Academic journal article Genetics

Hubby and Lewontin on Protein Variation in Natural Populations: When Molecular Genetics Came to the Rescue of Population Genetics

Academic journal article Genetics

Hubby and Lewontin on Protein Variation in Natural Populations: When Molecular Genetics Came to the Rescue of Population Genetics

Article excerpt

THE back-to-back papers of Hubby and Lewontin (1966) and Lewontin and Hubby (1966) on genetic variability in Drosophila pseudoobscura represent a landmark in the study of variation in natural populations. The authors introduced the concept of studying variability across the genome,unbiasedbypriorknowledgeofvariabilityattheloci in question. Their experimental technique was gel electrophoresis of enzymes and soluble proteins, which detects most charge change variants. Electrophoresis had already been used to study within-species variation at specificloci (Hubby 1963; Shaw 1965). It had also provided a tool for studying genetic divergence between species (Hubby and Throckmorton 1965), which continued to be employed through the 1980s (e.g., Coyne and Orr 1989). Our main focus in this Perspectives is on unbiased studies of variation within species.

Hubby and Lewontin (1966) and Lewontin and Hubby (1966), together with the slightly earlier paper by Harris (1966) on human electrophoretic variability, initiated the modern era of the study of natural genetic variation at the molecular level. While Harris explicitly recognized the need for unbiased surveys of enzyme variability, his work was more concerned with problems in human genetics than general questions in evolutionary genetics, and has thus been somewhat less influential. As Lewontin (1974, 1991) eloquently explained, his work with Jack Hubby was motivated by the impasse that had been reached by the use of classical and quantitative genetics methods for studying genetic variability in nature. There was evidence for abundant genetic variation in quantitative traits, as well for "concealed variability" revealed by inbreeding experiments, but the numbers of genes involved, the frequencies of allelic variants at the underlying loci, and the sizes of their effects on the traits in question, were all unknown. A few examples were known of single-gene inheritance of polymorphisms for visible traits in natural populations, and chromosomal polymorphisms had been studied in Drosophila and a few other species, as well as a handful of biochemical polymorphisms such as human blood groups. But the 1950s debate between the "classical" and "balance" views of variability remained unresolved.

The classical view was that the typical state of a gene in a population was a functional wild-type allele, with deleterious mutant alleles present at low frequencies (Muller 1950). In contrast, the balance hypothesis proposed that many genes might have two or more alleles maintained at intermediate frequencies in populations by balancing selection (Dobzhansky 1955). Without a way to measure genetic variability at the level of individual genes, strong tests of these hypotheses could not be carried out.

The Problem and Its Solution

Hubby and Lewontin (1966) began their paper with a lucid outline of the problem and the requirements for solving it, a summary that could hardly be bettered today:

A cornerstone of the theory of evolution by gradual change is that the rate of evolution is absolutely limited by the amount of genetic variation in the evolving population. Fisher's Fundamental Theorem of Natural Selection" (1930) is a mathematical statement of this generalization, but even without mathematics it is clear that genetic change caused by natural selection presupposes genetic differences already existing, on which natural selection can operate. In a sense, a description of the genetic variation in a population is the fundamental datum of evolutionary studies; and it is necessary to explain the origin and maintenance of this variation and to predict its evolutionary consequences. It is not surprising, then, that a major effort of genetics in the last 50 years has been to characterize the amounts and kinds of genetic variation existing in natural or laboratory populations of various organisms.

The reason for our present lack of knowledge about the amount of heterozygosity per locus in a population is that no technique has been available capable of giving a straightforward and unambiguous answer even under ideal experimentalconditions. …

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