The inspection paradox and whole-genome analysis

Abstract

One of the major challenges of modern biology is distinguishing meaningful patterns from the random fluctuations of DNA sequences resulting from chromosome shuffling in each generation. A disease-causing mutation is more likely to be found in a large recombination interval. The paradoxical observation that causal genetic variants are more likely to be found in larger intervals is a consequence of sampling bias and is known as the inspection paradox. According to this paradox, the interval containing a fixed point (the causal gene variant) is around double the length of an interval not subject to this constraint, but this average doubling of length is attenuated or neutralized at the ends of chromosomes, where the distribution of interval sizes gradually returns to normal. This prediction is experimentally testable. The consequences of sampling biases for haplotype patterns are small in large studies of many families, but may be more marked when trying to counsel an individual family, because the doubling of the size of segments is only a large-number average, and the effect may be much larger for an unusual number of recombination events. The challenge of identifying a causal signature from haplotype patterns is illustrated by the problem of the proportion of X-linked mutations in pairs of affected brothers.