Heredity is, of course, at the heart of any theory of evolution, and more specifically at the heart of the Darwinian hypothesis of evolution by natural selection: it is inherited variability that provides the raw material upon which natural selection can operate. In 1868 Darwin presented a “provisional hypothesis of pangenesis,” in The Variation of Animals and Plants under Domestication. Pangenes, representing all organs, were assembled in the gametes and merged in the zygote to be farmed out to the respective newly formed organs (Darwin, 1868). Although Darwin conceived of “[t]wo distinct elements [that] are included under the term ‘inheritance,’ namely the transmission and the development of characters” (Darwin, 1981 [1871], 279), his hypothesis was essentially a top-down hypothesis of reproduction. As a hypothesis of inheritance it was unacceptable on both theoretical and empirical grounds. Already in 1867, Fleeming Jenkins had shown that in Darwin's blending model of inheritance all variation would be “swamped out” long before it could be established by natural selection (see Hull, 1973, 302–350). Others, like Thomas H. Huxley and, later, Francis Galton, were just as worried about the empirical evidence of the nonheredity of (most of) the intraspecific variation (Falk, 1995, 226).

PANGENES AND FAKTOREN

Contrary to common lore, Mendel's paper was not unknown in the thirty-four years between its publication and its acceptance as significant (see letters to Roberts, in Stern and Sherwood, 1966; Jahn, 1957/58; and Weinstein, 1977).

de Vries and Bateson introduced the hybridist analytic methodology to challenge morphogenists' thinking about Darwinian evolution. Asking to what extent could ecologically related continuous variations of local populations become characteristics of distinct taxonomic strains and eventually species, they adopted not only a reductionist, particulate conception of organisms but also a rather determinist notion of the inherent nature of these unit characters. They established Mendelian genetics on determinist foundations in which Faktoren served as preformed unit characters.

Deterministic notions such as Faktoren becoming unit characters were anathema to both natural historians in the field and embryologists in the laboratory. Richard Woltereck's objective was to provide a rejoinder to what he called the Mendelian teaching following Weismann's and de Vries's conception of the origin of species (Woltereck, 1909). In his “investigations on the change of species, with emphasis on quantitative species-specific difference” he showed that when the conditions under which strains of Daphnia species from different lakes in Germany existed were modified, their morphology changed to simulate that of another acknowledged species. Furthermore, each strain had its specific inherent Norm of Reaction, that is, its characteristic morphological response pattern to variation in environmental conditions. Such specific norms of reaction made it meaningless to predict the properties (the form characteristics) of one strain under one set of conditions from those under another set of conditions or from those of another strain under the same conditions (Woltereck, 1909; see also Falk, 2000a).

Mendelian nomenclature of symbolic representation of genes and their alleles makes it readily amenable to algebraic presentation of population events. Mendel himself was the first to take notice of this when he explained Gärtner's and Kölreuter's observations “that hybrids have a tendency to revert to parental forms” in algebraic terms:

In the last line of the tabulation Mendel generalized the results for the nth generation of selfing that follows mono-hybridization: the ratio of “A : Aa : a” would be 2n−1 : 2 : 2n−1.

Bateson adopted Mendel's hypothesis upon reading de Vries's paper because he believed that it was consistent with his notion of evolution by discontinuous steps. This placed him in opposition to the claim of the mathematical statistician Karl Pearson in favor of Galton's “Law of Ancestral Heredity” of continuous Darwinian evolution (Provine, 1971; and see Chapter 3). In a discussion following a talk by Bateson's colleague Punnett, it was suggested that “a dominant allele, once introduced into a population, would increase in frequency until reaching stability at 0.5, given the usual phenotypic ratio 3 dominant: 1 recessive thereafter” (Provine, 1971, 133–134).

In December 1992 Bertil Daneholt presented the Nobel laureates in physiology and medicine for that year to the assembly of the Karolinska Institute in Stockholm:

The phenomenon of dominance and its meaning accompanied the science of genetics from its initiation. Bateson interpreted it in terms of the Presence and Absence Hypothesis. R. A. Fisher, taking notice of the harmful effects of inbreeding, pointed out that “if we assume that adaptation is the result of selection, the majority of large mutations must be harmful” (Fisher, 1922, 323). Thus a major task of the evolution of dominance would be to equalize the phenotypes of the heterozygotes to that of the homozygote for the wild-type allele (Fisher, 1928). However, doubts were raised about the efficiency of natural selection in carrying out the task (Wright, 1929a). According to Wright's theory of the functional organization of the cell that related the genotype to the phenotype, dominance would be the outcome of interaction:

Haldane (1930) and Muller (1932), following Shull (1909, 415) and Wright, suggested that the amount of product produced by the alleles of a gene varied asymptotically, and that the wild-type alleles in diploids have been selected to function in the relatively saturated segment of the asymptotic gene/product curve (see Chapter 14).

A century ago, “genes” endowed with the instrumental reductionist status of the Mendelian Faktoren were introduced to overcome the notion of the unit character. The gene was an empiric, functionally defined entity. For Johannsen, gene was a word derived from genotype that should express “only the simple imaging” that “through ‘something’ in the gametes a property of the developing organism is conditioned or is, or could be co-determined” (Johannsen, 1909, 124).

Yet, the meaning of the gene, whether as an intervening variable, a heuristic device for the study of inheritance, or a hypothetical construct, an entity in the physico-chemical world, and what kind of such an entity, became a major issue of genetic analysis. From Richard Goldschmidt's “physiological” perspective genes were merely centers of gravity along the integral units of the chromosome. For Hermann Muller genes were discrete structural entities along the chromosomes. Others, like East, Morgan, and Stadler adopted an operational approach of “instrumental reductionism” (Falk, 1986, 141).

Toward the 1940s genetics became a self-confident autonomous discipline. The Nobel Prize awarded to Morgan in 1933 was a symbol of this autonomy and it certainly also added to its self-confidence.

During the first decades of the twentieth century, the methodology of hybridization analysis of discrete traits was established, and a conceptual framework for the mechanics of inheritance was formulated: genes were inherited entities that (within given environmental circumstances) determined the properties of morphological, physiological, as well as behavioral traits of living organisms; the chromosomal theory of inheritance situated the genes along the chromosomes and mapped them; the analysis of mutations combined with cytogenetic observations indicated that there was a material basis for the Mendelian Faktoren and demonstrated the mechanics of their inheritance. Geneticists in Morgan's group and elsewhere now invaded other disciplines and explored them more aggressively: Dobzhansky's Genetics and the Origin of Species (Dobzhansky, 1937) declared his intent to expand into the sphere of evolutionary research.

Already in 1900 Correns suggested that Mendel's “numerical ratio 1:1 strongly suggests that the separation occurs during a nuclear division, the reduction division of Weismann” (Correns, in Stern and Sherwood, 1966, 127). It was, however, only after the establishment of Mendel's laws that cytologists came to share a set of common assumptions which led them to agree on what they saw under the microscope and eventually to accept the link between chromosomes and Mendelian factors. Chromosome continuity and integrity and their specificity were derived from Boveri's experiments; chromosomes' simulation of multi-factorial Mendelian segregation further supported their role in inheritance, as Wilson and his associates indicated in studies of sex-determination in various insect species. But the behavior of chromosomes could not be simply observed; it had to be interpreted: were these just certain other structure-properties that obeyed the Mendelian laws of segregation or were these elements that causally determined the observed Mendelian laws of segregation? The establishment of the distinction between genotype and phenotype, overcoming the preformationist notion of unit character, was crucial for such an examination.

Morgan's discovery of a correlation between the pattern of inheritance of a Mendelian factor of Drosophila and that of its sex-chromosome suggested a causal relationship, but only the finding that the inheritance of several independent Mendelian factors was similarly correlated with sex-chromosomes allowed the hypothesis that the chromosome was the causal mediator of inheritance.

In 1966 George Williams made a heroic attempt to maintain the strict, reductionist approach of the New Synthesis of Darwinian evolution in his Adaptation and Natural Selection: A Critique of Some Current Evolutionary Thought. For Williams,

This uncompromising bottom-up doctrine opposed and rejected “certain of the recently advocated qualifications and additions to the theory of natural selection, such as genetic assimilation, group selection, and cumulative progress in adaptive evolution” (Williams, 1974 [1966], 4).

When methods for in vitro hybridization of polynucleotide molecules were developed by Doty and Marmur and their colleagues (Marmur and Lane, 1960), it opened new vistas for genetic research. These new methods soon transformed and extended much of genetic research to genetic analysis of hybridization at the polynucleotide level. Such notions had been anticipated by Crick regarding the genetics and taxonomy of proteins (1958, 142): “Biologists should realize that before long we shall have a subject which might be called ‘protein taxonomy’ – the study of the amino acid sequences of the proteins of an organism and the comparison of them between species.” The beginnings of these analyses, developmental (pathological) on the one hand and taxonomic on the other, were already evident from the studies of changes of single amino acids in hemoglobin molecules (Ingram, 1957, 1963).

Hoyer, Bolton, and McCarthy isolated RNA complementary to DNA, based on the demonstration that specific cellular RNA could be hybridized with heat-denatured DNA from the same cells. The hybrids were isolated by cesium chloride density gradient centrifugation (Bolton and McCarthy, 1962). These researchers examined primarily bacterial species relationships, “where there exists only the faintest paleontological record and the simplest of all ontogenetic processes.”

To beget a son in one's own image was considered an attribute of reproduction and generation. In biblical times, inheritance referred to the transmission of material commodities or land-ownership from one person to another:

Although inheritance also extended to the succession of titles and rights, it only rarely referred to the transmission of the natural traits of living creatures. Eventually, however, inheritance acquired more metaphoric connotations: “What must I do to inherit eternal life” (Mark 10, 17; Luke 10, 25 and 18, 18).

In Greek philosophy biological continuity was acknowledged as early as the fifth century BC in the Iliad, where the metaphoric inheritance of the heroic qualities of the father by the son was taken for granted. And in Euripides' Electra the continuity of traits by descendants is alluded to when a servant, finding a lock of hair, attempts to identify Orestes by its resemblance to his sister's hair.

In the Roman Empire inheritance of property was encoded in a voluminous set of laws.

Upon irradiation, the X-ray's energy absorbed in a tissue causes electrons to be expelled from atoms. These high-energy primary electrons eventually expel secondary electrons from atoms, leaving ionized molecules in their track through the tissue. It is the secondary ionization(s) at the end of the primarily induced electrons' tracks that are “biologically effective.” Quantitative analysis of X-ray-induced recessive lethal mutations in the X-chromosome of Drosophila melanogaster revealed a reasonable linear increase with the dose of the radiation given to spermatozoa. In roughly 3 percent of the X-chromosomes lethal mutations were induced per 1000r (r = roentgen unit of absorbed radiation: 100r = 1 Gray unit). The rate of induced mutations was independent of the intensity of radiation (dose/time) and – when extrapolated – apparently with no threshold dose (above that calculated to be due to natural cosmic gamma-radiation). This indicated that X-ray-induced mutations were basically single-hit events. If a single hit was sufficient to induce a localizable lethal mutation, the target must be discrete and the mutation must have been a “point mutation” rather than a (minute double-hit) aberration. On the other hand, the kinetics of the induction of rearrangements, like translocations – obviously a multiple-hit event – was, as expected, of a higher order than the linear relationship. In reality, the aberration induction curves were only to the 3/2 power of the dose (up to a dose of circa 2000r).

On March 26, 1900, a notice, Sur la loi de disjunction de hybrids [Concerning the law of segregation of hybrids] appeared in the Compes Rendus de l'Academie de Sciences. Its author, the well-known Dutch botanist Hugo de Vries, stated:

In this short notice, de Vries reminded his readers of his hypothesis of reproduction and generation, according to which an organism may be reduced to preformed units in the gametes that will unfold into mature organs at embryogenesis. His thesis, however, suggests that, besides the morphogenists' tradition of the study of these units “by the phenomena of variability and mutability,” an effective research method is offered by the hybridist tradition, namely, hybridization. This notice presents the segregation principle of the progeny of monohybrids, of “75 per 100N and 25 per 100B” of the dominant character to that of the recessive character.

A more detailed report, submitted twelve days earlier, on March 14, 1900, as a preliminary communication to the Berichte der deutschen botanischen Gesellschaft, was published after the short notice:

1. Of the two antagonistic characteristics, the hybrid carries only one, and that in complete development. Thus in this respect the hybrid is indistinguishable from one of the two parents. There are no transitional forms.

2. […]

In the beginning of the 1950s, when I was a graduate student in Stockholm, my professor, Gert Bonnier, asked during one of our lunch breaks, what is the difference between a gene and a locus? I answered: “none,” and failed. Mendel, like Kepler, strove to analyze the laws according to which (God's) world is run. He adopted the hybridist research tradition as the experimental method of analysis and followed the laws of segregation of factors for discernible trait variants. It was de Vries who imposed on genetics the notion that organisms are nothing but the consequences of the (physical chemical) properties of their components. Johannsen rejected such preformationism and defined genes as that something which represents hereditary transmission of trait variations. Finally, with Morgan's chromosomal theory of inheritance a locus was assigned to each gene. Genes' properties in replication, function, and mutation were assigned to specific loci on the chromosomes.

Although much of genetic analysis was performed without bothering about whether the entities that were discussed – the genes – were molecules of DNA or pieces of cardboard, the effort “to grind genes in a mortar and cook them in a beaker” (Muller, 1922) intensified. Genetic analysis became reductionist, not only in research methodology, but also increasingly in conception. Once Watson and Crick proposed the structure of DNA as the “genetic material,” it was ascribed the role of the determinant genotype.

When recombination was observed in bacteria, Lederberg re-evoked the old idea of copy-choice that Belling (1928) and Freese (1957) had suggested, proposing that it could also be extended to eukaryotic chromosomes in order to overcome abnormalities such as gene conversion (see Chapter 6): If daughter chromatids were formed by conservative replication, then a copy-choice mechanism might switch synthesis from one chromatid to another, and if the synthesis of the two daughter chromatids from each parental chromosome was not quite synchronized, both might be copied over a short interval from the same parent, thereby giving rise to a 3:1 ratio at a heterozygous site. Replicas can switch from copying off one chromosome to copying off the other repeatedly in short regions of effective pairing, and the switching need not be reciprocal, resulting in both gene conversion and negative interference (Holliday, 1964; Whitehouse, 1965, 317). However, as noted earlier (Chapter 5), there were serious experimental inconsistencies with any copy-choice model of eukaryotic chromosome replication: The model predicted recombination between only the two replicated daughter chromatids, ignoring the fact that all possible pairs of the four chromatids may be involved in crossing-over events; chromosome replication occurred at the S-phase of the cell cycle, prior to meiosis and to its chromosome pairing (Swift, 1950); and this replication of the DNA was semi-conservative (Taylor, 1959).