Analysis of recombination and natural selection in human enterovirus 71

The development of effective vaccines and antiviral prophylaxis against human enterovirus 71 (EV71) has been hampered by the extensive antigenic diversity of the virus. To gain new insights into the evolutionary processes that create this genetic diversity, the TreeOrder Scan Method and RDP program were employed to detect recombination events in the genome, and then parsimony-based and maximum-likelihood-based methods were used to detect natural selection effects on viral proteins. Recombination analysis provided strong evidence for recombination events in the majority of the sequences analyzed. Recombination events were found to be distributed nonrandomly with the highest frequency at the 3D region. Furthermore, positive selection was only detected at site 145 of VP1 by the maximum likelihood-based method. These results reveal that EV71 proteins are extensively influenced by stabilizing selection. We conclude that recombination may play a more important role than positive selection in the formation of genetic diversity.     

Genomic landscape of positive natural selection in Northern European populations

Analyzing genetic variation of human populations for detecting loci that have been affected by positive natural selection is important for understanding adaptive history and phenotypic variation in humans. In this study, we analyzed recent positive selection in Northern Europe from genome-wide data sets of 250 000 and 500 000 single-nucleotide polymorphisms (SNPs) in a total of 999 individuals from Great Britain, Northern Germany, Eastern and Western Finland, and Sweden. Coalescent simulations were used for demonstrating that the integrated haplotype score (iHS) and long-range haplotype (LRH) statistics have sufficient power in genome-wide data sets of different sample sizes and SNP densities. Furthermore, the behavior of the F_ST statistic in closely related populations was characterized by allele frequency simulations. In the analysis of the North European data set, 60 regions in the genome showed strong signs of recent positive selection. Out of these, 21 regions have not been discovered in previous scans, and many contain genes with interesting functions (eg, RAB38, INFG, NOS1AP, and APOE). In the putatively selected regions, we observed a statistically significant overrepresentation of genetic association with complex disease, which emphasizes the importance of the analysis of positive selection in understanding the evolution of human disease. Altogether, this study demonstrates the potential of genome-wide data sets to discover loci that lie behind evolutionary adaptation in different human populations.     

Respiratory changes and structure of sleep in young high-altitude dwellers in the Andes of Peru

Summary Sleep organisation in eight young [mean (SD); 20·9 (2·6) years] Peruvian high-altitude residents was studied in a laboratory in Cerro de Pasco at 4300 m. Electroencephalograms, electromyograms, electro-oculograms, electrocardiograms, respiratory movements and arterial oxyen saturation were recorded on an 8-channel Medilog recorder and analysed later in England. Haematocrits ranged from 48% to 64% [57.9 (5.6)%]. The amount of slow wave rapid eye movement (REM) sleep was similar to that reported in young lowlanders sleeping at sea level but very different to the disturbed sleep in visitors sleeping at high altitude. All the Peruvians showed episodes of periodic breathing and respiratory apnoeas [29 (15) night^–1] resulting in marked arterial oxygen desaturation [81 (4.5)%; changes of 6 (2.5)%]. These events occurred either during stage 2 or REM sleep and were more frequent in those with lower haematocrits. The amount of wakefulness during the night was 2–3 times greater than would be expected in an age-matched lowland population at sea level. The awakenings were strongly associated with apnoeas (P<0.02) but were negatively correlated with the haematocrit, although this was only significant for seven of the subjects (P<0.05).     

Selective cross-talk among natural cytotoxicity receptors in human natural killer cells

The cytolytic activity of human natural killer cells is induced by several triggering cell surface receptors upon interaction with specific cellular ligands. These receptors include NKp46, NKp30 and NKp44, collectively termed natural cytotoxicity receptors (NCR). Co-operation among NCR has been shown to occur for optimal recognition and killing of most tumor target cells. In this study, we show that the mAb-mediated engagement and clustering of one or another NCR results in the activation of an identical set of tyrosine kinases. These kinases are included in the signaling cascade leading to tyrosine phosphorylation of different receptor-associated signal transducing molecules i.e. CD3 zeta (associated with NKp46 and NKp30) and KARAP/DAP12 (associated with NKp44). In line with the notion that the engagement of inhibitory receptors prevents NCR-mediated responses, we show that the engagement of CD94/NKG2A virtually abrogates the tyrosine phosphorylation of the NCR-associated signaling molecules, i.e. it acts at the very early steps of the signaling cascade. Importantly, the engagement of a single NCR resulted in the activation of the signaling cascades associated with the other NCR. This "cross-talk" is confined to NKp46, NKp30 and NKp44 since neither CD16-nor KIR2DS4-associated signaling polypeptides were phosphorylated following the NCR engagement. These results suggest that a functional cross-talk specifically occurs among different NCR, possibly resulting in the amplification of the activating signals.     

Effects of prolonged high-altitude exposure on peripheral adrenergic receptors in young healthy volunteers

The regulation of adrenergic receptors during hypoxia is complex, and the results of published reports have not been consistent. In the present study blood cell adrenoceptor characteristics at sea level (SL) before and after prolonged exposure to high altitude (HA) were measured in seven trained young male lowlanders. Sympathoadrenal activity and clinical haemodynamic parameters were also evaluated before departure (SLB), after 1 week (HA1) and 4 weeks (HA4) at HA and 1 week after return to sea level (SLA). As compared to pre-departure sea level values, urinary norepinephrine excretion increased significantly during altitude exposure [SLB: 10.26 (3.04) μg · 3 h⁻¹; HA1: 23.2 (4.19) μg · 3 h⁻¹; HA4: 20.3 (8.68) μg · 3 h⁻¹] and fell to pre-ascent values 1 week after return to sea level [SLA: 9 (2.91) μg · 3 h⁻¹]. In contrast, mean urinary epinephrine levels did not increase over time at HA. Both systolic and diastolic blood pressures, as well as heart rate, were increased during HA exposure. The circadian blood pressure and heart rate rhythms were preserved during all phases of altitude exposure. Mean maximal binding (B _max) of the α₂-adrenoceptor antagonist [³H]rauwolscine to platelet membranes was significantly reduced (P < 0.001) after exposure to chronic hypoxia [SLB: 172.6 (48.5) fmol · mg⁻¹ protein versus SLA: 136.8 (56.1) fmol · mg⁻¹ protein] without change in the dissociation constant (K _D). Neither the lymphomonocyte β₂-adrenoceptor B _max [SLB: 38.5 (13.6) fmol · mg⁻¹ protein, versus SLA: 32.4 (12.1) fmol · mg⁻¹ protein] nor the K _D for [³H]dihydroalprenolol was affected by chronic hypoxia. Cyclic AMP (adenosine 3′,5′-cyclic monophoshate) generation in lymphomonocytes by maximal isoproterenol stimulation was not modified after prolonged HA exposure. In conclusion, the down-regulation of α₂-adrenoceptors appears to be an important component of the adrenergic system response to HA exposure. Accepted: 20 April 2000     

基因组学研究在藏族高原适应遗传机制研究中的实践与运用

世居高原藏族在长期的高原低氧适应过程中,其多项生理特征显著不同于世居平原民族,这些指标变化可能与特殊环境所导致的基因组序列变异相关.近年来随着高通量测序以及全基因组关联分析等新型研究平台的迅猛发展,它们广泛应用到藏族高原适应的遗传机制的研究中.此文就基因组学领域藏族高原适应的遗传机制进展进行综述,为进一步探索高原适应机制和高原病发病机制提供参考,并为高原病的防治寻找新的思路和靶点.     

Genetic diversity and purifying selection in West Nile virus populations are maintained during host switching

To investigate differential evolutionary rates and selective forces of WNV in hosts and vectors, we measured the genetic diversity that arose during alternating passage in mosquitoes and birds. Within-host genetic diversity was monitored in each of three experimentally passed replicates, and the complete genome sequence of each WNV strain was determined after passage. The intrahost genetic diversity that arose during alternating passage was significantly greater than the diversity generated during chicken-only passage and similar to mosquito-only passage. dN/dS ratios suggested purifying selection similar to chick-passed virus, but not to mosquito-passed virus. Thus, the abundant genetic variation contributed to WNV populations through infection of mosquitoes and the strong purifying selection contributed by infection of birds may be maintained despite frequent host switching.     

Molecular and population analysis of natural selection on the human haptoglobin duplication

Haptoglobin binds free haemoglobin that prevents oxidative damage produced by haemolysis. There is a copy number variant (CNV) in the haptoglobin gene (HP) consisting of two alleles, Hp1 (no duplication), and Hp2 (1.7kb duplication involving two exons). The spread of the Hp2 allele is believed to have taken place under selective pressures conferred by malaria resistance. However, molecular evidence is lacking and Hp did not emerge in genomewide SNPs surveys for evidence of selection. In Europe, there is geographical constancy of Hp2 frequency, indicative of absence of clinal pressures and that modern day European alleles represent a "snapshot" of their out-of-Africa migrations. In this work we test for signatures of natural selection acting on the Hp CNV in a sample from the UK population (Avon Longitudinal Study of Parents and Children, ALSPAC). We present here heterozygosity decay, pairwise F(ST) values observed between ALSPAC and 301 populations from all five populated continents, extended haplotype homozygosity analyses involving the CNV and 80 SNPs surrounding the CNV ～500kb in each direction, and linkage disequilibrium and pairwise haplotypic analyses involving 160 SNPs on chromosome 16q22.1. Taken together, our results represent the first molecular analysis of natural selection in the Hp CNV genetic region.     

某进藏工作团体状态-特质焦虑、抑郁状况调查

目的 研究从低海拔地区进入高海拔地区工作人群的状态-特质焦虑、抑郁特点.方法 采用抑郁自评量表(SDS)和采用状态-特质焦虑问卷(STAI),对某进高原工作的团体111名人员进行团体测评,将抑郁、焦虑得分与一般人群比较;以性别、年龄、海拔和进入高原次数进行分组,采用t检验、单因素方差分析进行组间比较.结果 ①进藏工作团...     

Recombination and natural selection in hepatitis E virus genotypes

To gain new insights into the evolutionary processes that created the genetic diversity of the hepatitis E virus (HEV), the Recombination Detection Program (RDP) and SimPlot program were employed to detect recombination events in the genome, then the fixed-effects likelihood (FEL) method was used to detect natural selection effects on viral proteins. Recombination analysis provided strong evidence for both intergenotype and intragenotype recombination events in the sequences analyzed. Recombination events were found to be distributed non-randomly, with the highest frequency in the X domain and the helicase. Strain DQ450072 was identified as intergenotype-recombinant. Natural selection analysis revealed that codons under both negative selection and positive selection were distributed non-randomly. ORF1 and ORF2 have experienced strong purifying selection across genotypes. Furthermore, potentially important sites were also found under positive selection in the N-terminal end of ORF2 and the C-terminal end of ORF3. No significant difference was found among the selective pressures on different genotypes.     

Detecting gene duplications in the human lineage

Gene duplications represent an important class of evolutionary events that is likely to have contributed to the unique human phenotype in the short evolutionary time since the human-chimpanzee divergence. With the availability of both human and chimpanzee genome drafts in high coverage re-sequencing assemblies and the high annotation quality of most human genes, it should now be possible to identify all human lineage-specific gene duplication events (human inparalogues) and a few pioneering studies have attempted to do that. However, the different levels of coverage in the human and chimpanzee's genomes assemblies, and the differing levels of gene annotation, have led to problematic assumptions and oversimplifications in the algorithms and the datasets used to detect human lineage-specific gene duplications. In this study, we have developed a set of bioinformatic tools to overcome a number of the conceptual problems that are prevalent in previous studies and have collected a reliable and representative set of human inparalogues.     

Detecting novel hypermethylated genes in Breast cancer benefiting from feature selection

The aberrant hypermethylation of CpG islands in promoter regions of genes plays an important role in the onset and progression of Breast cancer. Meanwhile, it is highly associated with human genomic features. Two feature selection algorithms: t-test and CfsSubsetEval were used to obtain efficient feature subsets. We discovered 14 significant feature subsets by CfsSubsetEval, which can distinguish hypermethylated genes from control genes. As a result, 393 unconfirmed hypermethylated genes in Breast cancer were prioritized. These genes were assigned the hypermethylated scores and were supported by literature and Gene Ontology enrichment. This paper suggests that the feature subsets could be served as discriminating genomic markers to infer novel hypermethylated genes in cancer potentially.     

自然选择及其分子信号

摘要：本综述拟介绍有关自然选择的一些基本概念。在人类进化过程中,自然选择会在基因组中留下一些分子信号,我们重点分析如何利用这些信号来识别自然选择尤其是正向选择,因为发生正向选择作用的基因组区域一定具有重要的功能。     

Look-ahead fixations: anticipatory eye movements in natural tasks

During performance of natural tasks subjects sometimes fixate objects that are manipulated several seconds later. Such early looks are known as “look-ahead fixations” (Pelz and Canosa in Vision Res 41(25–26):3587–3596, 2001). To date, little is known about their function. To investigate the possible role of these fixations, we measured fixation patterns in a model-building task. Subjects assembled models in two sequences where reaching and grasping were interrupted in one sequence by an additional action. Results show look-ahead fixations prior to 20% of the reaching and grasping movements, occurring on average 3 s before the reach. Their frequency was influenced by task sequence, suggesting that they are purposeful and have a role in task planning. To see if look-aheads influenced the subsequent eye movement during the reach, we measured eye-hand latencies and found they increased by 122 ms following a look-ahead to the target. The initial saccades to the target that accompanied a reach were also more accurate following a look-ahead. These results demonstrate that look-aheads influence subsequent visuo-motor coordination, and imply that visual information on the temporal and spatial structure of the scene was retained across intervening fixations and influenced subsequent movement programming. Additionally, head movements that accompanied look-aheads were significantly smaller in amplitude (by 10°) than those that accompanied reaches to the same locations, supporting previous evidence that head movements play a role in the control of hand movements. This study provides evidence of the anticipatory use of gaze in acquiring information about objects for future manipulation. Electronic supplementary material Supplementary material is available in the online version of this article at and is accessible for authorized users.     

Absence of the HLA-G*0105N allele in Amerindian populations from the Brazilian Amazon Region: a possible role of natural selection

The human leukocyte antigen G (HLA-G) null allele (G*0105N) is defined by a DeltaC deletion at exon 3. Its high frequency in populations from areas with high pathogen loads and the putative role of HLA-G in placental development suggest that the reduced G1 expression in G*0105N heterozygous placentas may improve the intrauterine defense against infections. The G*0105N allele frequencies were evaluated in 143 Amerindians from six isolated tribes that inhabit the Central Amazon to determine the existence of genotype frequencies that suggest balancing selection in favor of G*0105N heterozygotes. No copy of the null allele was found by exon 3 sequencing. Although this finding may be because of demographic or other selective factors, it also suggests no evidence of G*0105N heterozygous advantage.     

Control of erythropoiesis after high altitude acclimatization

Erythropoiesis was studied in 11 subjects submitted to a 4-h hypoxia (HH) in a hypobaric chamber (4,500 m, barometric pressure 58.9 kPa) both before and after a 3-week sojourn in the Andes. On return to sea level, increased red blood cells (+3.27%), packed cell volume (+4.76%), haemoglobin (+6.55%) (P<0.05), and increased arterial partial pressure of oxygen (+8.56%), arterial oxygen saturation (+7.40%) and arterial oxygen blood content (C_aO₂) (+12.93%) at the end of HH (P<0.05) attested high altitude acclimatization. Reticulocytes increased during HH after the sojourn only (+36.8% vs +17.9%, P<0.01) indicating a probable higher reticulocyte release and/or production despite decreased serum erythropoietin (EPO) concentrations (–46%, P<0.01). Hormones (thyroid, catecholamines and cortisol), iron status (serum iron, ferritin, transferrin and haptoglobin) and renal function (creatinine, renal, osmolar and free-water clearances) did not significantly vary (except for lower thyroid stimulating hormone at sea level, P<0.01). Levels of 2,3-diphosphoglycerate (2,3-DPG) increased throughout HH on return (+14.7%, P<0.05) and an inverse linear relationship was found between 2,3-DPG and EPO at the end of HH after the sojourn only (r=–0.66, P<0.03). Inverse linear relationships were also found between C_aO₂ and EPO at the end of HH before (r=–0.63, P<0.05) and after the sojourn (r=–0.60, P=0.05) with identical slopes but different ordinates at the origin, suggesting that the sensitivity but not the gain of the EPO response to hypoxia was modified by altitude acclimatization. Higher 2,3-DPG levels could partly explain this decreased sensitivity of the EPO response to hypoxia. In conclusion, we show that altitude acclimatization modifies the control of erythropoiesis not only at sea level, but also during a subsequent hypoxia.     

HIV感染症状长期不进展者NK细胞变化研究

目的探讨HIV长期不进展者NK细胞的变化. 方法应用流式细胞术对HIV长期不进展者、典型进展者和HIV-抗体阴性正常对照外周血NK细胞、NKT细胞及NK细胞趋化因子受体等进行研究. 结果长期不进展者NKT细胞绝对计数与正常对照差异无统计学意义(P＝0.301),高于HIV感染者和艾滋病病人(P＝0.01, P＝0.002);长期不进展者NK细胞绝对计数低于正常对照(P＝0.03),高于HIV感染者和艾滋病病人(P＝0.005, P＜0.0001);长期不进展者NK细胞与CD4+ T淋巴细胞呈正相关(r＝0.393,P＝0.001);NKT细胞与CD8+ T淋巴细胞呈正相关(r＝0.372,P＝0.002).长期不进展者NK细胞表达的CCR5受体低于典型进展者和正常对照(P＜0.01). 结论 NK细胞的变化与HIV疾病进展相关,值得深入研究.     

Preferential amplification and phenotypic selection in a population of deleted and wild-type mitochondrial DNA in cultured cells

In order to study the still poorly understood dynamics of mitochondrial gene segregation, we attempted to alter the percentage of deleted mtDNA (del-mtDNA) over wild-type mtDNA in cell-culture by manipulating respiratory chain capacity. For this purpose, we used a cell-line harbouring a 6-kb mtDNA-deletion which normally was present in 70% of the molecules. The results show that in the presence of low concentrations of doxycycline (DC), an inhibitor of mitochondrial protein synthesis, the average percentage of del-mtDNA in culture steadily declined. After short-term DC treatment most cells still contained del-mtDNA and removal of DC led to a rapid increase in the proportion of del-mtDNA. In contrast, long-term DC treatment rendered del-mtDNA undetectable by Southern analysis, reflecting the complete absence of del-mtDNA in most cells. In this case, del-mtDNA in culture remained at a constant low level after removal of the drug. The results clearly show the importance of phenotypic selection in the segregation of a deleterious mtDNA mutation. Received: 24 March / 12 May 1997     

Uterine natural killer (uNK) cells and their missions during pregnancy: A review

Natural killer (NK) cells are lymphocytes of the innate immune system. The aim of this review is to describe the properties and roles of NK cells in the human uterus during pregnancy. Uterine natural killer cells (uNK) constitute a major lymphocyte population during early gestation in the uterus. The uterine natural killer cells are recognized owing to their CD56^bright, CD16⁻, CD3⁻ phenotype. Their number increases in the first trimester with a subsequent decline as pregnancy progresses. They have been shown to be closely associated with cells of the extravillous trophoblast (EVT) and spiral arteries. They play important roles in remodeling of the spiral arteries, control of trophoblast invasion and in the development of the placenta. Some studies have shown the number and repertoire of receptors of uNK differ between women with healthy pregnancies and those with pathologic pregnancies, such as pre-eclampsia or intrauterine growth retardation. During pregnancy, the cytotoxic characteristics of the uterine killer cells are not directed towards the fetus, and scientists continue to question and explore this phenomenon with increasing evidence that these cells may perform differing beneficial roles during pregnancy. Contrary to their previously suspected “hostile” characteristics, the uterine killer cells are considered to be “friendly” and appear to be essential and very important regulators of successful implantation and pregnancy.     

高原红细胞增多症的骨髓细胞形态和活检病理组织的系列观察

目的:对高原红细胞增多症(HAPC)70例,经髓后上棘取材,观察骨髓形态、组织病理、超级结构,以揭示在高原低氧环境下,骨髓红细胞系统过度异常增生,是HAPC发病的重要因素.方法:骨髓涂片用瑞氏染色、形态学计数和分类.其中12例行骨髓活检,取出10～15mm活组织,分成两块,观察骨髓病理和骨髓超微结构.结果:骨髓形态学、组织病理、超微结构共同改变,即红系列增生极活跃,均有核浆发育不平衡的表现,有核红细胞的分裂指数、细胞分裂象在骨髓分裂中、红与粒细胞的比例均明显高于正常值.形态上红系以间接丝状分裂为主,骨髓组织病理可见,造血组织容积增加,含铁血黄素减少或消失.超微结构红系统的内质网、溶媒体、线粒体减少,线粒体排列紊乱,可见巨大线粒体.结论:HAPC的骨髓红系统过度增生,聚集在增多扩张的静脉窦中,并迅速进入血循环中,以改善低氧情况,但红系的核浆发育不平衡,细胞器的异常改变,所致的病态造血和红细胞的释放失控,可能是HAPC发病的组织结构基础.