BACKGROUND & AIMS: -2

背景与目标： -2

BACKGROUND & AIMS: -2

背景与目标： -2

BACKGROUND & AIMS: -2

背景与目标： -2

BACKGROUND & AIMS: -2

背景与目标： -2

BACKGROUND & AIMS: -2

背景与目标： -2

BACKGROUND & AIMS: -2

背景与目标： -2

BACKGROUND & AIMS: BACKGROUND:Klippel-Feil syndrome (KFS) represents a rare anomaly characterized by congenital fusion of the cervical vertebrae. The underlying molecular etiology remains largely unknown because of the genetic and phenotypic heterogeneity. METHODS:We consecutively recruited a Chinese cohort of 37 patients with KFS. The clinical manifestations and radiological assessments were analyzed and whole-exome sequencing (WES) was performed. Additionally, rare variants in KFS cases and controls were compared using genetic burden analysis. RESULTS:We primarily examined rare variants in five reported genes (GDF6, MEOX1, GDF3, MYO18B and RIPPLY2) associated with KFS and detected three variants of uncertain significance in MYO18B. Based on rare variant burden analysis of 96 candidate genes related to vertebral segmentation defects, we identified BAZ1B as having the highest probability of association with KFS, followed by FREM2, SUFU, VANGL1 and KMT2D. In addition, seven patients were proposed to show potential oligogenic inheritance involving more than one variants in candidate genes, the frequency of which was significantly higher than that in the in-house controls. CONCLUSIONS:Our study presents an exome-sequenced cohort and identifies five novel genes potentially associated with KFS, extending the spectrum of known mutations contributing to this syndrome. Furthermore, the genetic burden analysis provides further evidence for potential oligogenic inheritance of KFS.

背景与目标： 背景：Klippel-Feil综合征（KFS）代表一种罕见的异常，其特征是先天性颈椎融合。由于遗传和表型的异质性，潜在的分子病因仍是未知之数。
方法：我们连续招募了37例KFS患者的中国队列。分析了临床表现和放射学评估，并进行了全外显子测序（WES）。此外，使用遗传负担分析比较了KFS病例和对照中的罕见变异。
结果：我们主要检查了与KFS相关的五个报告基因（GDF6，MEOX1，GDF3，MYO18B和RIPPLY2）中的稀有变异体，并检测到MYO18B中三个具有不确定意义的变异体。基于对与椎骨节段缺陷相关的96个候选基因的罕见变异负荷分析，我们确定BAZ1B与KFS关联的可能性最高，其次是FREM2，SUFU，VANGL1和KMT2D。此外，提议了7名患者表现出潜在的寡聚遗传，涉及候选基因中的一种以上变异，其发生频率显着高于内部对照中的变异。
结论：我们的研究提出了一个外显子组测序队列，并鉴定了可能与KFS相关的五个新基因，从而扩展了导致该综合征的已知突变的范围。此外，遗传负担分析为KFS的潜在寡聚遗传提供了进一步的证据。

BACKGROUND & AIMS: :Persistent hyperplastic primary vitreous (PHPV) is an idiopathic congenital malformation confined to the eye that has no obvious cause and that is usually unilateral and sporadic. The clinical features of the classic PHPV syndrome include white, vascularized tissue covering some or all of the posterior surface of the lens; centrally dragged ciliary processes; secondary glaucoma caused by swelling of the lens or caused by contracture of the retrolental tissue, with anterior shifting of the lens-iris diaphragm; extensive intravitrael hemorrhaging; persistence of the hyaloid artery; and occasionally retinal detachment. In the present study we describe a patient with bilateral PHPV not associated with other diseases. Normal developmental milestones were reported. Family pedigree analysis revealed a similarly affected father, grandfather, 2 aunts, 1 paternal uncle and a grand uncle with 2 affected daughters. On examination the height, weight and skull circumference were on the 5th percentile. Bilateral B&A eye scan ultrasonography (B mode is two dimensional brightness mode ultrasonography, while A mode is one dimensional where echoes are represented by spikes of variable amplitude and timing) of both the patient and the father revealed a picture suggestive of persistent hyperplastic primary vitreous. Cytogenetics study by conventional culture technique using the CTG banding technique revealed a normal male karyotype 46, XY for both of them. Review of the London Dysmorphology Data Base (LDDB), OMIM, and recent medical literature revealed that this case to our knowledge represents the second report supporting autosomal dominant inheritance of PHPV not associated with other anomalies.

背景与目标： 永久性原发性玻璃体增生症（PHPV）是一种特发性先天性畸形，局限于眼睛，无明显原因，通常为单侧和散发性。经典的PHPV综合征的临床特征包括覆盖白色或部分晶状体后表面的白色血管组织。集中拖拉睫状过程；由晶状体肿胀或由后突组织挛缩引起的继发性青光眼，晶状体-虹膜隔膜前移；大量玻璃体内出血；舌骨动脉的持续性;偶尔视网膜脱离。在本研究中，我们描述了双侧PHPV与其他疾病无关的患者。报告了正常的发展里程碑。家庭血统分析显示，父亲，祖父，2个阿姨，1个父亲叔叔和1个有2个受影响女儿的祖父也受到同样的影响。经检查，身高，体重和颅骨围在第5个百分点。患者和父亲的双侧B＆A眼部扫描超声检查（B模式是二维亮度模式超声检查，而A模式是一维，其中回声由可变幅度和定时的尖峰表示），显示出提示持续性增生性原发性玻璃体的图像。通过常规培养技术使用CTG显带技术进行细胞遗传学研究，发现两者均具有正常的男性核型46，XY。对伦敦变形形态数据库（LDDB），OMIM和最新医学文献的审查显示，据我们所知，此病例代表了第二个支持PHPV的常染色体显性遗传而不与其他异常相关的报告。

BACKGROUND & AIMS: :Certain long-distance migratory animals, such as salmon and sea turtles, are thought to imprint on the magnetic field of their natal area and to use this information to help them return as adults. Despite a growing body of indirect support for such imprinting, direct experimental evidence thereof remains elusive. Here, using the fruit fly as a magnetoreceptive model organism, we demonstrate that exposure to a specific geographic magnetic field during a critical period of early development affected responses to a matching magnetic field gradient later in life. Specifically, hungry flies that had imprinted on a specific magnetic field from 1 of 3 widely separated geographic locations responded to the imprinted field, but not other magnetic fields, by moving downward, a geotactic behavior associated with foraging. This same behavior occurred spontaneously in the progeny of the next generation: female progeny moved downward in response to the field on which their parents had imprinted, whereas male progeny did so only in the presence of these females. These results represent experimental evidence that organisms can learn and remember a magnetic field to which they were exposed during a critical period of development. Although the function of the behavior is not known, one possibility is that imprinting on the magnetic field of a natal area assists flies and their offspring in recognizing locations likely to be favorable for foraging and reproduction.

背景与目标： ：某些远距离迁徙动物，例如鲑鱼和海龟，被认为会印在其出生地的磁场上，并利用这些信息帮助它们成年后返回。尽管越来越多的人间接支持这种压印，但其直接实验证据仍然难以捉摸。在这里，我们使用果蝇作为磁感受模型生物，证明了在早期发育的关键时期暴露于特定的地理磁场会影响生命后期对匹配的磁场梯度的响应。具体而言，已经从3个相距较远的地理位置中的1个上烙印在特定磁场上的饥饿的苍蝇通过向下移动来响应与该觅食相关的地势行为，从而对烙印的磁场做出了响应，但对其他磁场没有响应。相同的行为在下一代的子代中自发发生：雌性子代响应其父母的足迹而向下移动，而雄性子代只有在这些雌性的存在下才这样做。这些结果代表了实验证据，表明生物体可以学习和记住在关键的发育时期所暴露于的磁场。尽管行为的功能尚不清楚，但一种可能性是，在出生区域的磁场上留下印记有助于苍蝇及其后代识别可能有利于觅食和繁殖的位置。

BACKGROUND & AIMS: :Cutaneous malignant melanoma in Sinclair swine is a hereditary disease that develops in utero or during the first 6 weeks of life. In many cases, the tumors regress and piglets survive the disease. Two different sets of gene(s) might be involved in the disease: tumor initiator (suppressor) locus or loci and loci affecting the aggressiveness of the disease (number and stage of tumors). We develop maximum-likelihood methods for interval mapping for both types of loci. The experimental design consisted of a boar mated to tumor-bearing sows with recording of tumor status and number of tumors in the 6 weeks of life of the offspring. The model to search for the tumor initiator locus (with alleles T and t) was tested by computer simulation. Estimates of penetrances (Psi(TT) and Psi(Tt) for genotypes TT and Tt, respectively) were accurate even for small family sizes. Statistical power was >99% for a family size of 70 with Psi(TT) = 1 and Psi(Tt) = 0. The models to test for number of tumors incorporated genotype information for the tumor initiator locus. All models were tested with data from a single boar family of 72 piglets over swine chromosomes 6 and 8 (SSC6 and SSC8). No tumor evidence for initiator loci was found associated with these chromosomes. However, association of a QTL affecting number of tumors at birth near microsatellite SW1953 on SSC8 was chromosomewise significant (P<0.0124).

背景与目标： ：辛克莱猪的慢性恶性黑色素瘤是一种遗传性疾病，会在子宫内或生命的前6周内发展。在许多情况下，肿瘤消退，仔猪在疾病中幸存下来。该疾病可能涉及两套不同的基因：肿瘤引发剂（抑制子）基因座或基因座，以及影响疾病侵袭性（肿瘤的数量和阶段）的基因座。我们为两种基因座的区间作图开发了最大似然法。实验设计包括一个与带有肿瘤的母猪交配的公猪，并记录后代6周内的肿瘤状态和肿瘤数量。通过计算机模拟测试了用于寻找肿瘤引发剂基因座（具有等位基因T和t）的模型。外显率的估计（基因型TT和Tt分别为Psi（TT）和Psi（Tt））即使对于小型家庭来说也很准确。对于Psi（TT）= 1和Psi（Tt）= 0的70个家庭，统计功效> 99％。用于测试肿瘤数量的模型并入了肿瘤起始基因位点的基因型信息。所有模型均使用来自猪的第6和8号染色体（SSC6和SSC8）的72个仔猪的单个公猪家族的数据进行了测试。没有发现与这些染色体相关的起始位点的肿瘤证据。但是，影响SSC8上微卫星SW1953附近出生时肿瘤数量的QTL的关联在染色体上是显着的（P <0.0124）。

BACKGROUND & AIMS: :Beta thalassemia minor phenotypes with normal HbA2 levels and decreased MCV and MCH values are relatively rare beta-thalassemia traits. Here, we describe a case with normal HbA2 and decreased MCV and MCH level. Amplification refractory mutation system-polymerase chain reaction(ARMS-PCR) revealed IVS I-1 (G-->T) mutation in the beta-globin gene. Direct sequencing of the delta-globin gene revealed a previously reported Hb variant called Hb A2 Etolia (Gene Bank Accession No. DQ106871). This is the first case reporting HbA2 Etolia in association with the beta-IVS I-1 (G-->T) mutation in Iran. Reduced HbA2 expression by a co-inherited HbA2 variant resulting in decreased HbA2, in Cis or Trans, may cause problems in carrier diagnostics and eventually in genetic counseling and prenatal diagnosis when insufficient molecular analyses are performed.

背景与目标： HbA2水平正常且MCV和MCH值降低的β地中海贫血少数表型是相对罕见的β地中海贫血特征。在这里，我们描述了HbA2正常且MCV和MCH水平降低的情况。扩增难治性突变系统-聚合酶链反应（ARMS-PCR）显示β-珠蛋白基因中存在IVS I-1（G-> T）突变。 δ-珠蛋白基因的直接测序揭示了先前报道的称为Hb A2 Etolia的Hb变体（基因库登录号DQ106871）。这是伊朗第一例报告HbA2埃托利亚与β-IVSI-1（G-> T）突变有关的病例。通过共继承的HbA2变体降低的HbA2表达，导致顺式或反式中的HbA2降低，可能会在进行分子分析不足时导致携带者诊断以及遗传咨询和产前诊断方面的问题。

BACKGROUND & AIMS: :Over the last decades, the prevalence of myopia has suddenly increased, and at this rate, half of the world's population will be myopic by the year 2050. Contemporary behavioural and lifestyle circumstances, along with emergent technology, are thought to be responsible for this increase. Twin studies mostly reported a high heritability of refractive error across ethnicities. However, heritability is a population statistic and could vary as a result of changing environmental conditions. We studied the variance of refractive error in millennials with 100 twin pairs of university students in southeast Spain. The study population presented a high prevalence of myopia (77%). Statistical analysis showed the variance of refractive error in this group of young twins was mainly driven by the shared environment and, to a lesser extent, by additive genetic factors. We found an increase in myopia prevalence accompanied by a decrease in heritability in this sample of millennials in contrast with results from a previous generation group from the same ethnic origin.

背景与目标： ：在过去的几十年中，近视的患病率突然增加，到2050年，以这个速度，全世界一半的人口将成为近视眼。当代的行为和生活方式以及新兴的技术被认为是造成近视的原因。增加。双胞胎研究大多报告了跨种族屈光不正的遗传性。但是，遗传力是人口统计数据，可能会由于环境条件的变化而有所不同。我们研究了西班牙东南部100对双胞胎大学生在千禧一代中屈光不正的方差。研究人群的近视患病率很高（77％）。统计分析表明，这对年轻双胞胎的屈光不正的变化主要是由共同的环境所驱动，在较小程度上是由累加遗传因素所驱动。我们发现，与来自同一族裔的上一代人的研究结果相比，该千禧一代样本中近视患病率增加，而遗传力却下降。

BACKGROUND & AIMS: :Dissecting the genetic architecture of quantitative traits in autotetraploid species is a methodologically challenging task, but a pivotally important goal for breeding globally important food crops, including potato and blueberry, and ornamental species such as rose. Mapping quantitative trait loci (QTLs) is now a routine practice in diploid species but is far less advanced in autotetraploids, largely due to a lack of analytical methods that account for the complexities of tetrasomic inheritance. We present a novel likelihood-based method for QTL mapping in outbred segregating populations of autotetraploid species. The method accounts properly for sophisticated features of gene segregation and recombination in an autotetraploid meiosis. It may model and analyse molecular marker data with or without allele dosage information, such as that from microarray or sequencing experiments. The method developed outperforms existing bivalent-based methods, which may fail to model and analyse the full spectrum of experimental data, in the statistical power of QTL detection, and accuracy of QTL location, as demonstrated by an intensive simulation study and analysis of data sets collected from a segregating population of potato (Solanum tuberosum). The study enables QTL mapping analysis to be conducted in autotetraploid species under a rigorous tetrasomic inheritance model.

背景与目标： ：剖析同源四倍体物种数量性状的遗传结构在方法上具有挑战性，但对于育种具有全球重要性的粮食作物（包括马铃薯和蓝莓）以及观赏物种（如玫瑰）而言，是至关重要的目标。绘制数量性状基因座（QTL）现在是二倍体物种的常规做法，但在同源四倍体中进展较差，这主要是由于缺乏解释四体遗传复杂性的分析方法。我们提出了一种新的基于似然的方法在四倍体物种的近交隔离种群中进行QTL定位。该方法适当考虑了同源四倍体减数分裂中基因分离和重组的复杂特征。它可以使用或不使用等位基因剂量信息（例如来自微阵列或测序实验的等位基因剂量信息）对分子标记数据进行建模和分析。深入的模拟研究和数据集分析证明，开发的方法优于现有的基于二价的方法，后者可能无法在QTL检测的统计能力和QTL定位准确性方面对实验数据的全部范围进行建模和分析。从隔离的马铃薯种群中收获。该研究使得能够在严格的四体遗传模型下对四倍体物种进行QTL定位分析。

BACKGROUND & AIMS: :Alterations in epigenetic silencing have been associated with ageing and tumour formation. Although substantial efforts have been made towards understanding the mechanisms of gene silencing, novel regulators in this process remain to be identified. To systematically search for components governing epigenetic silencing, we developed a genome-wide silencing screen for yeast (Saccharomyces cerevisiae) silent mating type locus HMR. Unexpectedly, the screen identified the mismatch repair (MMR) components Pms1, Mlh1, and Msh2 as being required for silencing at this locus. We further found that the identified genes were also required for proper silencing in telomeres. More intriguingly, the MMR mutants caused a redistribution of Sir2 deacetylase, from silent mating type loci and telomeres to rDNA regions. As a consequence, acetylation levels at histone positions H3K14, H3K56, and H4K16 were increased at silent mating type loci and telomeres but were decreased in rDNA regions. Moreover, knockdown of MMR components in human HEK293T cells increased subtelomeric DUX4 gene expression. Our work reveals that MMR components are required for stable inheritance of gene silencing patterns and establishes a link between the MMR machinery and the control of epigenetic silencing.

背景与目标： ：表观遗传沉默的改变与衰老和肿瘤形成有关。尽管已经在理解基因沉默的机理上做出了巨大的努力，但是在这一过程中仍需要确定新的调节子。为了系统地搜索控制表观遗传沉默的成分，我们开发了用于酵母（酿酒酵母）沉默交配型基因座HMR的全基因组沉默筛选。出乎意料的是，屏幕将不匹配修复（MMR）组件Pms1，Mlh1和Msh2标识为在此基因座处沉默所需。我们进一步发现，鉴定出的基因对于端粒的正确沉默也是必需的。更有趣的是，MMR突变体引起了Sir2脱乙酰基酶的重新分布，从沉默的交配型基因座和端粒到rDNA区域。结果，在沉默交配型基因座和端粒处，组蛋白位置H3K14，H3K56和H4K16处的乙酰化水平增加，但在rDNA区域中降低。此外，在人类HEK293T细胞中敲低MMR组件可增加亚端粒DUX4基因表达。我们的工作表明，MMR组件是基因沉默模式稳定遗传所必需的，并且在MMR机制与表观遗传沉默的控制之间建立了联系。

BACKGROUND & AIMS: :In eukaryotic cells, cellular functions are compartmentalized into membrane-bound organelles. This has many advantages, as shown by the success of the eukaryotic lineage, but creates many problems for cells, such as the need to build and partition these organelles during cell growth and division. Diverse mechanisms for biogenesis of the endoplasmic reticulum and Golgi apparatus have evolved, ranging from de novo synthesis to the copying of a template organelle. The different mechanisms by which organelles are inherited in yeasts, protozoa and metazoans probably reflect the differences in the structure and copy number of these organelles.

背景与目标： 在真核细胞中，细胞功能被分隔成膜结合的细胞器。如真核细胞系的成功所表明的那样，这具有许多优点，但是给细胞带来了许多问题，例如在细胞生长和分裂过程中需要建立和分配这些细胞器。内质网和高尔基体生物发生的各种机制已经发展，从新合成到模板细胞器的复制。酵母，原生动物和后生动物中细胞器遗传的不同机制可能反映了这些细胞器的结构和拷贝数的差异。