A viable allele of Mcm4 causes chromosome instability and mammary adenocarcinomas in mice

Mcm4 (minichromosome maintenance-deficient 4 homolog) encodes a subunit of the MCM2-7 complex (also known as MCM2-MCM7), the replication licensing factor and presumptive replicative helicase. Here, we report that the mouse chromosome instability mutation Chaos3 (chromosome aberrations occurring spontaneously 3), isolated in a forward genetic screen, is a viable allele of Mcm4. Mcm4(Chaos3) encodes a change in an evolutionarily invariant amino acid (F345I), producing an apparently destabilized MCM4. Saccharomyces cerevisiae strains that we engineered to contain a corresponding allele (resulting in an F391I change) showed a classical minichromosome loss phenotype. Whereas homozygosity for a disrupted Mcm4 allele (Mcm4(-)) caused preimplantation lethality, Mcm(Chaos3/-) embryos died late in gestation, indicating that Mcm4(Chaos3) is hypomorphic. Mutant embryonic fibroblasts were highly susceptible to chromosome breaks induced by the DNA replication inhibitor aphidicolin. Most notably, >80% of Mcm4(Chaos3/Chaos3) females succumbed to mammary adenocarcinomas with a mean latency of 12 months. These findings suggest that hypomorphic alleles of the genes encoding the subunits of the MCM2-7 complex may increase breast cancer risk.     

Evolution and environment in the Hominoidea.

Between 10 and 20 million years ago, a variety of hominoid primates lived in Africa, Europe and Asia. The question of which of these, if any, lie closest to the ancestries of humans and modern apes remains a lively source of debate. Recent fossil discoveries, though, shed light on the environments in which the various groups of hominoid emerged and, it is hoped, on their evolution. But the lack of a hominid fossil record before about 5 million years ago--and any fossil record for the African apes--is still a frustrating barrier.     

A high-resolution survey of deletion polymorphism in the human genome

Recent work has shown that copy number polymorphism is an important class of genetic variation in human genomes. Here we report a new method that uses SNP genotype data from parent-offspring trios to identify polymorphic deletions. We applied this method to data from the International HapMap Project to produce the first high-resolution population surveys of deletion polymorphism. Approximately 100 of these deletions have been experimentally validated using comparative genome hybridization on tiling-resolution oligonucleotide microarrays. Our analysis identifies a total of 586 distinct regions that harbor deletion polymorphisms in one or more of the families. Notably, we estimate that typical individuals are hemizygous for roughly 30-50 deletions larger than 5 kb, totaling around 550-750 kb of euchromatic sequence across their genomes. The detected deletions span a total of 267 known and predicted genes. Overall, however, the deleted regions are relatively gene-poor, consistent with the action of purifying selection against deletions. Deletion polymorphisms may well have an important role in the genetics of complex traits; however, they are not directly observed in most current gene mapping studies. Our new method will permit the identification of deletion polymorphisms in high-density SNP surveys of trio or other family data.     

Forecasting with latent structure time series models: an application to nominal interest rates

In this paper we develop a latent structure extension of a commonly used structural time series model and use the model as a basis for forecasting. Each unobserved regime has its own unique slope and variances to describe the process generating the data, and at any given time period the model predicts a priori which regime best characterizes the data. This is accomplished by using a multinomial logit model in which the primary explanatory variable is a measure of how consistent each regime has been with recent observations. The model is especially well suited to forecasting series which are subject to frequent and/or major shocks. An application to nominal interest rates shows that the behaviour of the three‐month US Treasury bill rate is adequately explained by three regimes. The forecasting accuracy is superior to that produced by a traditional single‐regime model and a standard ARIMA model with a conditionally heteroscedastic error. Copyright © 1999 John Wiley & Sons, Ltd.     

Precursors to regulatory peptides: their proteolytic processing

Precursors to regulatory peptides undergo maturation processes which include proteolytic processing. The enzymes involved in this process remove the hydrophobic peptide located at the amino-terminus of the precursor. Endoprotease cleavage also occurs at single and two adjacent basic residues, this is followed by a removal of basic residues located at the C-terminus of the peptides by a carboxypeptidase-like enzyme.     

DNA sequence and analysis of human chromosome 9

Chromosome 9 is highly structurally polymorphic. It contains the largest autosomal block of heterochromatin, which is heteromorphic in 6-8% of humans, whereas pericentric inversions occur in more than 1% of the population. The finished euchromatic sequence of chromosome 9 comprises 109,044,351 base pairs and represents >99.6% of the region. Analysis of the sequence reveals many intra- and interchromosomal duplications, including segmental duplications adjacent to both the centromere and the large heterochromatic block. We have annotated 1,149 genes, including genes implicated in male-to-female sex reversal, cancer and neurodegenerative disease, and 426 pseudogenes. The chromosome contains the largest interferon gene cluster in the human genome. There is also a region of exceptionally high gene and G + C content including genes paralogous to those in the major histocompatibility complex. We have also detected recently duplicated genes that exhibit different rates of sequence divergence, presumably reflecting natural selection.