GENE GEOGRAPHY

History’s genetic legacy
Three Oxford professors are investigating how genetic structure varies geographically in the UK.

If you are from northern parts of the British Isles, particularly Scotland and the Orkneys, there may well be traces of Viking ancestry in your DNA. Or if you are from central England or East Anglia, you could be a distant descendant of the Saxons and Angles. The invasions that, for thousands of years, swept across these islands not only changed the political and cultural landscape but also left their imprint in the genes of modern Britons (see below).

At the University of Oxford, a new £2.3 million project, funded by the Wellcome Trust and led by cancer and population geneticist Professor Sir Walter Bodmer, aims to decipher the genetic structure of the UK. But the historical insights are a secondary concern; rather, the focus is on creating a tool for researchers tracking down genes associated with common human diseases.

Finding that a particular variant of a gene is more common in people with, say, diabetes than in those without is a clue that the gene may be increasing susceptibility to the disease. But is the association real, or are the different genetic make ups of the people involved in the study clouding the results?

To tackle the problem, Professor Bodmer has joined forces with two other Oxford researchers – Professor Peter Donnelly, an expert on population genetics and statistics, and gene-hunter and Wellcome Trust Principal Research Fellow Professor Lon Cardon. Their joint goal is a freely available set of genetic tools to aid researchers searching for genes linked to disease.

A classic method of tracking down genes associated with disease is the ‘case–control’ study. The idea is to examine whether a particular piece of DNA, a marker, is more frequent in a group of people with a disease than a similar group without the disease.

The first successes of this approach came in the late 1960s and early 1970s and involved the HLA genes, which are important in immune responses. The HLA variant B27, for example, is found in at least 90 per cent of people with ankylosing spondylitis (a form of arthritis primarily affecting the spine). “The associations between HLA variants and certain diseases are striking,” says Professor Bodmer. “Even if there is some genetic mixture in the population, it doesn’t mask the association because the real genetic effects are so large.”

Applying the same approach to complex diseases such as heart disease has been less straightforward. “Association analysis for small effects is problematic,” says Professor Bodmer. “There may be several different genes involved, and each gene may have one or more variants that differ in frequency. Some variants may be more common and have very small effects, others may be rare but have slightly more significant effects.”

Professor Cardon agrees, and adds that many studies have simply been too small. “People recognized that many genes are involved in complex diseases, but they expected a few to have large effects. The studies were small because they were looking for ‘low hanging fruit’; with a few exceptions, that has been a failed assumption.”