Using linked markers to infer the age of a mutation

Advances in sequencing and genotyping technologies over the last decade have enabled geneticists to easily characterize genetic variation at the nucleotide level. Hundreds of genes harboring mutations associated with genetic disease have now been identified by positional cloning. Using variation at closely linked genetic markers, it is possible to predict the times in the past at which particular mutations arose. Such studies suggest that many of the rare mutations underlying human genetic disorders are relatively young. Studies of variation at genetic markers linked to particular mutations can provide insights into human geographic history, and historical patterns of natural selection and disease, that are not available from other sources. We review two approaches for estimating allele age using variation at linked genetic markers. A phylogenetic approach aims to reconstruct the gene tree underlying a sample of chromosomes carrying a particular mutation, obtaining a “direct” estimate of allele age from the age of the root of this tree. A population genetic approach relies on models of demography, mutation, and/or recombination to estimate allele age without explicitly reconstructing the gene tree. Phylogenetic methods are best suited for studies of ancient mutations, while population genetic methods are better suited for studies of recent mutations. Methods that rely on recombination to infer the ages of alleles can be fine‐tuned by choosing linked markers at optimal map distances to maximize the information available about allele age. A limitation of methods that rely on recombination is the frequent lack of a fine‐scale linkage map. Maximum likelihood and Bayesian methods for estimating allele age that rely on intensive numerical computation are described, as well as “composite” likelihood and moment‐based methods that lead to simple estimators. The former provide more accurate estimates (particularly for large samples of chromosomes) and should be employed if computationally practical. Hum Mutat 18:87–100, 2001. © 2001 Wiley‐Liss, Inc.     

A Complementary Method for the Detection of Osteoblastic Metastases on Digitized Radiographs

Purpose This study was conducted to evaluate the diagnostic usefulness of gray level parameters in order to distinguish healthy bone from osteoblastic metastases on digitized radiographs. Materials and methods Skeletal radiographs of healthy bone (n = 144) and osteoblastic metastases (n = 35) were digitized using pixels 0.175 mm in size and 4,096 gray levels. We obtained an optimized healthy bone classification to compare with pathological bone: cortical, trabecular, and flat bone. The osteoblastic metastases (OM) were classified in nonflat and flat bone. These radiological images were analyzed by using a computerized method. The parameters (gray scale) calculated were: mean, standard deviation, and coefficient of variation (MGL, SDGL, and CVGL, respectively) based on gray level histogram analysis. Diagnostic utility was quantified by measurement of parameters on healthy and pathological bone, yielding quantification of area under the receiver operating characteristic (ROC) curve, AUC. Results All three image parameters showed high and significant values of AUC when comparing healthy trabecular bone and nonflat bone OM, showing MGL the best discriminatory ability (0.97). As for flat bones, MGL showed no ability to distinguish between healthy and flat bone OM (0.50). This could be achieved by using SDGL or CVGL, with both showing a similar diagnostic ability (0.85 and 0.83, respectively). Conclusion Our results show that the use of gray level parameters quantify healthy bone and osteoblastic metastases zones on digitized radiographs. This may be helpful as a complementary method for differential diagnosis. Moreover, our method will allow us to study the evolution of osteoblastic metastases under medical treatment.     

Identification of the novel allele HLA-A*6813 in two members of a family of Syrian origin: implications for bone marrow transplantation

The identification of the new allele HLA-A*6813, which was found in a woman of Syrian origin and her son, is described. In the sequence analysis the new allele differs from A*68011 by positions 259 (A>G) and 261 (C>G) in exon 2. As the structure is thus identical to the HLA-A consensus sequence it is likely that the new allele originated by gene conversion. At the protein level, the new allele has one amino acid difference from A*6801 (Asn63Glu), which results in a distinct banding pattern in one dimensional-isoelectric focusing. Amino acid residue 63 contributes to the formation of pocket A and B and is thus important for peptide binding. A*6813 was serologically detectable only by two of six polyclonal, but by three monoclonal antisera. The restricted serological A68 activity may be explained by altered peptide binding as presented peptides can affect the serological recognition of major histocompatibility complex (MHC) class I molecules. Moreover, our findings suggest that a possible mismatch with the other known A*68 variants may impair clinical outcome of bone marrow transplantation.     

Mild emphysema: a novel method using formalin-fixed lungs for computed tomography and pathological analyses

We evaluated a novel method of computed tomography (CT) analysis using formalin-fixed lungs of autopsy cases with mild emphysema. Eight formalin-inflated lungs (FILs) obtained at autopsy were examined using CT after draining off the formalin and air inflation with an air pump, and subjected to pathological study including pathological scoring of emphysema and microscopic image analysis (MIA). Satisfactory CT examination was carried out within 5 h of lung fixation. The mean alveolar area determined by MIA correlated highly with the lung volume (r=0.845) and CT score (r=0.722). This method is simple compared with conventional polyethylene glycol fixation for CT and enables CT examination of resected lungs without anxiety about biohazards. Mild emphysema can be detected by MIA.     

以傅立叶频谱滤波为手段的振荡电位波形分离方法

为克服传统方法(Calliper-square)和带通放大器在测量振荡电位(OPs)中的不足,应用计算机傅立叶频谱滤波技术,从ERG中分离出振荡电位波形。分离出的OPs能够摆脱a-波,b-波对它的影响而独立地表现出来,使得对OPs的测量变得直观、方便、准确,并把对ERG、OPs的研究,从时域分析扩展到频域分析。     

Effect of generalized seizures on the structure of the sleep-waking cycle and the EEG in rats with an inherited predisposition to audiogenic convulsions

Data are presented on the effects of generalized tonic-clonic seizures on the structure of the one-day sleep-waking cycle in Krushinskii-Molodkina (KM) rats, which have a genetic predisposition to audiogenic convulsions. Spectral and correlation analysis of EEG activity in the hippocampus, caudate nucleus, medial central nucleus of the thalamus, and in the somatosensory, visual, and auditory regions of the cortex of these animals was carried out for time intervals before and after convulsions. After seizures, rats showed a prolonged (up to 3.5 h) reduction in fast-wave sleep (FWS) with no subsequent compensatory increase in this shase in the sleep-waking cycle, while a disturbance in slow-wave sleep (SWS) was minor and short-lived (not more than 2 h). It is suggested that generalized paroxysmal attacks predominantly involve disorganization of the function of the systems regulating FWS, while the synchronizing mechanisms of the brain, responsible for SWS, are affected to a lesser extent. Laboratory of the Evolution of Sleep and Waking (Director G. A. Oganesyan), I. M. Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, St. Petersburg. Translated from Fiziologicheskii Zhurnal imeni I. M. Sechenova, Vol. 81, No. 10, pp. 1–8, October, 1995.     

大学生就业效能量表的编制

目的编制适用于我国大学生的就业的效能量表。方法在深入访谈和文献综述的基础上，编制出大学生就业效能量表，运用探索性和验证性因素分析技术对568名全日制在校本科生的就业效能的内在结构进行了探讨。结果大学生就业效能主要有3个因素组成：个性自我了解、就业信息与技能和就业应对信心，问卷的各项测量指标良好。结论本问卷可以作为测量大学生就业效能的工具。