A mouse model of human L1 retrotransposition

The L1 retrotransposon has had an immense impact on the size and structure of the human genome through a variety of mechanisms, including insertional mutagenesis. To study retrotransposition in a living organism, we created a mouse model of human L1 retrotransposition. Here we show that L1 elements can retrotranspose in male germ cells, and that expression of a human L1 element under the control of its endogenous promoter is restricted to testis and ovary. In the mouse line with the highest level of L1 expression, we found two de novo L1 insertions in 135 offspring. Both insertions were structurally indistinguishable from natural endogenous insertions. This suggests that an individual L1 element can have substantial mutagenic potential. In addition to providing a valuable in vivo model of retrotransposition in mammals, these mice are an important step in the development of a new random mutagenesis system.     

A cluster of cystic fibrosis mutations in the first nucleotide-binding fold of the cystic fibrosis conductance regulator protein.

The gene responsible for cystic fibrosis (CF) has recently been identified and is predicted to encode a protein of 1,480 amino acids called the CF transmembrane conductance regulator (CFTR). Several functional regions are thought to exist in the CFTR protein, including two areas for ATP-binding, termed nucleotide-binding folds (NBFs), a regulatory (R) region that has many possible sites for phosphorylation by protein kinases A and C, and two hydrophobic regions that probably interact with cell membranes. The most common CF gene mutation leads to omission of phenylalanine residue 508 in the putative first NBF, indicating that this region is functionally important. To determine whether other mutations occur in the NBFs of CFTR, we determined the nucleotide sequences of exons 9, 10, 11 and 12 (encoding the first NBF) and exons 20, 21 and 22 (encoding most of the second NBF) from 20 Caucasian and 18 American-black CF patients. One cluster of four mutations was discovered in a 30-base-pair region of exon 11. Three of these mutations cause amino-acid substitutions at residues that are highly conserved among the CFTR protein, the multiple-drug-resistance proteins and ATP-binding membrane-associated transport proteins. The fourth mutation creates a premature termination signal. These mutations reveal a functionally important region in the CFTR protein and provide further evidence that CFTR is a member of the family of ATP-dependent transport proteins.     

上市公司经营活动状况对金融资产规模影响探究

越来越多的非金融业上市公司开始参与金融投资.通过实证研究来探索非金融业上市公司经营状况对其金融资产投资规模的影响,发现上市公司的金融资产有显著规模效应,同一行业内经营活动状况较好的上市公司有较少的金融投资,经营活动收入稳定增长的上市公司有较少的金融投资.     

Recurrent mutations in haemophilia A give evidence for CpG mutation hotspots

Haemophilia A is a common disorder of blood coagulation caused by a deficiency of factor VIII. It is inherited as an X-linked recessive trait, and one-third of all cases are thought to result from de novo mutations. The clinical severity of haemophilia A varies markedly among different families and a subset of the patients with severe disease develop antibodies against factor VIII, called inhibitors. Because of this heterogeneity, it is likely that many different molecular lesions result in haemophilia A. Indeed, of the nine mutations described to date, all appear to be unique changes. However in this study of 83 patients with haemophilia A we have identified two different point mutations, one in exon 18 and one in exon 22, that have recurred independently in unrelated families. Each mutation produces a nonsense codon by a change of CG to TG, and each occurred de novo on the X-chromosome donated by the maternal grandfather. These observations strongly support the view that CpG dinucleotides are mutation hotspots.