Genome-wide association analysis reveals regulation of at-risk loci by DNA methylation in prostate cancer / 亚洲男科学杂志(英文版)

Epigenetic changes are potentially important for the ontogeny and progression of tumors but are not usually studied because of the complexity of analyzing transcript regulation resulting from epigenetic alterations. Prostate cancer (PCa) is characterized by variable clinical manifestations and frequently unpredictable outcomes. We performed an expression quantitative trait loci (eQTL) analysis to identify the genomic regions that regulate gene expression in PCa and identified a relationship between DNA methylation and clinical information. Using multi-level information published in The Cancer Genome Atlas, we performed eQTL-based analyses on DNA methylation and gene expression. To better interpret these data, we correlated loci and clinical indexes to identify the important loci for both PCa development and progression. Our data demonstrated that although only a small proportion of genes are regulated via DNA methylation in PCa, these genes are enriched in important cancer-related groups. In addition, single nucleotide polymorphism analysis identified the locations of CpG sites and genes within at-risk loci, including the 19q13.2-q13.43 and 16q22.2-q23.1 loci. Further, an epigenetic association study of clinical indexes detected risk loci and pyrosequencing for site validation. Although DNA methylation-regulated genes across PCa samples are a small proportion, the associated genes play important roles in PCa carcinogenesis.

QTL identification for downy mildew resistance in cucumber using genetic linkage map based on SSR markers

Fourteen cucumber lines were tested for genetic homozygosity and performed pairwise comparison to identify a pair with the highest DNA polymorphic level. Cucumber accessions CSL0067 and CSL0139 were selected to generate 315 F2 populations. The genetic linkage map based on 66 polymorphic SSR markers was constructed. It composed of eight linkage groups (LGs) spanning 474.4 cM. Downy mildew disease reaction was evaluated in cotyledons, first and second true leaf on 7, 10, and 14 day after inoculation. The results showed that downy mildew resistance was controlled by multiple recessive genes. The susceptible to resistant ratio of F2 progenies fit 9:7 susceptible/resistant segregation types corresponding to duplicate recessive epistasis. Fourteen QTLs were detected. The phenotypic variance ranged from 5.0 to 12.5%, while LOD values ranged from 3.538 to 9.165. Two major QTLs and two QTL hotspots were identified. Moreover, the additive effects data explained that these QTL reduced downy mildew susceptibility

Genetic dissection of yield associated traits in a cross between cowpea and yard-long bean (Vigna unguiculata (L.) Walp.) based on DArT markers

Both cowpea and yard-long bean belong to Vigna unguiculata ssp. unguiculata but have diverged through human induced evolution in sub-Saharan Africa and Asia, respectively. To map the quantitative trait loci (QTLs) for yield associated traits and derive new lines that may combine the attributes of both types, we developed a F2:3 mapping population derived from a cross between cowpea line TVu2185 and yard-long bean line TVu6642. Using DArT markers, a total of 30 QTLs accounting for 1.8–13.0% phenotypic variation was detected for pod and seed traits. Some novel major QTLs for peduncle number per plant (qPeN2.2), pod length (qPoL3), seed breadth (qSB4), length (qSL7.2) and thickness (qST9) identified on chromosomes 2, 3, 4, 7 and 9, respectively, are particularly interesting and need to be validated. Moreover, we confirmed previously reported QTLs for pod length (qPoL8) and 100-seed weight (qSW8) on chromosome 8 and for seed number per pod (qSN9.2) on chromosome 9 suggesting usefulness for marker-assisted-selection purpose. Notably, some QTLs for these traits were clustered especially on chromosomes 5, 7, 8, 9 and 10 indicating the presence of the same QTL or linked loci in these regions. Moreover, the involvement of epistasis was observed for trait expressions, but compared with the main effect QTLs, the phenotypic effects of epistatic-QTLs detected were much less. The present QTL analysis may provide a useful tool for breeders to formulate efficient breeding strategy for introgression of the desirable alleles for yield related traits in cowpea using molecular markers.

Identification of genomic regions associated with early plant vigour in lentil (Lens culinaris)

Lentil is one of the most important food legume species, however its genetic and genomic resources remained largely uncharacterized and unexploited. In the past few years, a number of genetic maps have been constructed and marker resources have been developed in lentil. These resources could be exploited for understanding the extent and distribution of genetic variation in genus Lens and also for developing saturated and consensus genetic maps suitable for quantitative trait loci (QTL) mapping and marker-assisted selection. The present study aims to enrich polymerase chain reaction-based linkage map of F10 recombinant inbred lines (RILs) population of 94 individuals derived from cross WA8649090 9 Precoz and identification of QTLs linked to early plant vigour traits. Of the 268 polymorphic markers (93 simple sequence repeats (SSR), three inter-simple sequence repeats (ISSRs) and 172 random amplified polymorphic DNA (RAPDs)), 265 (90 SSRs, three ISSRs and 172 RAPDs) were mapped on seven linkage groups, varying in length between 25.6 and 210.3 cM, coverage of 809.4 cM with an average marker spacing of 3.05 cM. The study also reported assigning of 24 new cross-genera SSRs of Trifolium pratense on the present linkage map. The RILs along with the parents were screened for shoot length, root length, seedling length, dry weight, number of leaves and number of branches based on two replications under polyhouse conditions. A QTLhotspot consisting of six QTLs for shoot length (cm), root length (cm) and seedling length (cm) was observed between a map distances of 56.61 and 86.81 cM on LG1.

The utility of NBS-profiling for characterization of yellow rust resistance in an F6 durum wheat population

Seedling and adult plant (field) resistance to yellow rust in the durum wheat (Triticum turgidum ssp. durum) cross Kunduru-1149 x Cham-1 was characterized using a functionally-targeted DNA marker system, NBS-profiling. Chi-squared analysis indicated a four gene model conferring seedling yellow rust resistance against Puccinia striiformis f. sp. tritici isolate WYR85/22 (virulent on Yr2, Yr6, Yr7 and Yr9). Interval mapping located two QTL for yellow rust resistance on the long arm of chromosome 1B, while Kruskal–Wallis single marker regression identified a number of additional marker loci associated with seedling and/or adult plant, field resistance to yellow rust. These results suggested that much of the yellow rust resistance seen in the field may be due to seedling expressed resistance (R) genes. Characterization of the DNA sequence of three NBS marker loci indicated that all showed significant homology to functionally-characterized R-genes and resistance gene analogues (RGAs), with the greatest homology being NBS-LRR-type R-genes and RGAs from cereal species.

Association analysis of EGR1 gene and Alzheimer's disease in Han Chinese people / 上海交通大学学报（医学版）

Objective: To investigate the association between early growth response gene 1 (EGR1) and Alzheimer's disease (AD) in Han Chinese people. Methods: A total of 715 AD patients and 760 health controls were recruited in two independent samples from Eastern China (382 AD patients and 426 normal individuals) and Southwest China (333 AD patients and 334 normal individuals). SNaPshot technique was utilized to analyse the single nucleotide polymorphism (SNP) of rs11743810. A public database was used to explore whether EGR1 gene was differentially expressed in the brain of AD patients and health controls. Then the protein-protein interaction (PPI) assessment was conducted using the STRING database, and the brain eQTL (expression quantitative trait loci) analysis was used to explore the difference in rs11743810 expression between different genotypes in different brain regions. Results: Cross-platform normalized data showed that there was significant difference of EGR1 expression in temporal cortex between AD patients and control subjects (|log2FC|=0.780, P=0.000 before FDR corrected; P=0.001 after FDR corrected). PPI analysis revealed that EGR1 was physically connected with amyloid precursor protein (APP) and clusterin (CLU) protein in the network. However, different genotypes of rs11743810 showed no significant difference in expression in 10 brain regions, and no significant difference in the genotype and allele frequency of rs11743810 between AD patients and controls were found in our two independent samples. Conclusion: The rs11743810 in EGR1 may not be major susceptibility gene site for AD in Han Chinese people.

Descifrando las moléculas ocultas en las sombras grises de la resistencia cuantitativa a patógenos / Unraveling the molecules hidden in the gray shadows of quantitative disease resistance to pathogens

ABSTRACT One of the most challenging questions in plant breeding and molecular plant pathology research is what are the genetic and molecular bases of quantitative disease resistance (QDR)?. The scarce knowledge of how this type of resistance works has hindered plant breeders to fully take advantage of it. To overcome these obstacles new methodologies for the study of quantitative traits have been developed. Approaches such as genetic mapping, identification of quantitative trait loci (QTL) and association mapping, including candidate gene approach and genome wide association studies, have been historically undertaken to dissect quantitative traits and therefore to study QDR. Additionally, great advances in quantitative phenotypic data collection have been provided to improve these analyses. Recently, genes associated to QDR have been cloned, leading to new hypothesis concerning the molecular bases of this type of resistance. In this review we present the more recent advances about QDR and corresponding application, which have allowed postulating new ideas that can help to construct new QDR models. Some of the hypotheses presented here as possible explanations for QDR are related to the expression level and alternative splicing of some defense-related genes expression, the action of "weak alleles" of R genes, the presence of allelic variants in genes involved in the defense response and a central role of kinases or pseudokinases. With the information recapitulated in this review it is possible to conclude that the conceptual distinction between qualitative and quantitative resistance may be questioned since both share important components.

RESUMEN Una de las preguntas más desafiantes del fitomejoramiento y de la fitopatología molecular es ¿cuáles son las bases genéticas y moleculares de la resistencia cuantitativa a enfermedades?. El escaso conocimiento de cómo este tipo de resistencia funciona ha obstaculizado que los fitomejoradores la aprovecharlo plenamente. Para superar estos obstáculos se han desarrollado nuevas metodologías para el estudio de rasgos cuantitativos. Los enfoques como el mapeo genético, la identificación de loci de rasgos cuantitativos (QTL) y el mapeo por asociaciones, incluyendo el enfoque de genes candidatos y los estudios de asociación amplia del genoma, se han llevado a cabo históricamente para describir rasgos cuantitativos y por lo tanto para estudiar QDR. Además, se han proporcionado grandes avances en la obtención de datos fenotípicos cuantitativos para mejorar estos análisis. Recientemente, algunos genes asociados a QDR han sido clonados, lo que conduce a nuevas hipótesis sobre las bases moleculares de este tipo de resistencia. En esta revisión presentamos los avances más recientes sobre QDR y la correspondiente aplicación, que han permitido postular nuevas ideas que pueden ayudar a construir nuevos modelos. Algunas de las hipótesis presentadas aquí como posibles explicaciones para QDR están relacionadas con el nivel de expresión y el splicing alternativo de algunos genes relacionados con la defensa, la acción de "alelos débiles" de genes R, la presencia de variantes alélicas en los genes implicados en la respuesta de defensa y un papel central de quinasas o pseudoqinasas. Con la información recapitulada en esta revisión es posible concluir que la distinción conceptual entre resistencia cualitativa y cuantitativa puede ser cuestionada ya que ambos comparten importantes componentes.

In silico analysis of disease resistance and defence-related genes for a major sheath blight qShb 9-2 QTL in rice

Aims@#Sheath blight disease (Rhizoctonia solani) is an important rice disease that causes heavy yield losses in rice annually. To date, no rice variety has been found to be completely resistant to this disease. The most desirable approach for the management of sheath blight disease is to introgress genes with major and durable resistance into the rice genome. Therefore, this study aims to identify disease resistance and defence genes within qShb 9-2, a major QTL found within moderately resistant rice population via in silico analysis. @*Methodology and results@#The sequences of tightly linked markers of qShb 9-2 from GRAMENE database was used to derive the 10.24 Mbp QTL region that contains 1581 genes according to MSU Rice Genome Annotation Project database. BLAST results showed that 11.4% of these genes were transposable elements which may be involved in gene duplication. Through Blast2GO, fifty-four (2.9%) defence-related genes were annotated within this QTL and can be classified into 5 major defence mechanisms. Further, fifty (2.7%) disease resistance genes were identified in qShb 9-2 based on the presence of NB-ARC, LRR-receptor kinase, Ser/Thr protein kinase and protein kinase domains. Lastly, directed acyclic graphs showing the interaction between all the disease resistance and defence-related genes were generated. @*Conclusion, significance and impact of study@#The presence of these genes indicates that qShb 9-2 region may contribute towards the defence against sheath blight disease. By deciphering the gene landscape within the QTL, it may be possible to further fine map the QTL into a smaller region for QTL pyramiding in breeding programmes. The resistance and defence genes are also a source for genetic engineering studies and a good source for marker development.

Dealing with iron metabolism in rice: from breeding for stress tolerance to biofortification

Abstract Iron is a well-known metal. Used by humankind since ancient times in many different ways, this element is present in all living organisms, where, unfortunately, it represents a two-way problem. Being an essential block in the composition of different proteins and metabolic pathways, iron is a vital component for animals and plants. That is why iron deficiency has a severe impact on the lives of different organisms, including humans, becoming a major concern, especially in developing countries where access to adequate nutrition is still difficult. On the other hand, this metal is also capable of causing damage when present in excess, becoming toxic to cells and affecting the whole organism. Because of its importance, iron absorption, transport and storage mechanisms have been extensively investigated in order to design alternatives that may solve this problem. As the understanding of the strategies that plants use to control iron homeostasis is an important step in the generation of improved plants that meet both human agricultural and nutritional needs, here we discuss some of the most important points about this topic.

Application of expression quantitative trait loci analysis in pharmacogenomics / 药学学报

In the era of genome-wide association study (GWAS), a large number of drug response-related loci have been identified in the non-coding sequences. The interpretation of these loci in mechanism is concerned with the effects on the mRNA expression level of these genes. Expression quantitative trait loci (eQTL) studies indicate the relationship of genome variants and the level of mRNA. Its elucidation of the relationship between genetic variation and gene expression, gene interaction and gene regulatory network provides an efficacious mean for pharmacogenomics. The effects of gene polymorphism on drug responses have been unraveled thoroughly in studies which combined pharmacogenomics with eQTL and GWAS.

Genetic Architecture of Transcription and Chromatin Regulation

DNA microarray and next-generation sequencing provide data that can be used for the genetic analysis of multiple quantitative traits such as gene expression levels, transcription factor binding profiles, and epigenetic signatures. In particular, chromatin opening is tightly coupled with gene transcription. To understand how these two processes are genetically regulated and associated with each other, we examined the changes of chromatin accessibility and gene expression in response to genetic variation by means of quantitative trait loci mapping. Regulatory patterns commonly observed in yeast and human across different technical platforms and experimental designs suggest a higher genetic complexity of transcription regulation in contrast to a more robust genetic architecture of chromatin regulation.

Genome-Wide Association Study of Metabolic Syndrome in Koreans

Metabolic syndrome (METS) is a disorder of energy utilization and storage and increases the risk of developing cardiovascular disease and diabetes. To identify the genetic risk factors of METS, we carried out a genome-wide association study (GWAS) for 2,657 cases and 5,917 controls in Korean populations. As a result, we could identify 2 single nucleotide polymorphisms (SNPs) with genome-wide significance level p-values (<5 x 10(-8)), 8 SNPs with genome-wide suggestive p-values (5 x 10(-8) < or = p < 1 x 10(-5)), and 2 SNPs of more functional variants with borderline p-values (5 x 10(-5) < or = p < 1 x 10(-4)). On the other hand, the multiple correction criteria of conventional GWASs exclude false-positive loci, but simultaneously, they discard many true-positive loci. To reconsider the discarded true-positive loci, we attempted to include the functional variants (nonsynonymous SNPs [nsSNPs] and expression quantitative trait loci [eQTL]) among the top 5,000 SNPs based on the proportion of phenotypic variance explained by genotypic variance. In total, 159 eQTLs and 18 nsSNPs were presented in the top 5,000 SNPs. Although they should be replicated in other independent populations, 6 eQTLs and 2 nsSNP loci were located in the molecular pathways of LPL, APOA5, and CHRM2, which were the significant or suggestive loci in the METS GWAS. Conclusively, our approach using the conventional GWAS, reconsidering functional variants and pathway-based interpretation, suggests a useful method to understand the GWAS results of complex traits and can be expanded in other genomewide association studies.

Genetics of obesity: an overview of current approaches and advancement.

Elucidation of obesity susceptibility genes through genome wide approaches as well as candidate gene approaches provides great promise in ultimately determining the genetic underpinnings of obesity. The complex nature of human obesity stems from the multiple interaction of several genes that control the physiology of food intake, energy expenditure, development of the body, and behavioural patterns towards food intake, and the environment. According to twin, adoptees and family studies, genetic factors account for 40-70% of the variability observed in human adiposity. Twin studies supported that the heritability of adiposity is higher than other quantitative traits. The heritability of obesity traits has been further evidenced by identification of quantitative trait loci (QTL) and genes through methods such as genome-wide scans (studies conducted on unrelated obese individuals), linkage analyses (conducted in families), and association studies (investigating the correlation between obesity and polymorphisms). The number of contributing genes, however, is still unknown. Although research on the genetic basis of obesity has advanced, the mechanisms underlying the condition are still complex due to its heterogeneity even within families.

Understanding Disease Susceptibility through Population Genomics

Genetic epidemiology studies have established that the natural variation of gene expression profiles is heritable and has genetic bases. A number of proximal and remote DNA variations, known as expression quantitative trait loci (eQTLs), that are associated with the expression phenotypes have been identified, first in Epstein-Barr virus-transformed lymphoblastoid cell lines and later expanded to other cell and tissue types. Integration of the eQTL information and the network analysis of transcription modules may lead to a better understanding of gene expression regulation. As these network modules have relevance to biological or disease pathways, these findings may be useful in predicting disease susceptibility.

Caracterização fenotípica e genotípica de caracteres agronômicos em uma população de linhagens recombinantes de aveia (Avena sativa L.) / Phenotypic and genotypic characterization agronomic traits in a population of recombinant inbred lines of oats (Avena sativa L.)

O melhoramento genético de aveia envolve a seleção de múltiplos caracteres quantitativos e qualitativos. O conhecimento das regiões genômicas que afetam essas características possibilita a seleção assistida por marcadores moleculares. Nesse sentido, o objetivo deste trabalho foi identificar regiões genômicas responsáveis por caracteres quantitativos (QTLs), associadas a marcadores moleculares previamente identificados. O experimento foi conduzido no ano de 2009, sendo empregadas 150 linhagens recombinantes de aveia, oriundas do cruzamento entre os genótipos UFRGS 8 e UFRGS 930605. O mapeamento de QTLs foi realizado através do método por intervalo composto. Foram detectados 16 QTLs para oito dos 9 caracteres avaliados, sendo estes distribuídos em sete grupos de ligação. A porção da variação fenotípica explicada pelos QTLs variou de 7,31 por cento a 16,06 por cento. Importantes QTLs foram identificados para caracteres de interesse aos programas de melhoramento de aveia, como a estatura de planta, o número de dias ao florescimento, o rendimento de grãos, o peso de panícula e o número de grãos por panícula. Os resultados gerados neste trabalho fornecem subsídios aos programas de melhoramento genético de aveia, proporcionando um maior entendimento dos mecanismos genéticos envolvidos com os caracteres de interesse. No entanto, estes resultados devem ser validados em outras populações para que a seleção assistida por marcadores moleculares possa ser realizada com sucesso.

The genetic improvement of oats requires selection of multiple quantitative and qualitative traits. Knowledge of the genomic regions controlling them makes possible the adoption of marker-assisted selection. Therefore, the objective of this study was to identify genomic regions responsible for quantitative traits loci (QTLs) associated with molecular maker previously identified. The experiment was conducted in 2009 and employed a population of 150 recombinant inbred lines of oats from the cross between the oat genotypes UFRGS 8 and UFRGS 930605. QTL mapping was carried out by composite interval analysis. In all, 16 QTLs were detected for 8 of 9 traits analyzed, which were also distributed in seven linkage groups. Phenotypic variation explained by the QTLs ranged from 7.31 percent to 16.06 percent. QTLs with important effect on the phenotypic variance were identified for traits of interest in oat breeding programs, such as plant height, number of days to flowering, grain yield, panicle weight and number of grains per panicle. The results generated in this work provide a better understanding of the genetic basis controlling traits of interest, which can be useful for oat breeding programs. However, these results should be validated in other populations in order to allow the marker-assisted selection to be successful.

Genome-wide linkage analysis for ocular and nasal anthropometric traits in a Mongolian population

Anthropometric traits for eyes and nose are complex quantitative traits influenced by genetic and environmental factors. To date, there have been few reports on the contribution of genetic influence to these traits in Asian populations. The aim of this study was to determine the genetic effect and quantitative trait locus (QTL) of seven traits eyes- and nose-related anthropometric measurements in an isolated Mongolian population. Frontal and lateral photographs were obtained from 1,014 individuals (434 males and 580 females) of Mongolian origin. A total of 349 short tandem repeat markers on 22 autosomes were genotyped for each individual. Heritability estimates of the seven ocular and nasal traits, adjusted for significant covariates, ranged from 0.48 to 0.90, providing evidence for a genetic influence. Variance-component linkage analyses revealed 10 suggestive linkage signals on 5q34 (LOD = 3.2), 18q12.2 (LOD = 2.7), 5q15 (LOD = 2.0), 9q34.2 (LOD = 1.9), 5q34 (LOD = 1.9), 17q22 (LOD = 1.9), 13q33.3 (LOD = 2.7), 1q36.22 (LOD = 1.9), 4q32.1 (LOD = 2.1) and 15q22.31 (LOD = 2.9). Our study provides the first evidence that genetics influences nasal and ocular traits in a Mongolian population. Additional collaborative efforts will further extend our understanding of the link between genetic factors and human anthropometric traits.

Analysis of genetic and non-genetic factors that affect the QTc interval in a Mongolian population: the GENDISCAN study

The QTc interval is a complex quantitative trait and a strong prognostic indicator of cardiovascular mortality in general, healthy people. The aim of this study was to identify non-genetic factors and quantitative trait loci that govern the QTc interval in an isolated Mongolian population. We used multiple regression analysis to determine the relationship between the QTc interval and non-genetic factors including height, blood pressure, and the plasma lipid level. Whole genome linkage analyses were performed to reveal quantitative trait loci for the QTc interval with 349 microsatellite markers from 1,080 Mongolian subjects. Among many factors previously known for association with the QTc interval, age, sex, heart rate, QRS duration of electrocardiogram and systolic blood pressure were also found to have influence on the QTc interval. A genetic effect for the QTc interval was identified based on familial correlation with a heritability value of 0.31. In a whole genome linkage analysis, we identified the four potential linkage regions 7q31-34, 5q21, 4q28, and 2q36.

A deterministic simulation study of embryo marker-assisted selection for age at first calving in Nellore (Bos indicus) beef cattle

We used deterministic simulation of four alternative multiple ovulation and embryo manipulation (MOET) closed nucleus schemes to investigate the benefits of using marker-assisted selection (MAS) of Nellore (Bos indicus) beef cattle embryos prior to transplantation to reduce the age at first calving (AFC). We found that MAS resulted in increased genetic gain as compared to selection without AFC quantitative trait loci (AFC-QTL) information. With single-stage selection the genetic response (GR) increased as follows: GR = 0.68 percent when the AFC-QTL explained 0.02 of the AFC additive genetic variance (sigma2A); GR = 1.76 percent for AFC-QTL explaining 0.05 sigma2A; GR = 3.7 percent for AFC-QTL explaining 0.1 sigma2A; and GR = 55.76 percent for AFC-QTL explaining 0.95 sigma2A. At the same total selected proportion, two-stage selection resulted in less genetic gain than single stage MAS at two-years of age. A single stage selection responses of > 95 percent occurred with pre-selected proportions of 0.4 (0.1 sigma2A explained by AFC-QTL), 0.2 (0.3 sigma2A explained by AFC-QTL) and 0.1 (0.5 sigma2A explained by AFC-QTL), indicating that the combined use of MAS and pre-selection can substantially reduce the cost of keeping recipient heifers in MOET breeding schemes. When the number of recipients was kept constant, the benefit of increasing embryo production was greater for the QTL explaining a higher proportion of the additive genetic variance. However this advantage had a diminishing return especially for QTL explaining a small proportion of the additive genetic variance. Thus, marker assisted selection of embryos can be used to achieve increased genetic gain or a similar genetic response at reduced expense by decreasing the number of recipient cows and number of offspring raised to two-years of age.