This approach was in one sense dictated by technology; for many years, common mutations were the only ones that could be worked with. But a theory developed to justify the approach — the “common disease, common variant” hypothesis — held that some mutations exerted their bad effects late in life, after people had had their children, and had become common because natural selection was powerless to act against them.

But the theory was wrong. Common variants have turned out to explain only a fraction of the genetic risk of common disease. The opposite hypothesis, the “common disease, rare variant” idea, “has become increasingly credible,” the GlaxoSmithKline team writes.

Jonathan Pritchard, a geneticist at the University of Chicago who drew attention to the possible role of rare variants in 2001, said it seemed a likely bet that rare variants were contributing to an important fraction of disease. In addition, many common variants may contribute risks that are too small to have shown up in current surveys, he said. But in either case, detecting the roots of common disease will prove much more difficult than envisaged under the “common variant, common disease” scenario. Mutations with small effect must be studied in large numbers of patients to be detectable. Even if the effects of some rare variants can be measured, assessing the significance of the millions that stud each individual’s genome will be challenging.

Though the cost of decoding an individual’s genome is fast approaching a mere $1,000, the difficulty of interpreting its mutations now seems much greater than before, raising doubts as to how soon genome sequencing will become a routine medical test. But Dr. Pritchard said personal genomics may soon be valuable in specific situations, like pediatric cases, cancer and the genetics of response to drugs.

Another complication underlined by the two new surveys is that many rare mutations, because they are so recent, are specific to particular populations, with Africans and Europeans having sets that do not overlap much. This means that medical knowledge about rare mutations may have to be developed independently for each population.