Redundancy and rewiring of genetic networks following genome-wide duplication events

Polyploidy or whole-genome duplication is a frequent phenomenon within the plant kingdom and has been associated with the occurrence of evolutionary novelty and increase in biological complexity. Because genome-wide duplication events duplicate whole molecular networks it is of interest to investigate how these networks evolve subsequent to such events. Although genome duplications are generally followed by massive gene loss, at least part of the network is usually retained in duplicate and can rewire to execute novel functions. Alternatively, the network can remain largely redundant and as such confer robustness against mutations. The increasing availability of high-throughput data makes it possible to study evolution following whole genome duplication events at the network level. Here we discuss how the use of 'omics' data in network analysis can provide novel insights on network redundancy and rewiring and conclude with some directions for future research.     

Quantifying the underestimation of relative risks from genome-wide association studies

Genome-wide association studies (GWAS) have identified hundreds of associated loci across many common diseases. Most risk variants identified by GWAS will merely be tags for as-yet-unknown causal variants. It is therefore possible that identification of the causal variant, by fine mapping, will identify alleles with larger effects on genetic risk than those currently estimated from GWAS replication studies. We show that under plausible assumptions, whilst the majority of the per-allele relative risks (RR) estimated from GWAS data will be close to the true risk at the causal variant, some could be considerable underestimates. For example, for an estimated RR in the range 1.2-1.3, there is approximately a 38% chance that it exceeds 1.4 and a 10% chance that it is over 2. We show how these probabilities can vary depending on the true effects associated with low-frequency variants and on the minor allele frequency (MAF) of the most associated SNP. We investigate the consequences of the underestimation of effect sizes for predictions of an individual's disease risk and interpret our results for the design of fine mapping experiments. Although these effects mean that the amount of heritability explained by known GWAS loci is expected to be larger than current projections, this increase is likely to explain a relatively small amount of the so-called "missing" heritability.     

Diversification of genes encoding granule-bound starch synthase in monocots and dicots is marked by multiple genome-wide duplication events

Starch is one of the major components of cereals, tubers, and fruits. Genes encoding granule-bound starch synthase (GBSS), which is responsible for amylose synthesis, have been extensively studied in cereals but little is known about them in fruits. Due to their low copy gene number, GBSS genes have been used to study plant phylogenetic and evolutionary relationships. In this study, GBSS genes have been isolated and characterized in three fruit trees, including apple, peach, and orange. Moreover, a comprehensive evolutionary study of GBSS genes has also been conducted between both monocots and eudicots. Results have revealed that genomic structures of GBSS genes in plants are conserved, suggesting they all have evolved from a common ancestor. In addition, the GBSS gene in an ancestral angiosperm must have undergone genome duplication ～251 million years ago (MYA) to generate two families, GBSSI and GBSSII. Both GBSSI and GBSSII are found in monocots; however, GBSSI is absent in eudicots. The ancestral GBSSII must have undergone further divergence when monocots and eudicots split ～165 MYA. This is consistent with expression profiles of GBSS genes, wherein these profiles are more similar to those of GBSSII in eudicots than to those of GBSSI genes in monocots. In dicots, GBSSII must have undergone further divergence when rosids and asterids split from each other ～126 MYA. Taken together, these findings suggest that it is GBSSII rather than GBSSI of monocots that have orthologous relationships with GBSS genes of eudicots. Moreover, diversification of GBSS genes is mainly associated with genome-wide duplication events throughout the evolutionary course of history of monocots and eudicots.     

The road to genome-wide association studies

The recent crop of results from genome-wide association studies might seem like a sudden development. However, this blooming follows a long germination period during which the necessary concepts, resources and techniques were developed and assembled. Here, I look back at how the necessary pieces fell into place, focusing on the less well-chronicled days before the launch of the HapMap project, and speculate about future developments.     

The temporal distribution of gene duplication events in a set of highly conserved human gene families

Using a data set of protein translations associated with map positions in the human genome, we identified 1520 mapped highly conserved gene families. By comparing sharing of families between genomic windows, we identified 92 potentially duplicated blocks in the human genome containing 422 duplicated members of these families. Using branching order in the phylogenetic trees, we timed gene duplication events in these families relative to the primate-rodent divergence, the amniote-amphibian divergence, and the deuterostome-protostome divergence. The results showed similar patterns of gene duplication times within duplicated blocks and outside duplicated blocks. Both within and outside duplicated blocks, numerous duplications were timed prior to the deuterostome-protostome divergence, whereas others occurred after the amniote-amphibian divergence. Thus, neither gene duplication in general nor duplication of genomic blocks could be attributed entirely to polyploidization early in vertebrate history. The strongest signal in the data was a tendency for intrachromosomal duplications to be more recent than interchromosomal duplications, consistent with a model whereby tandem duplication-whether of single genes or of genomic blocks-may be followed by eventual separation of duplicates due to chromosomal rearrangements. The rate of separation of tandemly duplicated gene pairs onto separated chromosomes in the human lineage was estimated at 1.7 x 10(-9) per gene-pair per year.     

A genome-wide RNAi screen to dissect centriole duplication and centrosome maturation in Drosophila

Centrosomes comprise a pair of centrioles surrounded by an amorphous pericentriolar material (PCM). Here, we have performed a microscopy-based genome-wide RNA interference (RNAi) screen in Drosophila cells to identify proteins required for centriole duplication and mitotic PCM recruitment. We analysed 92% of the Drosophila genome (13,059 genes) and identified 32 genes involved in centrosome function. An extensive series of secondary screens classified these genes into four categories: (1) nine are required for centriole duplication, (2) 11 are required for centrosome maturation, (3) nine are required for both functions, and (4) three genes regulate centrosome separation. These 32 hits include several new centrosomal components, some of which have human homologs. In addition, we find that the individual depletion of only two proteins, Polo and Centrosomin (Cnn) can completely block centrosome maturation. Cnn is phosphorylated during mitosis in a Polo-dependent manner, suggesting that the Polo-dependent phosphorylation of Cnn initiates centrosome maturation in flies.     

A gene-centric approach to genome-wide association studies

Genic variants are more likely to alter gene function and affect disease risk than those that occur outside genes. Variants in genes, however, might not be sufficiently covered by the existing approaches to genome-wide association studies. Our analysis of the HapMap ENCODE data indicates that this concern is valid, and that an alternative approach that focuses on genic variants provides a more complete coverage of functionally important regions and a greater genotyping efficiency. We therefore argue that resources should be developed to make gene-centric genome-wide association studies feasible.     

Investigating ancient duplication events in the Arabidopsis genome

The complete genomic analysis of Arabidopsis thaliana has shown that a major fraction of the genome consists of paralogous genes that probably originated through one or more ancient large-scale gene or genome duplication events. However, the number and timing of these duplications still remains unclear, and several different hypotheses have been put forward recently. Here, we reanalyzed duplicated blocks found in the Arabidopsis genome described previously and determined their date of divergence based on silent substitution estimations between the paralogous genes and, where possible, by phylogenetic reconstruction. We show that methods based on averaging protein distances of heterogeneous classes of duplicated genes lead to unreliable conclusions and that a large fraction of blocks duplicated much more recently than assumed previously. We found clear evidence for one large-scale gene or even complete genome duplication event somewhere between 70 to 90 million years ago. Traces pointing to a much older (probably more than 200 million years) large-scale gene duplication event could be detected. However, for now it is impossible to conclude whether these old duplicates are the result of one or more large-scale gene duplication events. abbreviations dA, fraction of amino acid substitutions; Kn, number of nonsynonymous substitutions per nonsynonymous site; Ks, number of synonymous substitutions per synonymous site; MYA, million years ago     

Diversification of non-TIR class NB-LRR genes in relation to whole-genome duplication events in Arabidopsis

Arabidopsis thaliana is believed to have experienced at least two and possibly three whole-genome duplication events in its evolutionary history. In order to investigate the evolutionary relationships between these duplication events and diversification of disease resistance (R) genes, segmental-duplication events containing R genes belonging to the nucleotide binding-leucine rich repeat (NB-LRR) class were identified. Of 153 segmental-duplication events containing NB-LRR genes, only 22 contained NB-LRR genes in both members of the duplication pair, indicating a high frequency of NB-LRR gene loss after whole-genome duplication. The relative age of the duplication events was estimated based on the average synonymous substitution rate of the duplicated gene pairs in the segments. These data were combined with phylogenetic analyses. NB-LRR genes present in segment pairs derived from the most recent whole-genome duplication event, estimated to have occurred only 20 to 40 million years ago, occupy very distant branches of the NB-LRR phylogenetic tree. These data suggest that when NB-LRR clusters are duplicated as part of a whole-genome duplication, homoeologous NB-LRR genes are preferentially lost, either by eliminating one copy of the cluster or by eliminating individual genes such that only paralogous NB-LRR genes are maintained.     

猪的全基因组水平SNP研究现状

SNP（single nucleotide polymorphism,单核苷酸多态）在猪基因组中的分布极其广泛,平均分布间隔为300～400 bp,相关数据库收录已达55万条。猪基因组测序已取得实质性进展,大规模搜索发现基因组及EST（expressed sequence tag）序列中的SNP已展开,应用于猪全基因组水平的SNP芯片已建立。在此基础上,基于猪SNP标记的遗传图谱绘制、QTL（quantitative trait loci）定位、遗传多样性检测及全基因组关联分析等也都相继出现。     

原发性高血压全基因组关联研究进展

原发性高血压是一种由遗传与环境因素共同导致的复杂疾病,具有高度的遗传异质性。自2007年首个高血压全基因组关联研究(Genome-wide association studies,GWAS)报道以来,许多GWAS相继开展。文章首先对2007年1月至2011年9月期间报道的24篇血压/高血压易感基因的GWAS按人种与染色体位置对其结果进行汇总,经统计位点rs17249754、rs1378942和rs11191548报道频数最多。其次介绍了GWAS方法学的研究进展,包括选择高质量的数量表型和选择多阶段研究设计来增加研究发现阳性关联的机会。统计分析方面,除强调了已经报道过的多重比较和重复(验证)研究等问题外,文章还介绍了通过Meta分析对GWAS数据进行深度发掘,并应用基因型填补法对缺失数据进行填补可以提高全基因组遗传标记的覆盖率的方法。尽管GWAS发现了许多我们未知的基因与疾病表型的关联,为了解高血压的发病机制提供了更多线索,但是目前GWAS发现的血压/高血压相关变异多为对人群血压的影响极其微弱的常见变异。因此今后的研究中可加强深度功能学研究对易感基因精细定位和外显子组测序技术的应用,结合GWAS的成果进行生物信息学通路分析和表观遗传学机制研究等,逐步揭示高血压的遗传机制。     

Current status of genome-wide association studies in cancer

Genome-wide association studies in cancer have already identified over 150 regions associated with two dozen specific cancers. Already, a handful of multi-cancer susceptibility regions have been uncovered, providing new insights into perhaps common mechanisms of carcinogenesis. For each new susceptibility allele, investigators now face the arduous task of interrogating each region beginning with fine mapping prior to pursuing the biological basis for the direct association of one or more variants. It appears that there may be a significant number of common alleles that contribute to the heritability of a specific cancer. Since each region confers a small contribution to the risk for cancer, it is daunting to consider any single nucleotide polymorphism (SNP) as a clinical test. Since the complex genomic architecture of each cancer differs, additional genotyping and sequence analysis will be required to comprehensively catalog susceptibility alleles followed by the formidable task of understanding the interactions between genetic regions as well as the environment. It will be critical to assess the applicability of genetic tests in specific clinical settings, such as when to perform screening tests with calculable risks (e.g., biopsies or chemoprevention), before incorporating SNPs into clinical practice. To advance the current genomic observations to the clinical venue, new studies will need to be designed to validate the utility of known genetic variants in assessing risk for cancer as well as its outcomes.     

A genome-wide survey of alternative translational initiation events in Homo sapiens

Alternative translational initiation is an important mechanism to increase the diversity of gene products. Although some of alternative translational initiation events have been reported, such information remains anecdotal and does not allow for any generalizations. The number of the known alternative translational initiation genes is so few that we know little about its mechanism. There is a great demand to discover more alternative translational initiation genes. However, it is arduously time-consuming to discover novel alternative translational initiation genes by the experimental method. Therefore we systematically analyzed protein sequences available in public database and predicted 1237 protein clusters as potential alternative translational initiation events. We concluded that about 8%—10% of human genes have alternative translational initiation sites. The results significantly increased the number of alternative translation initiation events and indicated that alternative translation initiation is an important and general regulation mechanism in the cellular process.     

Controlling for conservation in genome-wide DNA methylation studies

Background

A commonplace analysis in high-throughput DNA methylation studies is the comparison of methylation extent between different functional regions, computed by averaging methylation states within region types and then comparing averages between regions. For example, it has been reported that methylation is more prevalent in coding regions as compared to their neighboring introns or UTRs, leading to hypotheses about novel forms of epigenetic regulation.

Results

We have identified and characterized a bias present in these seemingly straightforward comparisons that results in the false detection of differences in methylation intensities across region types. This bias arises due to differences in conservation rates, rather than methylation rates, and is broadly present in the published literature. When controlling for conservation at coding start sites the differences in DNA methylation rates disappear. Moreover, a re-evaluation of methylation rates at intronexon junctions reveals that the magnitude of previously reported differences is greatly exaggerated. We introduce two correction methods to address this bias, an inferencebased matrix completion algorithm and an averaging approach, tailored to address different underlying biological questions. We evaluate how analysis using these corrections affects the detection of differences in DNA methylation across functional boundaries.

Conclusions

We report here on a bias in DNA methylation comparative studies that originates in conservation rate differences and manifests itself in the false discovery of differences in DNA methylation intensities and their extents. We have characterized this bias and its broad implications, and show how to control for it so as to enable the study of a variety of biological questions.

Electronic supplementary material

The online version of this article (doi:10.1186/s12864-015-1604-3) contains supplementary material, which is available to authorized users.     

Characterizing tumor response to chemotherapy at various length scales using temporal diffusion spectroscopy

Measurements of apparent diffusion coefficient (ADC) using magnetic resonance imaging (MRI) have been suggested as potential imaging biomarkers for monitoring tumor response to treatment. However, conventional pulsed-gradient spin echo (PGSE) methods incorporate relatively long diffusion times, and are usually sensitive to changes in cell density and necrosis. Diffusion temporal spectroscopy using the oscillating gradient spin echo (OGSE) sequence is capable of probing short length scales, and may detect significant intracellular microstructural changes independent of gross cell density changes following anti-cancer treatment. To test this hypothesis, SW620 xenografts were treated by barasertib (AZD1152), a selective inhibitor of Aurora B kinase which causes SW620 cancer cells to develop polyploidy and increase in size following treatment, ultimately leading to cell death through apoptosis. Following treatment, the ADC values obtained by both the PGSE and low frequency OGSE methods increased. However, the ADC values at high gradient frequency (i.e. short diffusion times) were significantly lower in treated tumors, consistent with increased intracellular restrictions/hindrances. This suggests that ADC values at long diffusion times are dominated by tumor microstructure at long length scales, and may not convey unambiguous information of subcellular space. While the diffusion temporal spectroscopy provides more comprehensive means to probe tumor microstructure at various length scales. This work is the first study to probe intracellular microstructural variations due to polyploidy following treatment using diffusion MRI in vivo. It is also the first observation of post-treatment ADC changes occurring in opposite directions at short and long diffusion times. The current study suggests that temporal diffusion spectroscopy potentially provides pharmacodynamic biomarkers of tumor early response which distinguish microstructural variations following treatment at both the subcellular and supracellular length scales.     

Plant traits respond to the competitive neighbourhood at different spatial and temporal scales

Background and Aims Clonal plants can plastically modify their traits in response to competition, but little is known regarding the spatio-temporal scale at which a competitive neighbourhood determines the variability in species traits. This study tests the hypothesis that the local neighbourhood can be expected to influence the processes that are involved in competition tolerance and avoidance, and that this effect depends on organ lifespan.Methods Fragments of the rhizomatous Elytrigia repens (Poaceae) were sampled in 2012 in experimental plant communities that varied in species identity and abundance. These communities had been cultivated since 2009 in mesocosms in a common garden. Fragment performance, shoot and clonal traits were measured, and the effects of past and present local neighbourhoods of five different radius sizes (5–25 cm) were examined. Past and present local neighbourhood compositions were assessed in 2011 and 2012, respectively.Key Results Most of the measured traits of E. repens responded to the local neighbourhood (5–10 cm radius), with an additional effect of the larger neighbourhood (20–25 cm radius) on ramet height, leaf dry matter content, maximal internode length and specific rhizome mass. Contrary to the expectation of the hypothesis, the temporal influence was not due to the organ lifespan. Indeed, five of the eight traits studied responded to both the past and present neighbourhoods. With the exception of specific rhizome mass, all trait responses were explained by the abundance of specific species.Conclusions This study demonstrates that the traits of a single clonal individual can respond to different competitive environments in space and time. The results thus contribute to the understanding of competition mechanisms.