A haplotype map of the human genomeThe International HapMap Consortium* Inherited genetic variation has a critical but as yet largely uncharacterized role in human disease. Here we report a public database of common variation in the human genome: more than one million single nucleotide polymorphisms (SNPs) for which accurate and complete genotypes have been obtained in 269 DNA samples from four populations, including ten 500-kilobase regions in which essentially all information about common DNA variation has been extracted. These data document the generality of recombination hotspots, a block-like structure of linkage disequilibrium and low haplotype diversity, leading to substantial correlations of SNPs with many of their neighbours. We show how the HapMap resource can guide the design and analysis of genetic association studies, shed light on structural variation and recombination, and identify loci that may have been subject to natural selection during human evolution.

Natural killer/T-cell lymphoma (NKTCL) is a malignant proliferation of CD56(+) and cytoCD3(+) lymphocytes with aggressive clinical course, which is prevalent in Asian and South American populations. The molecular pathogenesis of NKTCL has largely remained elusive. We identified somatic gene mutations in 25 people with NKTCL by whole-exome sequencing and confirmed them in an extended validation group of 80 people by targeted sequencing. Recurrent mutations were most frequently located in the RNA helicase gene DDX3X (21/105 subjects, 20.0%), tumor suppressors (TP53 and MGA), JAK-STAT-pathway molecules (STAT3 and STAT5B) and epigenetic modifiers (MLL2, ARID1A, EP300 and ASXL3). As compared to wild-type protein, DDX3X mutants exhibited decreased RNA-unwinding activity, loss of suppressive effects on cell-cycle progression in NK cells and transcriptional activation of NF-κB and MAPK pathways. Clinically, patients with DDX3X mutations presented a poor prognosis. Our work thus contributes to the understanding of the disease mechanism of NKTCL.

Determining the extent of adaptive evolution at the genomic level is central to our understanding of molecular evolution. A suitable observation for this purpose would consist of polymorphic data on a large and unbiased collection of genes from two closely related species, each having a large and stable population. In this study, we sequenced 419 genes from 24 lines of Drosophila melanogaster and its close relatives. Together with data from Drosophila simulans, these data reveal the following. (i) Approximately 10% of the loci in regions of normal recombination are much less polymorphic at silent sites than expected, hinting at the action of selective sweeps.(ii) The level of polymorphism is negatively correlated with the rate of nonsynonymous divergence across loci. Thus, even under strict neutrality, the ratio of amino acid to silent nucleotide changes (A:S) between Drosophila species is expected to be 25-40% higher than the A:S ratio for polymorphism when data are pooled across the genome. (iii) The observed A/S ratio between species among the 419 loci is 28.9% higher than the (adjusted) neutral expectation. We estimate that nearly 30% of the amino acid substitutions between D. melanogaster and its close relatives were adaptive. (iv) This signature of adaptive evolution is observable only in regions of normal recombination. Hence, the low level of polymorphism observed in regions of reduced recombination may not be driven primarily by positive selection. Finally, we discuss the theories and data pertaining to the interpretation of adaptive evolution in genomic studies.McDonald-Kreitman test ͉ selection ͉ polymorphism R ecent studies based on DNA sequence data from large numbers of genes have increasingly suggested the prevalence of adaptive evolution in coding (1-5) as well as noncoding (6, 7) regions. The extent to which positive selection influences DNA polymorphism and divergence appears to be incompatible with the Neutral Theory of Molecular Evolution (8). This theory posits that the overall pattern of DNA evolution can be accounted for by mutation, genetic drift, and negative selection. It does not deny the operation of positive selection on some loci but only asserts that the overall pattern of genomic evolution can be explained without invoking adaptive evolution. Presumably, adaptive changes at any given time involve too small a fraction of the genome to be a statistically significant factor, despite their overwhelming biological significance.The evidence used to test the Neutral Theory can be classified as divergence among species (9-11), polymorphism within species (12-14) or a combination of these (15, 16). The combined approach, as exemplified by the McDonald-Kreitman (MK) test and its derivatives, can separate the effects of negative and positive selection and is especially informative about adaptive evolution. Many such studies have concluded that positive selection may play a significant role in driving amino acid substitutions in the human and Drosophila melanogaster lineages (1-5).However, as...

Schistosoma japonicum causes schistosomiasis in humans and livestock in the Asia-Pacific region. Knowledge of the genome of this parasite should improve understanding of schistosome-host interactions, biomedical aspects of schistosomiasis and invertebrate evolution. We assigned 43,707 expressed sequence tags (ESTs) derived from adult S. japonicum and their eggs to 13,131 gene clusters. Of these, 35% shared no similarity with known genes and 75% had not been reported previously in schistosomes. Notably, S. japonicum encoded mammalian-like receptors for insulin, progesterone, cytokines and neuropeptides, suggesting that host hormones, or endogenous parasite homologs, could orchestrate schistosome development and maturation and that schistosomes modulate anti-parasite immune responses through inhibitors, molecular mimicry and other evasion strategies.

BACKGROUND:Although microRNAs (miRNAs) play essential roles in spermatogenesis, little is known about seminal plasma miRNAs in infertile men. We investigated the profile of seminal plasma miRNAs in infertile men to identify miRNAs that are altered in infertility; we then evaluated their diagnostic value.

Preadipocyte differentiation occurs during distinct periods of human development and is a key determinant of body mass. Transcriptional events underlying adipogenesis continue to emerge, but the link between chromatin remodeling of specific target loci and preadipocyte differentiation remains elusive. We have identified Krü ppel-like factor-6 (KLF6), a recently described tumor suppressor gene, as a repressor of the proto-oncogene Delta-like 1 (Dlk1), a gene encoding a transmembrane protein that inhibits adipocyte differentiation. Forced expression of KLF6 strongly inhibits Dlk1 expression in preadipocytes and NIH 3T3 cells in vivo, whereas down-regulation of KLF6 in 3T3-L1 cells by small interfering RNA prevents adipogenesis. Repression of Dlk1 requires HDAC3 deacetylase activity, which is recruited to the endogenous Dlk1 promoter where it interacts with KLF6. Our studies identify the interaction between HDAC3 and KLF6 as a potential mechanism underlying human adipogenesis, and highlight the role of KLF6 as a multifunctional transcriptional regulator capable of mediating adipocyte differentiation through gene repression.

Although phospholipid scramblase 1 (PLSCR1) was originally identified based on its capacity to promote transbilayer movement of membrane phospholipids, subsequent studies also provided evidence for its role in cell proliferation, maturation, and apoptosis. In this report, we investigate the potential role of PLSCR1 in leukemic cell differentiation. We show that all-trans retinoic acid (ATRA) , IntroductionHuman phospholipid scramblase 1 (PLSCR1), 1,2 also known as MmTRA1b (Mm-1 cell-derived transplantability-associated gene 1b), 3 is a multiply palmitoylated, calcium-binding, lipid raftassociated endofacial plasma membrane protein. 4 PLSCR1 was originally identified based on its capacity to promote rapid transbilayer movement of phospholipids (PLs) in response to the elevation of Ca 2ϩ and has been proposed to play a role in the cell-surface exposure of phosphatidylserine (PtdSer) following cell activation, injury, or apoptosis. [1][2][3] However, its role in membrane PL scrambling is controversial. While overexpression of PLSCR1 was reported to increase cell-surface exposure of PtdSer or to induce apoptosis in a variety of cells, [5][6][7] an increase in PL scrambling activity with elevated expression of PLSCR1 was not observed in other studies. 8,9 Blood platelets from PLSCR1 Ϫ/Ϫ mice also showed normal capacity to expose PtdSer upon cell activation. 10 Although the precise biologic function(s) of PLSCR1 remains to be determined, recent studies provide strong evidence for its role in cell signaling and in cell maturation. PLSCR1 has been reported to be a substrate of several kinases that participate in cell proliferation, differentiation, or apoptotic responses, including c-Abl, c-Src, and protein kinase C␦ (PKC␦). [11][12][13][14] In response to growth factors such as epidermal growth factor (EGF), tyrosine phosphorylation of PLSCR1 by c-Src resulted in association of phosphorylated PLSCR1 with the adaptor protein Shc and the activated EGF receptor complex, and, in cells deficient in PLSCR1, signaling through the EGF receptor is markedly attenuated. 12,13 Furthermore, PLSCR1 itself is transcriptionally up-regulated by a number of selective growth factors and cytokines, including interferon. 9,15 Interestingly, whereas palmitoylation of PLSCR1 is required for its anchoring in the plasma membrane, PLSCR1 was found in the nucleus after transcriptional induction by cytokines and in circumstances in which palmitoylation is prevented. Such nuclear localization of PLSCR1 was shown to be actively mediated by import through a nuclear localization signal within the polypeptide, and once imported, the protein was shown to bind to genomic DNA, implying a possible effect on gene transcription. 16,17 Proliferation and terminal differentiation of myeloid precursor cells in response to selective growth factors are impaired in PLSCR1 Ϫ/Ϫ mice, and in both monocytic and granulocytic lineages, the expression of PLSCR1 markedly increases upon K.-W.Z, X.L., and Q.Z. contributed equally to this study. Guo-Qiang Chen, No. 280, Chon...

BackgroundDrought stress is one of the major natural challenges in the main tea-producing regions of China. The tea plant (Camellia sinensis) is a traditional beverage plant whose growth status directly affects tea quality. Recent studies have revealed that microRNAs (miRNAs) play key functions in plant growth and development. Although some miRNAs have been identified in C. sinensis, little is known about their roles in the drought stress response of tea plants.ResultsPhysiological characterization of Camellia sinensis ‘Tieguanyin’ under drought stress showed that the malondialdehyde concentration and electrical conductivity of leaves of drought-stressed plants increased when the chlorophyll concentration decreased under severe drought stress. We sequenced four small-RNA (sRNA) libraries constructed from leaves of plants subjected to four different treatments, normal water supply (CK); mild drought stress (T1); moderate drought stress (T2) and severe drought stress (T3). A total of 299 known mature miRNA sequences and 46 novel miRNAs were identified. Gene Ontology enrichment analysis revealed that most of the differentially expressed-miRNA target genes were related to regulation of transcription. Kyoto Encyclopedia of Genes and Genomes analysis revealed that the most highly enriched pathways under drought stress were D-alanine metabolism, sulfur metabolism, and mineral absorption pathways. Real-time quantitative PCR (qPCR) was used to validate the expression patterns of 21 miRNAs (2 up-regulated and 19 down-regulated under drought stress). The observed co-regulation of the miR166 family and their targets ATHB-14-like and ATHB-15-like indicate the presence of negative feedback regulation in miRNA pathways.ConclusionsAnalyses of drought-responsive miRNAs in tea plants showed that most of differentially expressed-miRNA target genes were related to regulation of transcription. The results of study revealed that the expressions of phase-specific miRNAs vary with morphological, physiological, and biochemical changes. These findings will be useful for research on drought resistance and provide insights into the mechanisms of drought adaptation and resistance in C. sinensis.Electronic supplementary materialThe online version of this article (10.1186/s12870-017-1172-6) contains supplementary material, which is available to authorized users.