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Our Dark Matter

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That’s important, because a major impetus for exploring the human genome has been to identify genes involved in human disorders—with the ultimate goal of finding new treatments. Massive genome-wide association studies (GWAS) have compared the genetic makeup of healthy people with the genes of those who have heart disease, diabetes, obesity, Alzheimer’s, arthritis and other conditions. Intriguingly, though, many GWAS pointed toward noncoding areas in which previously undetected regulatory elements might lie. To help determine what’s out there, the National Human Genome Research Institute has funded the international Encyclopedia of DNA Elements (ENCODE) Consortium.

In this developing picture, the noncoding genome appears to yield both subtle and profound effects, from helping faces and hands emerge with human characteristics to causing cancer or physical defects. While many findings have their detractors, the cumulative effect is forcing scientists to rethink some of their most basic assumptions about genetics.

The first solid evidence that a long noncoding RNA might be important involved the X chromosome in females. Unlike men, who inherit both an X and a Y chromosome, females have two Xs, and one must be inactivated to avoid problems that would arise if both chromosomes expressed all of their genes. That silencing happens in embryos through a tricky procedure involving something called Xist, once thought to be a protein but in fact a lncRNA.

In 1991, researchers discovered that Xist “coats” the X chromosome that’s designated to be silent, shielding it from the factors that would activate its genes. “But it took a very long time to prove that Xist works as a long noncoding RNA,” says Jeannie Lee, a molecular biologist at Massachusetts General Hospital who observed the first hint of this idea in 2006. The scenario that she and others have worked out is that, early in the development of an embryo, the two X chromosomes temporarily align, making physical contact that allows communication between an area on each chromosome known as the “X inactivation center” (Xic) to determine which of the two to inactivate. Then the Xist RNA unfurls from the Xic of the designated silent chromosome and binds to a protein (polycomb repressive complex 2 or PRC2) that suppresses the activity of many of that chromosome’s genes. The silent X condenses, becoming a tightly packed shape called a Barr body.

Yet when a cell divides and must duplicate its chromosomes, the Xist/PRC2 shroud falls off and must be reassembled in each daughter cell. But that’s a faster, easier process than it was in the early embryo. Each new cell retains a memory of which X is to be silenced, and the Xist cloud settles evenly over the entire chromosome.

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What Is Genetic Dark Matter?

Researchers are only beginning to understand genetic dark matter's many mysteries.


1. “Genome Regulation by Long Noncoding RNAs,” by John L. Rinn and Howard Y. Chang, Annual Review of Biochemistry, July 2012. The authors, who have made major contributions to the understanding of long noncoding RNAs, review technologies enabling these studies and highlight emerging themes.

2. “The Evolution of Lineage-Specific Regulatory Activities in the Human Embryonic Limb,” by James P. Noonan et al., Cell, July 3, 2013. Noonan describes enhancers associated with the embryonic development of the distinctive human hand and foot.

3. “Xist RNA Is a Potent Suppressor of Hematologic Cancer in Mice,” by Jeannie T. Lee et al., Cell, Feb. 14, 2013. Some breast cancers have extra copies of the X chromosome, suggesting that these cancers may have malfunctioning Xist, a long noncoding RNA responsible for silencing the second X chromosome in females. Here, Lee and colleagues investigate whether Xist dysregulation might cause cancer, using blood cancer in mice as a test case.

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