Frequent ploidy changes in Salicaceae indicates widespread sharing of the salicoid whole genome duplication by the relatives of Populus L. and Salix L.

BACKGROUNDS: Populus and Salix belong to Salicaceae and are used as models to investigate woody plant physiology. The variation of karyotype and nuclear DNA content can partly reflect the evolutionary history of the whole genome, and can provide critical information for understanding, predicting, and potentially ameliorating the woody plant traits. Therefore, it is essential to study the chromosome number (CN) and genome size in detail to provide information for revealing the evolutionary process of Salicaceae. RESULTS: In this study, we report the somatic CNs of seventeen species from eight genera in Salicaceae. Of these, CNs for twelve species and for five genera are reported for the first time. Among the three subfamilies of Salicaceae, the available data indicate CN in Samydoideae is n = 21, 22, 42. The only two genera, Dianyuea and Scyphostegia, in Scyphostegioideae respectively have n = 9 and 18. In Salicoideae, Populus, Salix and five genera closely related to them (Bennettiodendron, Idesia, Carrierea, Poliothyrsis, Itoa) are based on relatively high CNs from n = 19, 20, 21, 22 to n = 95 in Salix. However, the other genera of Salicoideae are mainly based on relatively low CNs of n = 9, 10, 11. The genome sizes of 35 taxa belonging to 14 genera of Salicaceae were estimated. Of these, the genome sizes of 12 genera and all taxa except Populus euphratica are first reported. Except for Dianyuea, Idesia and Bennettiodendron, all examined species have relatively small genome sizes of less than 1 pg, although polyploidization exists. CONCLUSIONS: The variation of CN and genome size across Salicaceae indicates frequent ploidy changes and a widespread sharing of the salicoid whole genome duplication (WGD) by the relatives of Populus and Salix. The shrinkage of genome size after WGD indicates massive loss of genomic components. The phylogenetic asymmetry in clade of Populus, Salix, and their close relatives suggests that there is a lag-time for the subsequent radiations after the salicoid WGD event. Our results provide useful data for studying the evolutionary events of Salicaceae.

Congenital hypopituitarism in two brothers with a duplication of the 'acrogigantism gene' GPR101: clinical findings and review of the literature.

PURPOSE: Congenital hypopituitarism (CH) can cause significant morbidity or even mortality. In the majority of patients, the etiology of CH is unknown. Understanding the etiology of CH is important for anticipation of clinical problems and for genetic counselling. Our previous studies showed that only a small proportion of cases have mutations in the known 'CH genes'. In the current project, we present the results of SNP array based copy number variant analysis in a family with unexplained congenital hypopituitarism. METHODS: DNA samples of two affected brothers with idiopathic CH and their mother were simultaneously analyzed by SNP arrays for copy number variant analysis and Whole Exome Sequencing (WES) for mutation screening. DNA of the father was not available. RESULTS: We found a 6 Mb duplication including GPR101 and SOX3 on the X-chromosome (Xq26.2-q27.1) in the two siblings and their mother, leading to 2 copies of this region in the affected boys and 3 copies in the mother. Duplications of GPR101 are associated with X-linked acrogigantism (the phenotypic 'opposite' of the affected brothers), whereas alterations in SOX3 are associated with X-linked hypopituitarism. CONCLUSION: In our patients with hypopituitarism we found a 6 Mb duplication which includes GPR101, a gene associated with X- linked gigantism, and SOX3, a gene involved in early pituitary organogenesis that is associated with variable degrees of hypopituitarism. Our findings show that in duplications containing both GPR101 and SOX3, the growth hormone deficiency phenotype is dominant. This suggests that, if GPR101 is duplicated, it might not be expressed phenotypically when early patterning of the embryonic pituitary is affected due to SOX3 duplication. These results, together with the review of the literature, shed a new light on the role of GPR101 and SOX3 in pituitary function.

Identification, evolution and expression analyses of whole genome-wide TLP gene family in Brassica napus.

BACKGROUND: Brassica is a very important genus of Brassicaceae, including many important oils, vegetables, forage crops, and ornamental horticultural plants. TLP family genes play important regulatory roles in the growth and development of plants. Therefore, this study used a bioinformatics approach to conduct the systematic comparative genomics analysis of TLP gene family in B. napus and other three important Brassicaceae crops. RESULTS: Here, we identified a total of 29 TLP genes from B. napus genome, and they distributed on 16 chromosomes of B. napus. The evolutionary relationship showed that these genes could be divided into six groups from Group A to F. We found that the gene corresponding to Arabidopsis thaliana AT1G43640 was completely lost in B. rapa, B. oleracea and B. napus after whole genome triplication. The gene corresponding to AT1G25280 was retained in all the three species we analysed, belonging to 1:3:6 ratios. Our analyses suggested that there was a selective loss of some genes that might be redundant after genome duplication. This study proposed that the TLP genes in B. napus did not directly expansion compared with its diploid parents B. rapa, and B. oleracea. Instead, an indirect expansion of TLP gene family occurred in its two diploid parents. In addition, the study further utilized RNA-seq to detect the expression pattern of TLP genes between different tissues and two subgenomes. CONCLUSIONS: This study systematically conducted the comparative analyses of TLP gene family in B. napus, discussed the loss and expansion of genes after genome duplication. It provided rich gene resources for exploring the molecular mechanism of TLP gene family. Meanwhile, it provided guidance and reference for the research of other gene families in B. napus.

Evolution of the RNA N 6-Methyladenosine Methylome Mediated by Genomic Duplication.

RNA N 6-methyladenosine (m6A) modification is the most abundant form of RNA epigenetic modification in eukaryotes. Given that m6A evolution is associated with the selective constraints of nucleotide sequences in mammalian genomes, we hypothesize that m6A evolution can be linked, at least in part, to genomic duplication events in complex polyploid plant genomes. To test this hypothesis, we presented the maize (Zea mays) m6A modification landscape in a transcriptome-wide manner and identified 11,968 m6A peaks carried by 5,893 and 3,811 genes from two subgenomes (maize1 and maize2, respectively). Each of these subgenomes covered over 2,200 duplicate genes. Within these duplicate genes, those carrying m6A peaks exhibited significant differences in retention rate. This biased subgenome fractionation of m6A-methylated genes is associated with multiple sequence features and is influenced by asymmetric evolutionary rates. We also characterized the coevolutionary patterns of m6A-methylated genes and transposable elements, which can be mediated by whole genome duplication and tandem duplication. We revealed the evolutionary conservation and divergence of duplicated m6A functional factors and the potential role of m6A modification in maize responses to drought stress. This study highlights complex interplays between m6A modification and gene duplication, providing a reference for understanding the mechanisms underlying m6A evolution mediated by genome duplication events.

Functional Characterization and Evolutionary Analysis of Glycine-Betaine Biosynthesis Pathway in Red Seaweed Pyropia yezoensis.

The red seaweed Pyropia yezoensis is an ideal research model for dissecting the molecular mechanisms underlying its robust acclimation to abiotic stresses in intertidal zones. Glycine betaine (GB) was an important osmolyte in maintaining osmotic balance and stabilizing the quaternary structure of complex proteins under abiotic stresses (drought, salinity, etc.) in plants, animals, and bacteria. However, the existence and possible functions of GB in Pyropia remain elusive. In this study, we observed the rapid accumulation of GB in desiccated Pyropia blades, identifying its essential roles in protecting Pyropia cells against severe osmotic stress. Based on the available genomic and transcriptomic information of Pyropia, we computationally identified genes encoding the three key enzymes in the GB biosynthesis pathway: phosphoethanolamine N-methyltransferase (PEAMT), choline dehydrogenase (CDH), and betaine aldehyde dehydrogenase (BADH). Pyropia had an extraordinarily expanded gene copy number of CDH (up to seven) compared to other red algae. Phylogeny analysis revealed that in addition to the one conservative CDH in red algae, the other six might have originated from early gene duplication events. In dehydration stress, multiple CDH paralogs and PEAMT genes were coordinating up-regulated and shunted metabolic flux into GB biosynthesis. An elaborate molecular mechanism might be involved in the transcriptional regulation of these genes.

Spontaneous Changes in Ploidy Are Common in Yeast.

Changes in ploidy are relatively rare, but play important roles in the development of cancer and the acquisition of long-term adaptations. Genome duplications occur across the tree of life, and can alter the rate of adaptive evolution. Moreover, by allowing the subsequent loss of individual chromosomes and the accumulation of mutations, changes in ploidy can promote genomic instability and/or adaptation. Although many studies have been published in the last years about changes in chromosome number and their evolutionary consequences, tracking and measuring the rate of whole-genome duplications have been extremely challenging. We have systematically studied the appearance of diploid cells among haploid yeast cultures evolving for over 100 generations in different media. We find that spontaneous diploidization is a relatively common event, which is usually selected against, but under certain stressful conditions may become advantageous. Furthermore, we were able to detect and distinguish between two different mechanisms of diploidization, one that requires whole-genome duplication (endoreduplication) and a second that involves mating-type switching despite the use of heterothallic strains. Our results have important implications for our understanding of evolution and adaptation in fungal pathogens and the development of cancer, and for the use of yeast cells in biotechnological applications.

Genomic Identification and Comparative Expansion Analysis of the Non-Specific Lipid Transfer Protein Gene Family in Gossypium.

Plant non-specific lipid transfer proteins (nsLTPs) are involved in many biological processes. In this study, 51, 47 and 91 nsLTPs were identified in Gossypium arboreum, G. raimondii and their descendant allotetraploid G. hirsutum, respectively. All the nsLTPs were phylogenetically divided into 8 distinct subfamilies. Besides, the recent duplication, which is considered cotton-specific whole genome duplication, may have led to nsLTP expansion in Gossypium. Both tandem and segmental duplication contributed to nsLTP expansion in G. arboreum and G. hirsutum, while tandem duplication was the dominant pattern in G. raimondii. Additionally, the interspecific orthologous gene pairs in Gossypium were identified. Some GaLTPs and GrLTPs lost their orthologs in the At and Dt subgenomes, respectively, of G. hirsutum. The distribution of these GrLTPs and GaLTPs within each subfamily was complementary, suggesting that the loss and retention of nsLTPs in G. hirsutum might not be random. Moreover, the nsLTPs in the At and Dt subgenomes might have evolved symmetrically. Furthermore, both intraspecific and interspecific orthologous genes showed considerable expression variation, suggesting that their functions were strongly differentiated. Our results lay an important foundation for expansion and evolutionary analysis of the nsLTP family in Gossypium, and advance nsLTP studies in other plants, especially polyploid plants.

Duplicated crabp1 and crabp2 genes in medaka (Oryzias latipes): gene structure, phylogenetic relationship and tissue-specific distribution of transcripts.

Here we report the genomic organization of duplicated cellular retinoic acid-binding protein genes, crabp1 and crabp2, in medaka (Japanese ricefish; Oryzias latipes), the phylogenetic relationship of medaka Crabp1a, Crabp1b, Crabp2a and Crabp2b with other Crabp/CRABP sequences from teleosts/tetrapods, and the tissue-specific distribution of crabp1a, crabp1b, crabp2a, and crabp2b transcripts in adult medaka. The duplicated medaka crabp1 and crabp2 genes contain four exons separated by three introns, which encode polypeptides of 137 and 142 amino acids, respectively. Sequence alignment revealed that medaka Crabp sequences share highest sequence identity and similarity with their orthologs from vertebrates. Phylogenetic analysis confirmed the orthology of the medaka Crabps as they form a distinct clade with their orthologous polypeptides from vertebrates. Conserved gene synteny was evident between the duplicated crabp1 and crabp2 genes from medaka, and CRABP1 and CRABP2 genes from human, which provides compelling evidence that the identified duplicated crabp1 and crabp2 genes from medaka most likely arose owing to teleost-specific whole-genome duplication. The tissue-specific distribution of zebrafish (Danio rerio) and medaka crabp1a, crabp1b, crabp2a, and crabp2b gene transcripts suggests acquisition of new function by these genes in medaka, which may explain potential evolutionary processes that led to the retention of sister duplicates of crabp1 and crabp2 genes in the medaka genome.

Prognostic impact of allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia patients with internal tandem duplication of FLT3.

The FLT3 gene with internal tandem duplication (ITD) is a poor prognostic factor in patients with acute myeloid leukemia (AML), and the efficacy of allogeneic hematopoietic stem cell transplantation (HSCT) for AML patients with FLT3-ITD is controversial. We examined 122 AML patients; 34 patients had FLT3-ITD and 39 patients received allogeneic HSCT. The median overall survival (OS) of patients with wtFLT3/nonHSCT, wtFLT3/HSCT, FLT3-ITD/nonHSCT and FLT3-ITD/HSCT was 40.7 months, 53.4 months, 9.8 months and not reached, respectively (p=0.006). Compared to the wtFLT3/nonHSCT patients, the hazard ratio (95% CI) of OS for wtFLT3/HSCT, FLT3-ITD/nonHSCT and FLT3-ITD/HSCT was 1.39 (0.61-3.18), 3.57 (1.58-8.10) and 0.40 (0.11-1.59), respectively, after adjustment of age, sex, WBC, LDH, karyotype, NPM, and FAB classification. This result indicated that patients with FLT3-ITD/nonHSCT had a significantly worse outcome, but allogeneic HSCT improved the prognosis for patients with FLT3-ITD.

The fate of duplicated genes in a polyploid plant genome.

Polyploidy is generally not tolerated in animals, but is widespread in plant genomes and may result in extensive genetic redundancy. The fate of duplicated genes is poorly understood, both functionally and evolutionarily. Soybean (Glycine max L.) has undergone two separate polyploidy events (13 and 59 million years ago) that have resulted in 75% of its genes being present in multiple copies. It therefore constitutes a good model to study the impact of whole-genome duplication on gene expression. Using RNA-seq, we tested the functional fate of a set of approximately 18 000 duplicated genes. Across seven tissues tested, approximately 50% of paralogs were differentially expressed and thus had undergone expression sub-functionalization. Based on gene ontology and expression data, our analysis also revealed that only a small proportion of the duplicated genes have been neo-functionalized or non-functionalized. In addition, duplicated genes were often found in collinear blocks, and several blocks of duplicated genes were co-regulated, suggesting some type of epigenetic or positional regulation. We also found that transcription factors and ribosomal protein genes were differentially expressed in many tissues, suggesting that the main consequence of polyploidy in soybean may be at the regulatory level.

Stress hematopoiesis reveals abnormal control of self-renewal, lineage bias, and myeloid differentiation in Mll partial tandem duplication (Mll-PTD) hematopoietic stem/progenitor cells.

One mechanism for disrupting the MLL gene in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) is through partial tandem duplication (MLL-PTD); however, the mechanism by which MLL-PTD contributes to MDS and AML development and maintenance is currently unknown. Herein, we investigated hematopoietic stem/progenitor cell (HSPC) phenotypes of Mll-PTD knock-in mice. Although HSPCs (Lin(-)Sca1(+)Kit(+) (LSK)/SLAM(+) and LSK) in Mll(PTD/WT) mice are reduced in absolute number in steady state because of increased apoptosis, they have a proliferative advantage in colony replating assays, CFU-spleen assays, and competitive transplantation assays over wild-type HSPCs. The Mll(PTD/WT)-derived phenotypic short-term (ST)-HSCs/multipotent progenitors and granulocyte/macrophage progenitors have self-renewal capability, rescuing hematopoiesis by giving rise to long-term repopulating cells in recipient mice with an unexpected myeloid differentiation blockade and lymphoid-lineage bias. However, Mll(PTD/WT) HSPCs never develop leukemia in primary or recipient mice, suggesting that additional genetic and/or epigenetic defects are necessary for full leukemogenic transformation. Thus, the Mll-PTD aberrantly alters HSPCs, enhances self-renewal, causes lineage bias, and blocks myeloid differentiation. These findings provide a framework by which we can ascertain the underlying pathogenic role of MLL-PTD in the clonal evolution of human leukemia, which should facilitate improved therapies and patient outcomes.

Mll partial tandem duplication and Flt3 internal tandem duplication in a double knock-in mouse recapitulates features of counterpart human acute myeloid leukemias.

The MLL-partial tandem duplication (PTD) associates with high-risk cytogenetically normal acute myeloid leukemia (AML). Concurrent presence of FLT3-internal tandem duplication (ITD) is observed in 25% of patients with MLL-PTD AML. However, mice expressing either Mll-PTD or Flt3-ITD do not develop AML, suggesting that 2 mutations are necessary for the AML phenotype. Thus, we generated a mouse expressing both Mll-PTD and Flt3-ITD. Mll(PTD/WT):Flt3(ITD/WT) mice developed acute leukemia with 100% penetrance, at a median of 49 weeks. As in human MLL-PTD and/or the FLT3-ITD AML, mouse blasts exhibited normal cytogenetics, decreased Mll-WT-to-Mll-PTD ratio, loss of the Flt3-WT allele, and increased total Flt3. Highlighting the adverse impact of FLT3-ITD dosage on patient survival, mice with homozygous Flt3-ITD alleles, Mll(PTD/WT):Flt3(ITD/ITD), demonstrated a nearly 30-week reduction in latency to overt AML. Here we demonstrate, for the first time, that Mll-PTD contributes to leukemogenesis as a gain-of-function mutation and describe a novel murine model closely recapitulating human AML.

Evolutionary history of c-myc in teleosts and characterization of the duplicated c-myca genes in goldfish embryos.

c-Myc plays an important role during embryogenesis in mammals, but little is known about its function during embryonic development in teleosts. In addition, the evolutionary history of c-myc gene in teleosts remains unclear, and depending on the species, a variable number of gene duplicates exist in teleosts. To gain new insight into c-myc genes in teleosts, the present study was designed to clarify the evolutionary history of c-myc gene(s) in teleosts and to subsequently characterize DNA methylation and early embryonic expression patterns in a cyprinid fish. Our results show that a duplication of c-myc gene occurred before or around the teleost radiation, as a result of the teleost-specific whole genome duplication giving rise to c-myca and c-mycb in teleosts and was followed by a loss of the c-mycb gene in the Gasterosteiforms and Tetraodontiforms. Our data also demonstrate that both c-myc genes previously identified in carp and goldfish are co-orthologs of the zebrafish c-myca. These results indicate the presence of additional c-myca duplication in Cyprininae. We were able to identify differences between the expression patterns of the two goldfish c-myca genes in oocytes and early embryos. These differences suggest a partial sub-functionalization of c-myca genes after duplication. Despite differences in transcription patterns, both of the c-myca genes displayed similar DNA methylation patterns during early development and in gametes. Together, our results clarify the evolutionary history of the c-myc gene in teleosts and provide new insight into the involvement of c-myc in early embryonic development in cyprinids.

[Biological functions of the duplicated GGAA-motifs in various human promoter regions].

Transcription is one of the most fundamental cellular functions and is an enzyme-complex mediated reaction that converts DNA sequences into mRNA. TATA-box is known to be an important motif for transcription. However, there are majority of promoters that have no TATA-box. They are called as TATA-less promoters and possess other elements that determine the transcription start site (TSS) of the genes. Multiple protein factors including ETS family proteins are known to recognize and bind to the GGAA containing sequences. In addition, it has been reported that the ETS binding motifs play important roles in regulation of various promoters. Here, we propose that the duplication and multiplication of the GGAA motifs are responsible for the initiation of transcription from TATA-less promoters.

Impact of gene dosage, loss of wild-type allele, and FLT3 ligand on Flt3-ITD-induced myeloproliferation.

Acquisition of homozygous activating growth factor receptor mutations might accelerate cancer progression through a simple gene-dosage effect. Internal tandem duplications (ITDs) of FLT3 occur in approximately 25% cases of acute myeloid leukemia and induce ligand-independent constitutive signaling. Homozygous FLT3-ITDs confer an adverse prognosis and are frequently detected at relapse. Using a mouse knockin model of Flt3-internal tandem duplication (Flt3-ITD)-induced myeloproliferation, we herein demonstrate that the enhanced myeloid phenotype and expansion of granulocyte-monocyte and primitive Lin(-)Sca1(+)c-Kit(+) progenitors in Flt3-ITD homozygous mice can in part be mediated through the loss of the second wild-type allele. Further, whereas autocrine FLT3 ligand production has been implicated in FLT3-ITD myeloid malignancies and resistance to FLT3 inhibitors, we demonstrate here that the mouse Flt3(ITD/ITD) myeloid phenotype is FLT3 ligand-independent.

Elevated frequencies of leukemic myeloid and plasmacytoid dendritic cells in acute myeloid leukemia with the FLT3 internal tandem duplication.

Some 30% of acute myeloid leukemia (AML) patients display an internal tandem duplication (ITD) mutation in the FMS-like tyrosine kinase 3 (FLT3) gene. FLT3-ITDs are known to drive hematopoietic stem cells towards FLT3 ligand independent growth, but the effects on dendritic cell (DC) differentiation during leukemogenesis are not clear. We compared the frequency of cells with immunophenotype of myeloid DC (mDC: Lin(-), HLA-DR(+), CD11c(+), CD86(+)) and plasmacytoid DC (pDC: Lin(-), HLA-DR(+), CD123(+), CD86(+)) in diagnostic samples of 47 FLT3-ITD(-) and 40 FLT3-ITD(+) AML patients. The majority of ITD(+) AML samples showed high frequencies of mDCs or pDCs, with significantly decreased HLA-DR expression compared with DCs detectable in ITD(-) AML samples. Interestingly, mDCs and pDCs sorted out from ITD(+) AML samples contained the ITD insert revealing their leukemic origin and, upon ex vivo culture with cytokines, they acquired DC morphology. Notably, mDC/pDCs were detectable concurrently with single lineage mDCs and pDCs in all ITD(+) AML (n = 11) and ITD(-) AML (n = 12) samples analyzed for mixed lineage DCs (Lin(-), HLA-DR(+), CD11c(+), CD123(+)). ITD(+) AML mDCs/pDCs could be only partially activated with CD40L and CpG for production of IFN-α, TNF-α, and IL-1α, which may affect the anti-leukemia immune surveillance in the course of disease progression.

Heart chamber size in zebrafish is regulated redundantly by duplicated tbx2 genes.

The Tbx2 transcription factor is implicated in growth control based on its association with human cancers. In the heart, Tbx2 represses cardiac differentiation to mediate development of the atrioventricular canal (AVC). The zebrafish genome retains two tbx2 genes, and both are required for formation of the AVC. Here, we show that both genes are also expressed earlier in the primitive heart tube, and we describe a previously unrecognized role for Tbx2 in promoting proliferation of presumptive myocardium at the heart tube stage. In contrast to single knockdowns, depletion of both gene products causes chamber defects, resulting in an expanded atrium and a smaller ventricle, associated with decreased proliferation of ventricular cardiomyocytes. The phenotype correlates with changes in the expression for known cardiac growth factors. Therefore, in zebrafish, two tbx2 genes are functionally redundant for regulating chamber development, while each gene is required independently for development of the AVC.

TRPV5 and TRPV6 in transcellular Ca(2+) transport: regulation, gene duplication, and polymorphisms in African populations.

TRPV5 and TRPV6 are unique members of the TRP super family. They are highly selective for Ca(2+) ions with multiple layers of Ca(2+)-dependent inactivation mechanisms, expressed at the apical membrane of Ca(2+) transporting epithelia, and robustly responsive to 1,25-dihydroxivitamin D(3). These features are well suited for their roles as Ca(2+) entry channels in the first step of transcellular Ca(2+) transport pathways, which are involved in intestinal absorption, renal reabsorption of Ca(2+), placental transfer of Ca(2+) to fetus, and many other processes. While TRPV6 is more broadly expressed in a variety of tissues such as esophagus, stomach, small intestine, colon, kidney, placenta, pancreas, prostate, uterus, salivary gland, and sweat gland, TRPV5 expression is relatively restricted to the distal convoluted tubule and connecting tubule of the kidney. There is only one TRPV6-like gene in fish and birds in comparison to both TRPV5 and TRPV6 genes in mammals, indicating TRPV5 gene was likely generated from duplication of TRPV6 gene during the evolution of mammals to meet the needs of complex renal function. TRPV5 and TRPV6 are subjected to vigorous regulations under physiological, pathological, and therapeutic conditions. The elevated TRPV6 level in malignant tumors such as prostate and breast cancers makes it a potential therapeutic target. TRPV6, and to a lesser extent TRPV5, exhibit unusually high levels of single nucleotide polymorphisms (SNPs) in African populations as compared to other populations, indicating TRPV6 gene was under selective pressure during or after humans migrated out of Africa. The SNPs of TRPV6 and TRPV5 likely contribute to the Ca(2+) conservation mechanisms in African populations.

Chromatin landscape: methylation beyond transcription.

The nucleus is organized and compartmentalized into a highly ordered structure that contains DNA, RNA, chromosomal and histone proteins. The dynamics associated with these various components are responsible for making sure that the DNA is properly duplicated, genes are properly transcribed, and the genome is stabilized. It is no surprise that alterations in these various components are directly associated with pathologies like cancer. This Point of View focuses on the role the chromatin modification landscape, especially histone 3 lysine 9 methylation (H3K9me), and heterochromatin proteins (HP1) play in regulating DNA-templated processes, with a particular focus on their role at non-genic regions and effects on chromatin structure. These observations will be further extended to the role that alterations in chromatin landscape will contribute to diseases. This Point of View emphasizes that alterations in histone modification landscapes are not only relevant to transcription but have broad range implications in chromatin structure, nuclear architecture, cell cycle, genome stability and disease progression.

The WTX/AMER1 gene family: evolution, signature and function.

BACKGROUND: WTX is a novel gene mutated in a proportion of Wilms' tumors and in patients suffering from sclerosing bone dysplasia. On the molecular level WTX has been shown to act as an antagonist of canonical Wnt/ß-catenin signaling in fish and mammals thus linking it to an essential pathway involved in normal development and cancer formation. Interestingly, WTX seems to also localize to an intranuclear component called paraspeckles. In spite of the growing interest of molecular biologists in WTX, little is known about its paralogs and its phylogenetic history. RESULTS: Using the amino-acid sequence of WTX/AMER1 as a tool for the assignment of orthology and paralogy, we here identify two novel proteins, AMER2 and AMER3, as "WTX" related. This Amer gene family is present in all currently available vertebrate genome sequences, but not invertebrate genomes and is characterized by six conserved blocks of sequences. The phylogenetic analysis suggests that the protoAmer gene originated early in the vertebrate lineage and was then duplicated due to whole genome duplications (WGD) giving rise to the three different Amer genes. CONCLUSION: Our study represents the first phylogenetic analysis of Amer genes and reveals a new vertebrate specific gene family that is likely to have played an important role in the evolution of this subphylum. Divergent and conserved molecular functions of Wtx/Amer1, Amer2 and Amer3 are discussed.