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The mixture of maternal and paternal sets of chromosomes in diploid organisms makes it difficult to determine haplotypes. Fan et al. and Kitzman et al. describe experimental approaches to genome-wide haplotyping using microfluidics and multiplexed large-insert cloning, respectively. Credit: Marina Corral & Erin Dewalt, based on Colored LM of a normal male karyotype by L. Willatt, East Anglian Regional Genetics Service/Photo Researchers, Inc.
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The Japanese Intellectual Property High Court recently issued two decisions that bolster the market exclusivity period for brand biologic manufacturers.
Experimental haplotyping of whole genomes is now feasible, enabling new studies aimed at linking sequence variation to human phenotypes and disease susceptibility.
Interviews with leading scientists highlight several notable breakthroughs in computational biology from the past year and suggest areas where computation may drive biological discovery.
The two copies of each chromosome in a diploid organism may contain different patterns of genetic variants. Fan et al. describe a microfluidic device capable of isolating each of the sister chromatids from single cells, allowing whole-genome haplotyping by sequencing and arrays.
Sequencing a human genome using next-generation methods does not distinguish between the two copies of each chromosome. Kitzman et al. determine a haplotype-resolved genome sequence by efficiently constructing and sequencing long-insert clones that cover the diploid genome with a low likelihood of overlap.
Cui et al. generate transgenic rats and mice bearing targeted genomic integrations by enhancing the rate of homologous recombination in single-cell embryos with zinc-finger nucleases. The approach avoids the time-consuming backcrossing involved in generating mutant mice with ES cells and should be applicable to species for which ES cells have not been isolated.
Song et al. present the first method for global analysis of 5-hydroxymethylcytosine, a recently identified epigenetic modification in mammalian cells. They use a bacteriophage-derived enzyme to tag the hydroxymethyl group with an azide-modified glucose residue that can be used for affinity purification and sequencing of modified genomic DNA fragments.
If transgenes are to be introduced into the genome for cell therapies, the integration events should permit high transgene expression without altering the expression of endogenous genes. Papapetrou et al. propose five criteria to define such 'safe harbors' in the human genome and demonstrate high A-globin expression from a safe-harbor site in erythroid-lineage cells derived from induced pluripotent stem (iPS) cells.
The use of shRNA in vivo to investigate genes involved in proliferation and survival is confounded by the competitive advantage of cells with insufficient shRNA expression. Zuber et al. address this issue with a system that combines Tet-regulated shRNA expression, two fluorescent reporters and robust transactivator production.