Nature Genetics pp949 - 951

In the September issue of Nature Genetics, a study led by Dr. Charles Lee and Dr. Stephen Scherer reports that gains or losses of large DNA segments are common among normal, healthy individuals in the human population. These large-scale copy-number variations, or LCVs, frequently overlap with genes and could explain some of the natural variation seen among people.

The authors made their discovery by comparing DNA from 55 unrelated individuals across the entire genome. They found 255 different DNA segments that showed comparative gains or losses among the samples they tested. On average, each individual contained 12.4 LCVs per genome, and 24 of the most common LCVs were found in more than 10% of the individuals examined. Significantly, more than half of these variable regions overlap with genes, and thus, could have important functional consequences by changing the levels of the proteins encoded by these genes.

The authors have collated all of the available information on LCVs into a publicly accessible database called the Genome Variation Database (http://projects.tcag.ca/variation) that will be a crucial resource for correlating LCVs with natural human variation and clinical outcomes.

Nature Genetics pp 1003 - 1007

In the September issue of Nature Genetics, Spyro Mousses and colleagues report a novel approach to identifying the genes that become damaged in cancer. A generation of scientists has searched one by one for the tumor suppressor genes mutated in various cancers but Mousses and colleagues have developed a way to look at mutations across the whole genome of cancer cells.

Their strategy is based on preserving mutated, cancer-causing RNA messages which are normally degraded. Using these new methods, the authors identify a candidate tumor suppressor gene EPHB2 found inactivated in prostate cancers. EphB2 is a member of a class of receptors known to regulate intracellular signaling pathways involved in cell growth, migration and adhesion. This approach will be widely applicable, opening new possibilities for identifying the genetic basis of a wide range of cancers.

Nature Genetics pp 984 - 988

The molecular mechanisms involved in normal cells progressing to invasive metastatic cancer have been well studied in cell culture. These include changes in genome stability and reactivation of telomerase enzyme activity – a critical event that protects the ends of chromosomes allowing cancer cells to continue dividing indefinitely. Reporting in the September issue of Nature Genetics, Joe Gray and colleagues provide new insight into how breast cancer develops by examining the way the genome loses its integrity within the cells in the tumor itself.

The study traces the stage-specific evolution of genome instability occurring during the benign to malignant transition in breast cancer. The authors find that increases in genome instability occur in bursts, with the highest levels occurring at the same time that cells reactivate telomerase and attain the capacity to continue dividing. This raises a new paradigm of episodic, as opposed to progressive, genome instability in the progression to cancer.

Nature Genetics pp 1008 - 1013

In the September issue of Nature Genetics, Christopher Walsh and colleagues report the first gene associated with Joubert syndrome (JS), a brain disorder associated with motor and behavioral abnormalities. This work is important for understanding the evolution of human motor programs.

Individuals affected with Joubert syndrome suffer from weakness, abnormal breathing and eye movements, clumsiness, cognitive difficulties, and autistic behaviors. The gene identified was found highly expressed in the brain, particularly during early development. By comparing the sequence of the gene in humans relative to non human primates, the authors also show that the gene has been under positive evolutionary in the human lineage. This suggests changes in this gene may have been important in evolution of motor behaviors distinctive to humans.