In Pursuit of the Gene

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master gene on chromosome II that was absolutely required for the expression
of the trait (but did not always result in truncation) and two factors on
chromosomes I and III, respectively, that increased both the rate and the severity
of truncation but could not, by themselves, cause the mutant phenotype.
The method turned on being able to demonstrate the presence of
genes for truncation, not only in affected flies, but also in flies that did not
overtly manifest the trait. To do this, Muller and Altenburg had taken advantage
of the fact that male flies did not undergo crossing over, which
made it possible to track the inheritance of whole chromosomes (and all
the genes on them) by single heterozygous genes (specifying eye or body
color) that had nothing to do with the trait under study.
As Muller pointed out, his method would require modification when
applied in humans, where crossing over takes place in both sexes (making it
impossible to follow an entire chromosome with a single marker). Whereas
it might be possible to get away with a limited number of well-defined
markers to map traditional single-gene diseases, mapping complex human
traits would require a huge number of identifying factors. Given a large
enough collection of markers spread evenly across the entire genome, Muller
reasoned, these markers could be employed to track small adjacent sections
of chromosomes that would be highly unlikely to be separated from a
neighboring marker by crossing over. But to find these markers, geneticists
would need to collect a different class of mutant genes. “Study of factors
[markers] which are inconspicuous, or unimportant in actual life, has been
largely avoided,” Muller pointed out, but “any two parents of a human
family would probably differ nearly always in a very large number of factors.”
With a detailed map of linked factors on every chromosome, one
could begin the search for genes behind the more complicated and important
human traits.
¨ EIGHTY YEARS WOULD PASS before Muller’s dream of using a set of
linked identifying factors to identify the genes involved in complex human
traits became possible. By the late 1990s it had become clear that there were
far more DNA polymorphisms in the form of single base pair changes than
any one had previously anticipated. Not only did these single-nucleotide