Global gene expression as a function of germline genetic variation

Common, functional, germline genetic polymorphisms have been associated with clinical cancer outcomes. Little attention has been paid to the potential phenotypic consequences of germline genetic variation on downstream genes. We determined the germline status of 16 well-characterized functional polymorphisms in 126 children with newly diagnosed acute lymphoblastic leukemia (ALL). We assessed whether global gene expression profiles of diagnostic ALL blasts from the same patients differed by these germline polymorphic genotypes. Gene expression values were adjusted for ALL-subtype-specific patterns. Of the 16 loci, only the UGT1A1 promoter repeat polymorphism [A(TA)nTAA] (UGT1A1*28) and GSTM1 deletion were significant predictors of global gene expression in a supervised approach, which divided patients based on their germline genotypes [UGT1A1: 124 probe sets, false discovery rate (FDR)=13%, P< or =0.0031; GSTM1: 112 probe sets, FDR=42.5%, P< or =0.0084]. Genes whose expression distinguished the UGT1A1 (TA) 7/7 genotype from the other UGT1A1 genotypes included HDAC1, RELA and SLC2A1; those that distinguished the GSTM1 null genotype from non-null genotype included NBS1 and PRKR. In an unsupervised approach, the gene expression profiles using the entire array delineated two major clusters of patients. The only germline genotype frequency that differed between the two clusters was UGT1A1 (P=0.002; Fisher's exact test). Although their expression is limited to specific tissues, both GSTM1 and UGT1A1 are involved in the conjugation (and thus transport, excretion and lipophilicity) of a broad range of endobiotics and xenobiotics, which could plausibly have consequences for gene expression in different tissues.     

Genetic diversity of HLA-A2: evolutionary and functional significance

HLA-A2 is the most common HLA class I specificity and is found at high frequency in most populations. Recent studies have shown that this specificity is encoded by at least 17 different alleles, whose distribution varies markedly between different populations. Here, Michael Browning and Peter Krausa explore the evolutionary and functional significance of the genetic diversity within HLA-A2.     

Molecular characterization of the human immunoglobulin V lambda I germline gene repertoire.

To advance our understanding of the human immunoglobulin V lambda germline gene contribution to normal as well as autoimmune responses, we have isolated and sequenced six germline genes of the V lambda I subgroup. These genes can be divided into three sub-subgroups on the basis of greater than or equal to 93% nucleotide sequence homology and greater than or equal to 88% deduced amino acid sequence similarity. Examination of all cDNA and protein sequences available for expressed V lambda I genes supports the assignment of these three sub-subgroups. Sequence comparisons also suggest that germline gene members of two of these sub-subgroups, I-a and I-b, are preferentially utilized in the expressed V lambda I repertoire. This finding may be at least partially attributable to regulatory sequence abnormalities apparent in two of the other V lambda I germline genes (Humlv101 and Humlv104) which may interfere with their expression.     

The evolutionary origin and significance of menopause

Contemporary women have long life expectancy (81 y, United States), especially relative to the age at menopause (51 y, United States). Menopause is a consequence of reproductive aging and follicular depletion (ovarian failure), yielding very low circulating estrogen serum concentrations and biologically disadvantageous metabolic alterations. Stated in terms of antagonistic pleiotropy, the ongoing hypoestrogenic endocrine environment, beneficial during lactation, results in acceleration of several age-related illnesses after menopause (ie, late postmenopausal osteoporosis, cardiovascular disease, and cognitive decline). Specifically, the similar hypoestrogenic hormonal milieu present during postpartum lactation provides biologic advantages (fitness) to both mother and newborn. These precepts of evolutionary medicine encourage a reassessment of hormone therapy, and on the basis of data presented the authors propose additional opportunities for disease prevention and morbidity reduction in postmenopausal women.     

Genomic organization of the immunoglobulin light chain gene loci in Xenopus tropicalis: evolutionary implications

Based on presently available genome data, we characterized the genomic organization of all three light chain gene (rho, sigma and type III) loci in Xenopus tropicalis. The rho gene locus in X. tropicalis, structurally similar to the kappa gene loci in mammals, was shown to contain a single C rho gene and nine J rho segments. The sigma locus also contains a single C gene, although two distinct C sigma genes have previously been found in Xenopus laevis (most likely due to chromosome polyploidy). Four J sigma gene segments were identified upstream of the C sigma. The type III light chain gene locus, spanning approximately 170 kb DNA, structurally resembles the topology of mammalian lambda gene loci, containing three C genes (C III 1-3). C III 2 and C III 3 are both preceded by single, unique, J genes, whereas C III 1 contains three J gene segments. Furthermore, two additional J gene segments, termed J III x1 and J III x2, were found in the intron separating V III 2 and pV III 1 (a pseudogene). Based on BLAST searches against the X. tropicalis EST database, all the C genes identified in this study were shown to be functional. On the basis of similarity of protein sequences, genomic organization and chromosomal location of the light chain genes among frogs and mammals, our data strongly support the previous suggestions that the rho genes belong to the kappa gene lineage, whereas the type III genes share a common origin with the lambda genes.     

The serotonin transporter gene and functional and pathological adaptation to environmental variation across the life span

In analogy with the accepted view that behaviour is shaped by gene × environment (G × E) interactions, G × E studies are exponentially increasing in the field of psychiatry. Whereas research was primarily driven by the premature view that negative environmental stimuli can trigger psychopathology in those subjects that are genetically predisposed, a closer look at the available data shows that G × E interactions are much more complex than initially thought. Here, we discuss G × E studies focussing on serotonin transporter (5-HTT, SERT, SLC6A4) gene variation in humans, monkeys, and rodents. Recent studies, across species, confirm the theorized ‘for-better-and-for-worse’ effect of low activity serotonin transporter genotypes. In addition, while 5-HTT × E interactions were thought to take place in early life, recent evidence illustrates that these interactions are also manifested in adulthood. Therefore, we discuss data based on 5-HTT × E interactions, and propose a model in which predictive adaptive responses (PARs), as shaped by early life 5-HTT × E interactions, shape responses to environmental challenges in later life, i.e. reflecting 5-HTT × E × E interactions.     

基于CT三维重建的肩胛上角形态学分型及临床意义

目的　探讨基于CT重建的肩胛上角形态学分型及临床意义。 方法　根据志愿者肩胛骨CT重建形态进行分型。设肩胛上角为A点,肩胛切迹最低点为B点,肩胛冈与肩胛骨内侧缘之交点为C点,A点在CE连线上的垂点为D点,冈盂切迹为E点,肩胛下角最低点为F点。研究参数：A点厚度;AB、AC、AD距离;∠A（AB连线与AC连线的夹角）;∠ACF在矢状面的度数;∠ACF在冠状面的度数。 结果　CT重建下肩胛上角分为3型：山丘型48%,冠状面∠A（93.76±7.69）°;山峰型47%,冠状面∠A（86.69±6.23）°;烟囱型5%,冠状面∠A（85.33±7.10）°。其中,山丘型及烟囱型A点均较山峰型薄（P<0.05）;在AB、AC、AD、∠A、∠ACF（冠状面）中,山丘型与山峰型对比有统计学差异（P<0.05）;在AD、∠A中,山丘型与烟囱型对比有统计学差异（P<0.05）。 结论　CT重建下肩胛上角分为3型：山丘型、山峰型、烟囱型;不同的肩胛上角分型可能对颈肩痛及肩胛提肌综合症有着潜在的影响。