Genome instability

Chromosome instability is common in human cleavage-stage embryos Vanneste, E. et al. Nature Med. 26 Apr 2009 (doi:10.1038/nm.1924)

This study describes the presence of a large amount of genomic instability early in human embryogenesis. The authors used new array-based methods to analyze genome-wide changes in copy number and loss of heterozygosity in multiple single cells of in vitro fertilization embryos taken from fertile women. Only 2 of the 23 cleavage stage embryos were chromosomally normal; the others were mosaic for deletions, duplications, amplifications and aneuploidies. These frequent and complex rearrangements might account for the low fertility rate in humans, or for the high rate of miscarriage.

Epigenetics

A C. elegans LSD1 demethylase contributes to germline immortality by reprogramming epigenetic memory Katz, D. J. et al. Cell 137, 308–320 (2009)

Some histone modifications, such as dimethylation of histone H3 at lysine 4 (H3K4me2), are thought to help cells to 'remember' patterns of transcription, and they are erased in the germ line to allow normal development. These authors found that mutation of spr-5, which encodes the Caenorhabditis elegans orthologue of LSD1 and removes H3K4me2, leads to increasing sterility across subsequent generations. Sterility correlates with increased H3K4me2 and with aberrant expression of spermatogenesis genes. This work provides insight into potential mechanisms of epigenetic memory and reprogramming.

Replication

Transcription initiation activity sets replication origin efficiency in mammalian cells Sequeria-Mendes, J. et al. PLoS Genet. 5, e1000446 (2009)

This study shows that DNA replication initiates preferentially at sites of active transcription in mouse embryonic stem cells, and that nearly half of all replication origins (ORIs) are at promoters. ORIs at promoters in CpG islands are the most efficient at initiating replication. The association between ORIs and transcriptional units is maintained in other cell types and is in agreement with earlier work in human cells. These findings provide further evidence of an intimate relationship between transcription and replication, and could reflect co-evolution of their regulatory regions.

Gene expression

Upstream open reading frames cause widespread reduction of protein expression and are polymorphic among humans Calvo, S. et al. Proc. Natl Acad. Sci. USA 13 Apr 2009 (doi: 10.1073/pnas.0810916106)

Approximately half of all human and mouse transcripts contain upstream ORFs (uORFs) — mRNAs that originate in the 5′UTR of a gene but are out of frame with the ORF. An expression analysis of ∼11,600 matched mouse mRNAs and proteins shows that uORFs significantly reduce downstream protein expression. Mutations that alter the uORFs of some disease-associated genes reduce the expression of the downstream protein, indicating that uORFs could affect disease phenotypes.