Howard Hughes Medical Institute, University of Pennsylvania, USA

A geneticist reflects on DNA sequence variants that influence gene expression and disease risk.

Most people are familiar with the Human Genome Project and the HapMap, which catalogued the millions of DNA-sequence differences among humans. But which of these differences influence our risk of developing diseases remains unclear. This is particularly true for disorders such as heart disease that involve not only many genes but also the interactions among them. In addition, the effects of variations in DNA sequence are often subtle, such as altered levels of gene expression. Identifying those DNA sequences that determine levels of expression across individuals could have great medical potential.

One paper that illustrates this point looks at the two major contractile proteins of the human heart, the - and -forms of the myosin heavy chain (E. van Rooij et al. Science 316, 575–579; 2007). Here, Eric Olson and his team at the University of Texas in Dallas identify a microRNA, called miR-208, that regulates how much of the -form heart cells produce.

A healthy heart requires a particular ratio of - and -heavy chains for its cells to function normally. When stressed, heart cells tend to make too much of the -form, causing the organ to enlarge, replete with fibrous connective tissue, and less able to contract. This often happens in people with heart disease.

In finding miR-208, the researchers have determined a key component in the molecular basis of heart failure. The next step might be to look for sequence variants of miR-208 and of other gene-expression regulators that could explain why some people are more susceptible to heart disease than others. In this way, whole biological networks could be pieced together and common medical problems more fully understood.