Cloning

Correction of a genetic defect by nuclear transplantation and combined cell and gene therapy.Rideout III, W. M. et al. Cell 109, 17–27 (2002)

In this proof-of-principle study, Rideout et al. have tested whether a genetic defect in somatic cells can be corrected using a combination of therapeutic cloning and gene therapy. They began by deriving ES cells from cloned blastocysts generated from the transferred nuclei of Rag2−/− mice. The Rag2 defect in these cells was then corrected by gene targeting, and mice were derived from the corrected cells by tetraploid complementation. These mice developed with normal B- and T-cell populations; moreover, when their bone marrow cells were transferred to Rag2−/− mice, they restored immune function in the transplanted mice. However, haematopoietic stem cells derived in vitro from the corrected ES cells were unable to repopulate the haematopoietic compartment in Rag2−/− mice because of natural-killer-cell-mediated graft rejection, raising the point that even genetically identical cells derived by therapeutic cloning can still face host-mediated transplantation barriers.

Complex disease

A polymorphism in the β1 adrenergic receptor is associated with resting heart rate.Ranade, K. et al. Am. J. Hum. Genet. 70, 935–942 (2002)

Resting heart rate is positively correlated with cardiovascular and coronary mortality, and so understanding the environmental and genetic factors that influence variation in resting heart rate in human populations could help to identify people at risk. By genotyping >1,000 individuals for two polymorphisms (Ser49Gly and Arg389Gly) in the β1 adrenergic receptor gene — which is required for cardiac function — the authors have shown that the Ser49Gly substitution is significantly associated with resting heart rate. This is the first time a specific polymorphism has been associated with this trait. Furthermore, the two alleles seem to be acting additively, with the heterozygote individuals having a mean resting heart rate intermediate to either homozygote.

Gene expresssion

A molecular link between gene-specific and chromosome-wide transcriptional repression.Chu, D. S. et al. Genes Dev. 16, 786–805 (2002)

A combination of local and global mechanisms of transcription regulation ensures appropriate gene expression. Although, in most cases, distinct proteins are responsible for each mechanism, Caenorhabditis elegans SDC-2 can bring about both. It triggers dosage compensation — a process in which a specialized protein complex associates with hermaphrodite X chromosomes to bring about a twofold reduction in X-linked gene expression. It also specifically downregulates her-1, an autosomal gene that directs male development. The authors show that it does so by recruiting the dosage-compensation machinery to the her-1 locus, and it seems that whether the mode of repression is local or global depends on the DNA target sites with which the complex interacts.