The Cause of Variation in a Population

John Dennehy of The Evilutionary Biologist has posted a wonderful article on This Week's Citation Classic. The classics are two back-to-back papers on genetic variation in fruit flies (Hubby and Lewontin (1966), Lewontin and Hubby (1966)). That's Lewontin on the left.

Please get on over to The Evilutionary Biologist and read what John has to say. These were very important and groundbreaking papers when they came out and everyone needs to know why.

Here's some background.

In the olden days there were two competing theories to explain variation (heterozygosity) in a population. The classical theory said that mutations are constantly being removed from the population by positive natural selection or purifying selection. Variation is a transient phenomenon that would disappear entirely if it weren’t for new mutations that arise at a significant rate.

The balance theory maintains that variation in a population is often due to balancing selection. The best known example of balancing selection is the allele for sickle cell disease. In the heterozygous state it confers resistance to malaria but in the homozygous state it is often lethal. Both the sickle cell allele and the wild type allele are maintained in the human population by balancing selection.

Hubby and Lewontin (1966) discovered that there was a huge amount of genetic variation in fruit flies. Their data suggested that 50% of all loci had multiple alleles. This is difficult to reconcile with the balance theory and it was also a big surprise to those who supported the classic theory. It seemed unlikely that at any given point in the evolutionary history of a species that so many genes could be undergoing selection. Further work confirmed that other species contained a huge amount of variation.

The solution to this surprising observation was the recognition that most of the alleles were neutral. The variation is explained by fact that fixation by random genetic drift is much slower than fixation by natural selection. Thus, while the variation is transient in the sense that it is a snapshot of an ongoing process, the process is not selection but drift.

The results of Hubby and Lewontin (1966) led directly to Neutral Theory.

The neutral theory also asserts that most intraspecific variability at the molecular level (including DNA and protein polymorphisms) is selectively neutral, and is maintained in the species by the balance between mutational input and random extinction. In other words, the neutral theory regards protein and DNA polymorphisms as a transient phase of molecular evolution and rejects the notion that the majority of such polymorphisms are adaptive and actively maintained in the species by some form of balancing selection.
                M. Kimura

This explanation is also known as the Neoclassical Theory. Balancing selection is now thought to play only a minor and insignificant role in the cause of variation in a population.

... the neoclassical theory is not refuted by occasional observations of overdominance for fitness, because the theory does not deny that cases exist but only that they are common and explain a significant proportion of natural variation. So it is no use trotting out that tired old Bucephalus, sickle-cell anemia, as a proof that single-locus heterosis can exist. Anyone who has taught genetics for a number of years is tired of sickle-cell anemia and embarrassed by the fact that it is the only authenticated case of overdominace available. “If balancing selection is so common," the neoclassicists say, "why do you always end up talking about sickle-cell anemia?"
                R. Lewontin

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[Photo credit: The photograph of Richard Lewontin is from (Photographs of Participants in the Molecular Evolution Workshop)]