Europeans, Native Americans and West Africans. RESULTS: The ancestral proportions of Tobago population are estimated as 94.0+/-1.2% African, 4.6+/-3.4% European and 1.4+/-3.6% Native American. CONCLUSIONS: We conclude that Tobago Afro-Caribbean men are predominantly of West African ancestry, with minimal European and Native American admixture. The Tobago population, thus, may carry a higher burden of high-risk alleles of African origin for certain diseases than the more admixed African-American population. Conversely, this population may benefit from a higher prevalence of protective alleles of African origin.     

Estimating the proportion of uncatchable animals in a population by double-sampling

Estimates of population size obtained by capture-recapture methods refer solely to the catchable portion of a population. Given a population containing marked animals, two closed-form maximum likelihood estimators of the proportion of uncatchable animals are presented. They are based on twice sampling the proportion of marked animals in the population: the first sample is drawn from catchable animals only, the second from mixed catchable and uncatchable animals. If the individuals in the first sample are not available to the second sample, both samples must be taken from a representative subpopulation of known size. The quantities required may be obtained during a standard capture-recapture session, provided the sampling methods meet the relevant assumptions; the ensuing estimate of population size can then be corrected for uncatchability. The technique is illustrated for eider ducks, using data from Coulson (1984, Ibis 126, 525-543).     

Isolation and characterization of microsatellite markers for Plathymenia reticulata (Fabaceae)

? Premise of the study: Microsatellite loci were isolated and characterized for use in population genetic studies of Plathymenia reticulata (Fabaceae), a tropical tree widespread in the Atlantic Forest and cerrado biomes of South America. ? Methods and Results: Nine microsatellite markers were developed using a simple sequence repeat-enriched library. Polymorphism was analyzed in 51 individuals from two populations. All loci were polymorphic, with the number of alleles per loci ranging from five to 15 (mean number of alleles: 10.22). Observed and expected heterozygosities per loci and population ranged from 0.313 to 1.000 and 0.280 to 0.869, respectively. ? Conclusions: These highly informative loci are potentially useful to estimate population genetic structure and to understand evolutionary processes and taxonomy of the species.     

白桦种群的稳定性与火干扰关系的研究

从种群生态学和干扰生态学的角度出发,在火史重建的基础上,采用种群世代划分的方法,研究了大兴安岭北部白桦群的稳定性与火干扰的关系,结果表明：白桦种群的耐火力与自我恢复力都较差,主要依靠很强的火后恢复力维持其稳定性,种群耐火力与长期火状况密切相关,表现为：低频类〈中频类〈高频类。高强类〈中强类〈低强类。火后恢复力与自我恢复力和最近一次火烧强度及距今时间密切相关,火后恢复力与自我恢复力都以低强类〉高强类