Serial translocation by means of circular intermediates underlies colour sidedness in cattle

Colour sidedness is a dominantly inherited phenotype of cattle characterized by the polarization of pigmented sectors on the flanks, snout and ear tips. It is also referred to as 'lineback' or 'witrik' (which means white back), as colour-sided animals typically display a white band along their spine. Colour sidedness is documented at least since the Middle Ages and is presently segregating in several cattle breeds around the globe, including in Belgian blue and brown Swiss. Here we report that colour sidedness is determined by a first allele on chromosome 29 (Cs(29)), which results from the translocation of a 492-kilobase chromosome 6 segment encompassing KIT to chromosome 29, and a second allele on chromosome 6 (Cs(6)), derived from the first by repatriation of fused 575-kilobase chromosome 6 and 29 sequences to the KIT locus. We provide evidence that both translocation events involved circular intermediates. This is the first example, to our knowledge, of a phenotype determined by homologous yet non-syntenic alleles that result from a novel copy-number-variant-generating mechanism.     

A Cenozoic record of the equatorial Pacific carbonate compensation depth

Atmospheric carbon dioxide concentrations and climate are regulated on geological timescales by the balance between carbon input from volcanic and metamorphic outgassing and its removal by weathering feedbacks; these feedbacks involve the erosion of silicate rocks and organic-carbon-bearing rocks. The integrated effect of these processes is reflected in the calcium carbonate compensation depth, which is the oceanic depth at which calcium carbonate is dissolved. Here we present a carbonate accumulation record that covers the past 53 million years from a depth transect in the equatorial Pacific Ocean. The carbonate compensation depth tracks long-term ocean cooling, deepening from 3.0-3.5?kilometres during the early Cenozoic (approximately 55?million years ago) to 4.6 kilometres at present, consistent with an overall Cenozoic increase in weathering. We find large superimposed fluctuations in carbonate compensation depth during the middle and late Eocene. Using Earth system models, we identify changes in weathering and the mode of organic-carbon delivery as two key processes to explain these large-scale Eocene fluctuations of the carbonate compensation depth.     

Accurate whole-genome sequencing and haplotyping from 10 to 20 human cells

Recent advances in whole-genome sequencing have brought the vision of personal genomics and genomic medicine closer to reality. However, current methods lack clinical accuracy and the ability to describe the context (haplotypes) in which genome variants co-occur in a cost-effective manner. Here we describe a low-cost DNA sequencing and haplotyping process, long fragment read (LFR) technology, which is similar to sequencing long single DNA molecules without cloning or separation of metaphase chromosomes. In this study, ten LFR libraries were made using only ～100?picograms of human DNA per sample. Up to 97% of the heterozygous single nucleotide variants were assembled into long haplotype contigs. Removal of false positive single nucleotide variants not phased by multiple LFR haplotypes resulted in a final genome error rate of 1 in 10?megabases. Cost-effective and accurate genome sequencing and haplotyping from 10-20 human cells, as demonstrated here, will enable comprehensive genetic studies and diverse clinical applications.     

Long‐run forecasting in multicointegrated systems

We extend the analysis of Christoffersen and Diebold (1998) on long‐run forecasting in cointegrated systems to multicointegrated systems. For the forecast evaluation we consider several loss functions, each of which has a particular interpretation in the context of stock‐flow models where multicointegration typically occurs. A loss function based on a standard mean square forecast error (MSFE) criterion focuses on the forecast errors of the flow variables alone. Likewise, a loss function based on the triangular representation of cointegrated systems (suggested by Christoffersen and Diebold) considers forecast errors associated with changes in both stock (modelled through the cointegrating restrictions) and flow variables. We suggest a new loss function based on the triangular representation of multicointegrated systems which further penalizes deviations from the long‐run relationship between the levels of stock and flow variables as well as changes in the flow variables. Among other things, we show that if one is concerned with all possible long‐run relations between stock and flow variables, this new loss function entails high and increasing forecasting gains compared to both the standard MSFE criterion and Christoffersen and Diebold's criterion. This paper demonstrates the importance of carefully selecting loss functions in forecast evaluation of models involving stock and flow variables. Copyright © 2004 John Wiley & Sons, Ltd.     

Block-Relaxation Approaches for Fitting the INDCLUS Model

A well-known clustering model to represent I?×?I?×?J data blocks, the J frontal slices of which consist of I?×?I object by object similarity matrices, is the INDCLUS model. This model implies a grouping of the I objects into a prespecified number of overlapping clusters, with each cluster having a slice-specific positive weight. An INDCLUS model is fitted to a given data set by means of minimizing a least squares loss function. The minimization of this loss function has appeared to be a difficult problem for which several algorithmic strategies have been proposed. At present, the best available option seems to be the SYMPRES algorithm, which minimizes the loss function by means of a block-relaxation algorithm. Yet, SYMPRES is conjectured to suffer from a severe local optima problem. As a way out, based on theoretical results with respect to optimally designing block-relaxation algorithms, five alternative block-relaxation algorithms are proposed. In a simulation study it appears that the alternative algorithms with overlapping parameter subsets perform best and clearly outperform SYMPRES in terms of optimization performance and cluster recovery.