Modern human ancestry at the peripheries: a test of the replacement theory

The replacement theory of modern human origins stipulates that populations outside of Africa were replaced by a new African species of modern humans. Here we test the replacement theory in two peripheral areas far from Africa by examining the ancestry of early modern Australians and Central Europeans. Analysis of pairwise differences was used to determine if dual ancestry in local archaic populations and earlier modern populations from the Levant and/or Africa could be rejected. The data imply that both have a dual ancestry. The diversity of recent humans cannot result exclusively from a single Late Pleistocene dispersal.     

Human evolution out of Africa: the role of refugia and climate change

Although an African origin of the modern human species is generally accepted, the evolutionary processes involved in the speciation, geographical spread, and eventual extinction of archaic humans outside of Africa are much debated. An additional complexity has been the recent evidence of limited interbreeding between modern humans and the Neandertals and Denisovans. Modern human migrations and interactions began during the buildup to the Last Glacial Maximum, starting about 100,000 years ago. By examining the history of other organisms through glacial cycles, valuable models for evolutionary biogeography can be formulated. According to one such model, the adoption of a new refugium by a subgroup of a species may lead to important evolutionary changes.     

The major genetic determinants of HIV-1 control affect HLA class I peptide presentation

Infectious and inflammatory diseases have repeatedly shown strong genetic associations within the major histocompatibility complex (MHC); however, the basis for these associations remains elusive. To define host genetic effects on the outcome of a chronic viral infection, we performed genome-wide association analysis in a multiethnic cohort of HIV-1 controllers and progressors, and we analyzed the effects of individual amino acids within the classical human leukocyte antigen (HLA) proteins. We identified >300 genome-wide significant single-nucleotide polymorphisms (SNPs) within the MHC and none elsewhere. Specific amino acids in the HLA-B peptide binding groove, as well as an independent HLA-C effect, explain the SNP associations and reconcile both protective and risk HLA alleles. These results implicate the nature of the HLA-viral peptide interaction as the major factor modulating durable control of HIV infection.     

基于掖478导入系的玉米产量性状QTL鉴定

 目的】鉴定玉米产量相关性状基因位点及包含有利等位基因的导入系,为了解产量性状形成的遗传基础及针对玉米自交系产量性状的分子设计提供参考和依据。【方法】以QB80和Qi319为供体亲本,掖478为轮回亲本,采用回交结合定向选择,分别构建含有61和72个家系的基础导入系群体。通过2年4点田间试验,利用完备复合区间作图进行产量及其相关性状的QTL（quantitative trait locus,QTL）分析。【结果】4个环境下,在QB80为供体的导入系群体中,共检测到9个性状的49个QTL;在Qi319为供体的导入系群体中,检测到9个性状的42个QTL。在2个及以上环境中均检测到的QTL有16个。同一性状在不同环境下所检测的QTL定位在相同的染色体区域,不同性状的QTL也定位在相同或临近的染色体区域,形成多个QTL富集区。2个群体所检测的QTL位点具有较少的一致性,说明2个供体材料中含有不同的有利基因位点。同时,导入片段中含有利基因的导入系,其相关性状明显得以改良,这些导入系可用于QTL聚合以改良掖478的产量相关性状。【结论】QB80较Qi319与掖478间的遗传差异更大,能检测更多的产量性状QTL;2个导入系群体中含有优良等位基因的导入系可用于QTL聚合改良掖478;QTL富集区是为产量性状基因的克隆提供可供参考的重要染色体区域。     

Microcephalin, a gene regulating brain size, continues to evolve adaptively in humans

The gene Microcephalin (MCPH1) regulates brain size and has evolved under strong positive selection in the human evolutionary lineage. We show that one genetic variant of Microcephalin in modern humans, which arose approximately 37,000 years ago, increased in frequency too rapidly to be compatible with neutral drift. This indicates that it has spread under strong positive selection, although the exact nature of the selection is unknown. The finding that an important brain gene has continued to evolve adaptively in anatomically modern humans suggests the ongoing evolutionary plasticity of the human brain. It also makes Microcephalin an attractive candidate locus for studying the genetics of human variation in brain-related phenotypes.     

HLA and HIV-1: heterozygote advantage and B*35-Cw*04 disadvantage

A selective advantage against infectious disease associated with increased heterozygosity at the human major histocompatibility complex [human leukocyte antigen (HLA) class I and class II] is believed to play a major role in maintaining the extraordinary allelic diversity of these genes. Maximum HLA heterozygosity of class I loci (A, B, and C) delayed acquired immunodeficiency syndrome (AIDS) onset among patients infected with human immunodeficiency virus-type 1 (HIV-1), whereas individuals who were homozygous for one or more loci progressed rapidly to AIDS and death. The HLA class I alleles B*35 and Cw*04 were consistently associated with rapid development of AIDS-defining conditions in Caucasians. The extended survival of 28 to 40 percent of HIV-1-infected Caucasian patients who avoided AIDS for ten or more years can be attributed to their being fully heterozygous at HLA class I loci, to their lacking the AIDS-associated alleles B*35 and Cw*04, or to both.     

Late Pleistocene human skull from Hofmeyr, South Africa, and modern human origins

The lack of Late Pleistocene human fossils from sub-Saharan Africa has limited paleontological testing of competing models of recent human evolution. We have dated a skull from Hofmeyr, South Africa, to 36.2 +/- 3.3 thousand years ago through a combination of optically stimulated luminescence and uranium-series dating methods. The skull is morphologically modern overall but displays some archaic features. Its strongest morphometric affinities are with Upper Paleolithic (UP) Eurasians rather than recent, geographically proximate people. The Hofmeyr cranium is consistent with the hypothesis that UP Eurasians descended from a population that emigrated from sub-Saharan Africa in the Late Pleistocene.     

利用基础导入系分析粳稻基因的遗传效应

 【目的】为了有效地评价粳稻等位基因在籼稻遗传背景中的遗传效应，为籼粳亚种间优良基因的利用提供理论和实践依据。【方法】以粳稻品种日本晴（Nipponbare）为供体亲本、籼稻品种珍汕97B（Zhenshan 97B）为受体亲本，经过杂交、回交，结合分子标记辅助选择，构建了88个基础导入系, 每个导入系具有相同的籼稻遗传背景，且只含有一个或少数粳稻的导入片段，每个导入系的导入片段叠加起来能覆盖整个粳稻的染色体。利用基础导入系群体进行单株产量、有效分蘖数、千粒重和每穗实粒数的数量性状基因（QTLs）定位和遗传效应分析。【结果】共检测到29个具有显著遗传效应的位点（QTLs）。其中6个QTL具有正向的加性效应和超显性效应，其余23个QTL具有负向的加性效应和超显性效应。【结论】一些粳稻基因导入到籼稻中能表现出不同程度的增产效应；超显性效应对水稻籼粳杂种优势起重要作用。     

Founder effects in the assessment of HIV polymorphisms and HLA allele associations

Escape from T cell-mediated immune responses affects the ongoing evolution of rapidly evolving viruses such as HIV. By applying statistical approaches that account for phylogenetic relationships among viral sequences, we show that viral lineage effects rather than immune escape often explain apparent human leukocyte antigen (HLA)-mediated immune-escape mutations defined by older analysis methods. Phylogenetically informed methods identified immune-susceptible locations with greatly improved accuracy, and the associations we identified with these methods were experimentally validated. This approach has practical implications for understanding the impact of host immunity on pathogen evolution and for defining relevant variants for inclusion in vaccine antigens.     

Identification of signal peptide peptidase,a presenilin-type aspartic protease

Signal peptide peptidase (SPP) catalyzes intramembrane proteolysis of some signal peptides after they have been cleaved from a preprotein. In humans, SPP activity is required to generate signal sequence-derived human lymphocyte antigen-E epitopes that are recognized by the immune system, and to process hepatitis C virus core protein. We have identified human SPP as a polytopic membrane protein with sequence motifs characteristic of the presenilin-type aspartic proteases. SPP and potential eukaryotic homologs may represent another family of aspartic proteases that promote intramembrane proteolysis to release biologically important peptides.     

结核分枝杆菌RD1区T细胞表位分布情况预测及分析

[目的]对结核分枝杆菌RD1区T细胞表位分布情况进行预测和分析。[方法]利用NetMHC server生物信息学软件,以和HLA-Ⅱ和HLA-Ⅰ类分子结合能力为指标,分别对结核分枝杆菌RD1区9个编码蛋白进行T细胞抗原表位预测。[结果]通过预测,共获得和HLA-Ⅱ类分子结合的抗原表位1580个和HLA-Ⅰ类分子结合的抗原表位336个。[结论]预测获得的T细胞抗原表位将对结核病特异性检测及新的结核疫苗研发起到借鉴作用。     

The influence of allogeneic cells on the human T and B cell repertoire

Clinical transplantation is often complicated by rejection episodes, in which the immune system of the recipient reacts to the foreign transplantation (HLA) antigens on the graft. This immune response includes humoral and cellular components. In the first, B lymphocytes form antibodies to the HLA alloantigens. In the second, CD8+ T lymphocytes recognize and react to HLA class I antigens, and CD4+ T cells react to HLA class II antigens. The frequency and severity of these rejection episodes can be diminished by immunosuppressive drugs, HLA matching between donor and recipient, and immune modulation by blood transfusion. Effective HLA matching between donor and recipient is not always possible and often not necessary. Insight into the factors that influence the T and B cell repertoire after blood transfusion might lead to new approaches to improve graft survival.     

Disruption of the CFTR gene produces a model of cystic fibrosis in newborn pigs

Almost two decades after CFTR was identified as the gene responsible for cystic fibrosis (CF), we still lack answers to many questions about the pathogenesis of the disease, and it remains incurable. Mice with a disrupted CFTR gene have greatly facilitated CF studies, but the mutant mice do not develop the characteristic manifestations of human CF, including abnormalities of the pancreas, lung, intestine, liver, and other organs. Because pigs share many anatomical and physiological features with humans, we generated pigs with a targeted disruption of both CFTR alleles. Newborn pigs lacking CFTR exhibited defective chloride transport and developed meconium ileus, exocrine pancreatic destruction, and focal biliary cirrhosis, replicating abnormalities seen in newborn humans with CF. The pig model may provide opportunities to address persistent questions about CF pathogenesis and accelerate discovery of strategies for prevention and treatment.     

藏绵羊DQA1基因多态性分析

 【目的】研究藏绵羊DQA1基因多态性,确定其等位基因数、核苷酸多态位点、氨基酸多态位点及各等位基因间的遗传关系,同时分析其进化意义。【方法】采用PCR-SSCP方法检测了900只藏绵羊DQA1基因第2外显子多态性;克隆、测序群体内变异产生的各等位基因序列,并分析序列数据。【结果】发现了17个DQA1的等位基因,包括缺失的1种基因,其中5个为发现的新等位基因。16个单倍型序列中发现56个核苷酸多态位点,27个氨基酸多态位点。【结论】藏绵羊DQA1基因第2外显子具有丰富的多态性,群体中可能蕴藏着更多的遗传资源;藏绵羊DQA1基因最初可能是由2个等位基因突变分化成两大类等位基因的;藏绵羊DQA1基因第2外显子序列与牛的DQA1基因第2外显子序列具有较高的同源性,预示绵羊和牛的DQA1基因最早可能来源于它们分歧以前的共同祖先原始序列;DQA1基因在与其相关的特定抗原刺激下发生的免疫应答反应在绵羊和牛上具有相似性;新等位基因C的139位发现了1个新的核苷酸突变位点（A/G）,属同义突变;5个新发现的DQA1等位基因遗传关系较近,可能由同一等位基因突变产生。     

结核分枝杆菌RD1区T细胞表位分布情况预测及分析

[目的]对结核分枝杆菌RD1区T细胞表位分布情况进行预测和分析。[方法]利用NetMHC server生物信息学软件,以和HLA-Ⅱ和HLAⅠ-类分子结合能力为指标,分别对结核分枝杆菌RD1区9个编码蛋白进行T细胞抗原表位预测。[结果]通过预测,共获得和HLA-Ⅱ类分子结合的抗原表位1 580个和HLA-Ⅰ类分子结合的抗原表位336个。[结论]预测获得的T细胞抗原表位将对结核病特异性检测及新的结核疫苗研发起到借鉴作用。     

Genetic Analysis of Cold Tolerance at Seedling Stage and Heat Tolerance atAnthesis in Rice (Oryza sativa L.)

A set of 240 introgression lines derived from the advanced backcross population of a cross between a japonica cultivar,Xiushui 09, and an indica breeding line, IR2061, was developed to dissect QTLs affecting cold tolerance (CT) at seedlingstage and heat tolerance (HT) at anthesis. Survival rate of seedlings (SRS) and spikelet fertility (SF), the index traits of CTand HT, showed significant differences between the two parents under stresses. A total of four QTLs (qSRS1, qSRS7,qSRS11a and qSRS11b) for CT were identified on chromosomes 1, 7, 11, and the Xiushui 09 alleles increased SRS at all lociexcept qSRS7. Four QTLs for SF were identified on chromosomes 4, 5, 6, and 11. These QTLs could be classified into twomajor types based on their behaviors under normal and stress conditions. The first was QTL expressed only under normalcondition; and the second QTL was apparently stress induced and only expressed under stress. Among them, two QTLs(qSF4 and qSF6) which reduced the trait difference between heat stress and normal conditions must have contributed toHT because of their obvious contribution to trait stability, and the IR2061 allele at the qSF6 and the Xiushui 09 allele at the qSF4improved HT, respectively. No similar QTL was found between CT at seedling stage and HT at anthesis. Therefore, it ispossible to breed a new variety with CT and HT by pyramiding the favorable CT- and HT-improved alleles at above locifrom Xiushui 09 and IR2061, respectively, through marker-assisted selection (MAS).     

Induction of B cell unresponsiveness to noninherited maternal HLA antigens during fetal life

Patients who have received many transfusions become highly sensitized and develop antibodies against almost all HLA alloantigens, so that finding a cross-match negative kidney donor is difficult. A survey of those patients showed that 50 percent did not form antibodies against the noninherited maternal HLA antigens. Apart from the obvious clinical implications, the data indicate that a human equivalent of murine neonatal or actively acquired tolerance has now been identified.     

The southern route "out of Africa": evidence for an early expansion of modern humans into Arabia

The timing of the dispersal of anatomically modern humans (AMH) out of Africa is a fundamental question in human evolutionary studies. Existing data suggest a rapid coastal exodus via the Indian Ocean rim around 60,000 years ago. We present evidence from Jebel Faya, United Arab Emirates, demonstrating human presence in eastern Arabia during the last interglacial. The tool kit found at Jebel Faya has affinities to the late Middle Stone Age in northeast Africa, indicating that technological innovation was not necessary to facilitate migration into Arabia. Instead, we propose that low eustatic sea level and increased rainfall during the transition between marine isotope stages 6 and 5 allowed humans to populate Arabia. This evidence implies that AMH may have been present in South Asia before the Toba eruption.     

Gene interaction at HLA-DQ enhances autoantibody production in primary Sj?gren's syndrome

Primary Sj?gren's syndrome is an autoimmune disorder characterized by dryness of the mouth and eyes. The human leukocyte antigen (HLA) locus DQ is related to the primary Sj?gren's syndrome autoantibodies that bind the RNA proteins Ro/SSA and La/SSB. Both DQ1 and DQ2 alleles are associated with high concentrations of these autoantibodies. An analysis of all possible combinations at DQ has shown that the entire effect was due to heterozygotes expressing the DQ1 and DQ2 alleles. These data suggest that gene interaction between DQ1 and DQ2 (or alleles at associated loci), possibly from gene complementation of trans-associated surface molecules, influences the autoimmune response in primary Sj?gren's syndrome.