The Long and Short of it

Scientists have discovered genes that influence height but are yet to explain the gap between the tallest and shortest of people:

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A meeting between two ordinary men in a remote locale in Mongolia hit the headlines all over the world in July last year. But neither Bao Xishun, 56, nor He Pingping, 19, holds a position of eminence. Nor are they film or sports celebrities. The encounter grabbed world attention because of the two men’s contrasting statures. While Xishun, at 2.36m, is the world’s tallest living man, the 74-cm Pingping claims he is the shortest.

Modern science may not be able to explain the yawning gap between the heights of these two men — both hailing from Inner Mongolia — but it has gained some genetic insight into the varying stature of billions of others who fall between Xishun and Pingping in terms of height.

For nearly a century, scientists have believed that genes handed down from parents are responsible for 90 per cent of the normal variation in human height in a population. And it is not just one gene but probably a few hundred that contribute towards making a person tall or short. But until last year, scientists were clueless about their location on the human genome, which consists of more than 3 billion DNA base pairs.

In September 2007, researchers from both sides of the Atlantic, while foraging through DNA from 35,000 people, stumbled upon a difference in a gene called HMGA2, which plays a decisive role in making people taller or shorter, albeit marginally. They found that if a person had two copies of a longer variant of HMGA2, he or she would be 1cm taller than one who has two shorter versions of it.

The HMGA2 gene thus became the first reliable genetic link to human height. Later, scientists zeroed in on yet another gene, GDF5, which makes for an average height difference of 0.4cm.

What made the discovery of such genes possible is what scientists call genome-wide association studies. This is a relatively new way of identifying genes involved in human diseases. Made possible by advances in genetics and sophistication in scientific tools, this method searches the genome for small variations, called single nucleotide polymorphisms (SNPs). The tools are so advanced that researchers can search for hundreds or thousands of SNPs simultaneously. Such studies pinpoint genes that may contribute to a person’s risk of developing a certain disease or those associated with a trait such as height or eye colour.

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If 2007 saw a beginning in understanding the role played by genes in deciding how tall a person will be, 2008 has so far proved to be a watershed. The same consortium of scientists who discovered the HMGA2 and GDF5 genes, now split into two groups, recently discovered 40 more genetic locations. Combined, they may be able to explain a height difference of up to 6cm, or 5 per cent of the population variation in height.

The number and variety of genetic regions discovered so far show that height is determined not just by a few genes operating in the long bones, notes Thomas Frayling of Peninsula Medical School in the UK. Frayling is the lead author of the one of the two studies that appeared in Nature Genetics last month.

Joel Hirschhorn, a paediatric endocrinologist at Broad Institute in the US, who led the other study, says that the new findings account for only a small fraction of the variation in height among people and that there is a lot more to discover. “This is much more than we had even last year. But we are not close to predicting adult height,” Hirschhorn told Knowhow.

The study of genes involved in determining adult height stems from more than sheer curiosity. By identifying which genes affect normal growth, it is easy to understand the processes that lead to abnormal growth, the scientists say. “There appears to be a definite correlation between height and some diseases,” says Michael Weedon, a colleague of Frayling. Weedon was not only part of the original team that discovered the HMGA2 gene but was also instrumental in the latest discovery of 20 new genetic locations linked to height. For instance, there is a strong association between shortness and a slightly increased risk of conditions such as heart disease. Similarly, tall people are more prone to certain cancers and, possibly, osteoporosis.

A predominant factor that determines one’s height may be heredity, but diet too has a role to play. In fact, improved nutrition means that each generation gets successively taller, as has been shown by a recent study on Indians.

That said, Indians still have some catching up to do: an average Indian man (165.3cm) is two centimetres shorter than an average Czech woman who stands 167.3cm tall.

Sources: The Telegraph (Kolkata, India)

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