ALL people are 99.9% alike, genetically speaking. That is to say, the DNA sequences of two unrelated people are 99.9% identical. It is the remaining tiny fraction of a percentage point that accounts for how people differ from each other. This includes how one person might be more prone to disease and how another might respond differently to treatment. Understanding these differences thus offers scientists the opportunity to understand and, potentially, treat complex diseases such as asthma, diabetes, high blood pressure, heart disease, obesity and even cancer.
An international team of researchers has now announced a big step towards achieving such goals. It has published the results of a three-year effort to chart the patterns of the most frequently occurring genetic differences in the world's population. The findings mean that the search for clinically relevant genes can be accelerated through the use of a clever short cut.
The human genome consists of about 3 billion base pairs (the chemical “letters” of which DNA is composed). Only a small fraction of these form 30,000 genes; the rest is thought to be junk. Each gene consists of a length of DNA that contains an instruction to do something. The command is usually to build the proteins that do the donkeywork of maintaining life, although some genes control how much protein to produce and when.
How people vary in their susceptibility to disease and their response to treatment is linked to places in the genome where the DNA sequence varies. Much genetic variation is caused by changes in single letters, or bases, called single nucleotide polymorphisms. As a result, every individual has a unique genetic code that typically differs in about 3m nucleotides from everybody else's. Like the rest of the genome, these small variations are inherited. Thus, in large societies, many individuals can carry the rarer version of the single letter variation in their DNA sequence.
Researchers trying to discover the genes that make some people susceptible to certain diseases compare a group of sick people with a group of healthy ones. This is like looking for the proverbial needle in a haystack—there are 10m different single-letter variations in societies where 1% or more of the population has the rarer form.
A cunning plan
The researchers, led by David Altshuler of Massachusetts General Hospital in Boston and Peter Donnelly of the University of Oxford in Britain, wanted to find a quicker way. Single-letter variations that are close together in the chromosome tend to be inherited as intact blocks of information. By putting these single-letter variations in the human genome into groups, called haplotypes, the team hoped to do the equivalent of identifying entire neighbourhoods by examining just a few of the houses on each of its streets.
Most of the common haplotypes occur in all human populations. However, their frequencies differ between ethnic groups. The researchers focused on four populations that were known to be sufficiently different to represent much of humanity when added together. The samples came from Yoruba in Ibadan, Nigeria; Japanese in Tokyo; Han Chinese in Beijing; and Utah residents with ancestry from northern and western Europe.
The researchers measured these variations in the DNA found in blood samples from 269 individuals living in these four societies. Specifically, they compared 1m of the single-letter differences to produce what is dubbed the “HapMap”. The map, published in the current issue of Nature, confirms that it is indeed possible to rely on a relatively small number of single-letter variations to see the bigger picture. It identifies the 250,000 to 500,000 single-letter variations that provide almost as much mapping information as all 10m single-letter variations. Thus, the researchers hope it will make searching the human genome for hereditary factors common in disease up to 20 times faster.
Quickly identifying which people are at risk of disease could be beneficial in itself. If, for example, the 10 to 20 genetic markers that predispose people to colon cancer were to be identified, individuals who had those genes could be kept under closer observation. That way, tumours could be removed when they were still small. At this stage, the cancer is 95% curable. Faster identification of genetic disease would also accelerate the development of treatments that could target disease-causing genes.
The HapMap provides researchers with indicators—Dr Donnelly likens them to Post-it notes—for focusing on genes involved in common diseases. However, like the Human Genome Project before it, the map is incomplete. The researchers have examined just 1m single-letter variations so far. They plan to take a look at a further 2m in the coming few years. Fundamentally, the study of human genomic variation can never be complete, because each person carries unique as well as common variations.
The similarities between the map of the human genome and the HapMap might not be as great as 99.9%. The race to map the human genome was between a large public consortium and a private company. HapMap is being published by publicly and privately funded scientists working collaboratively, although the information produced is freely available. What unites them is that both maps will greatly benefit human health.