27 Post Mendelian Theories

Dr. Mamta Jena

Content:

Mendel and the Laws of Heredity

The “rediscovery” of Mendel

The misuse of Mendel

Post Mendel

Mendel in the modern world

Summary

GREGOR MENDEL

Mendel is considered the father of Genetics. He was a monk, biologist and botanist born in Austria in 1822 and who died in 1884. During the years 1853 to 1863 he cultivated pea plants in the gardens of his monastery to be used in his research. His experiments consisted of crossing pea plants of distinct characteristics (size, color of the seeds, etc.), cataloging the results and interpreting them. The experiments led him to enunciate his laws, results published in 1886 with no scientific repercussion at that time. Only at the beginning of the 20th century, in 1902, 18 years after his death, were his merits broadly recognized.

Mendel and the Laws of Heredity

Gregor Mendel was born in the Silesian village of Heizendorf (now called Hynčice) one of five children. Originally named Johann, he was renamed Gregor in 1843. Mendel demonstrated his intellectual abilities at an early age and was sent at age eleven to the Piarist High School in Leipnik and then to the Gymnasium at Troppau (now called Opava). He completed his education there in 1840 and moved on to the University in Olmütz (Olomouc). After a brief illness he was advised to enter the priesthood in the monastery in Brno (Figure 1). Here, he entered a world in which, unlike the conventional view of a monastery, he was immersed in a well respected seat of scientific learning. Many of the members of the Augustinian order at Brno held professorships in the local university or left to assume similar positions at other universities. Thus he was able to continue on an academic track. In 1851 he was sent to the University in Vienna where he was influenced by a number of great minds who were leaders in their fields. The most influential of these to Mendel was Franz Unger (1800-1870), Professor of Plant Physiology. However, in addition to his studies with Unger in which he learned of the work of influential biologists such as Carl Naegeli (1817-1891) and Matthias Schleiden (1804-1881), Mendel learned the value of precise observation and the importance of statistical evaluation from the physicists in Vienna, notably Christian Doppler (1803-1853) and Andreas von Ettinghuasen (1796-1878).

During his years in Vienna Mendel, by virtue of his relationship with Unger, was well aware of a raging controversy in which Unger figured prominently. One of the dominant views in biology at the time was the fixity of species. That is, species were set and constant and, therefore, could not change and certainly could not evolve. Unger was a vocal proponent of the view that variants would arise in natural populations and that slight variants gave rise to varieties and sub-species while large variants would result in new species. So controversial was this view at the time that Unger was almost dismissed from the faculty in Vienna in 1856. One of the motivations ascribed to Mendel for beginning his plant hybridization experiments in the first place was to resolve this issue.

Figure 1. On the left is a portrait of Gregor Mendel from 1880 and on the right is a photograph of the gardens at the Brno monastery taken in the 1920s.

Regardless of his motivation, Mendel had set himself a monumental task. He was determined to catalog all of the different forms that hybrids could take and to carry out a statistical analysis of these forms. The experimental system he chose was the common garden pea, Pisum sativum (Figure 2). He began his crosses in earnest in the summer of 1856 and over the course of the next fifteen years he identified several traits in his plants that appeared to breed “true” and used them in his crosses. In all, he made tens of thousands of observations of which only a few are well known. However, it is these few well known traits that led to the formulation of what are now called Mendel’s Laws of Heredity.

Figure 2. A traditional rendering of the pea plant from a botany text of the time.

Mendel wrote of his experiments under the title Versuche über Pflanzen-Hybriden (Experiments in plant hybridization) published in Verh. Naturf. Ver. in Brunn, Abhandlungen (Proceedings of the Brunn Society for Natural History) in 1866.

In his paper, Mendel laid out his experimental procedures and noted that the traits he had selected to use, among others, related to the difference in the form of the ripe seeds, to the difference in the color of the seed albumin, and to the difference in the form of the ripe pods (Mendel, 1866 translation in Peters, 1959). Mendel noted the number of plants used for each cross and the forms of the hybrids. He then noted the circumstances and results of the next generation (the F2) of crosses. For example, Mendel noted for albumen color 258 plants yielded 8,023 seeds, 6,022 yellow, 2,001 green; their ratio, therefore, is as 3.01 to 1. He noted the results of various combinations of traits such as round and wrinkled seeds with yellow and green albumin. Among his observations was that, in the single trait crosses, one of the two forms of the trait would appear in the F1 generation intact and, therefore, “those characters which are transmitted entire, or almost unchanged in the hybridization, and therefore in themselves constitute the characters of the hybrid, are termed the dominant, and those which become latent in the process recessive.” Among his traits round seeds were dominant over wrinkled, yellow albumen was dominant over green, and smooth pods were dominant over rough. This led him to formulate his First Law, “… hybrids form seeds having one or the other of the two differentiating characters, and of these onehalf develop again the hybrid form, while the other half yield plants which remain constant and receive the dominant or the recessive characters [respectively] in equal numbers.” This is now called segregation. Take the character of albumin color, yellow is dominant over green. If Y is the symbol for yellow and y is the symbol for green, then, starting with pure lines in the parental generation;

The F1 will all be yellow and the F2 will display the 3 to 1 ratio of yellow to green. The outward, physical appearance is called the phenotype (literally, the form that is shown). The “particles” that create the phenotype are now known to be genes and, therefore, each phenotype has an underlying genotype. (Note: the terms gene and genotype did not exist in Mendel’s day, these terms were coined later by the Danish geneticist Wilhelm Johannsen, 1857-1927). Segregation refers to the separating of the particles in the F1 cross. A convenient means of keeping track of the segregating particles no matter how many there are was developed by and named for the English geneticist Reginald Crundell Punnett (1875-1967). Called the Punnett Square, the two forms of the gene (called alleles) are segregated by parent to permit an easy tabulation of the resulting offspring’s genotypes:

Mendel went on to consider various traits in combination. He observed that, “the hybrids in which several essentially different characters are combined exhibit the terms of a series of combinations, in which the developmental series for each pair of differentiating characters are united.” Further, “the relation of each pair of different characters in hybrid union is independent of the other differences in the two original parent stocks.” This is Mendel’s Second Law of Heredity called Independent Assortment. Taking yellow and green albumen together with round and wrinkled seeds, if the pure lines are yellow (YY) and round (RR) and green (yy) and wrinkled (rr):

Again, using the Punnett Square and assorting the two traits independently,

Parents: all yellow, round

Offspring: 9 yellow, round; 3 yellow, wrinkled; 3 green, round; 1 yellow, wrinkled

Many examples of using of the Punnett Square to work out various crosses and combinations of traits are presented in the Supplemental Material at the end of this tutorial.

THE “REDISCOVERY” OF MENDEL

Despite the fact that copies of the issue of the Proceedings in which Mendel’s work appeared were sent to numerous institutions such as the Royal Society and the Linnean Society as part of a regular mailing list, apart from a few letters exchanged with contemporary scientists, notably Carl Naegeli, the paper and its results went completely unnoticed until 1900. During the latter part of the 18th century, scientists were grappling not only with concepts of heredity but also with incorporating them into Darwin’s model of evolution. Notable among these scientists were the Dutch botanists Hugo de Vries (1848-1935) and Carl Correns (1864-1933), Austrian botanist Erich von Tschermak (1871-1962), and English biologist William Bateson (1861-1926). Correns, de Vries, and von Tschermak were all independently working along the same lines as Mendel and were reaching the same general conclusions at the close of the 18th century. Then, in 1900, each became aware of Mendel’s paper and de Vries sent a copy of a report on his own work to Bateson that contained a mention of Mendel. Bateson searched out the original publication of Mendel’s paper and an English translation appeared in 1901. An excellent account of the facts surrounding the rediscovery of Mendel is provided by Olby (1966). Most historians of science set the year 1900 as the birth of genetics because that is the year that Mendel’s paper was “rediscovered.” Much of what we regard as standard terminology and concepts were developed in the first few years after the translation of Mendel’s paper appeared. Bateson himself coined the term genetics, Johannsen defined and refined the terms gene, genotype, and phenotype, and the essential blending of Mendelian inheritance and Darwinian evolution was well under way. One of the lesserknown stories about the rediscovery of Mendel’s work was that some, including Bateson, believed that Mendel had enunciated three laws of heredity. In addition to segregation and independent assortment, many regarded the phenomenon of dominance as a hereditary law at the beginning. It was viewed as an inherent property of traits and that it was immutable. Evolutionary geneticists grappled with the idea that dominance was just another trait subject to Darwinian selection until, in 1928, Sir Ronald Fisher (1890-1962) published his view that dominance could be modified by modest levels of selection. Fisher reiterated and expanded upon this in his monumenta 1930 treatise The Genetical Theory of Natural Selection. Instead of settling the debate over the nature of dominance, Fisher’s work sparked a debate about the nature and role of selection with the great American population geneticist Sewell Wright (1889-1988) that had dominance as the center piece and lasted well into the 1980s with many of Fisher’s students and colleagues carrying on after his death [2]. The story of the evolution of dominance is a fascinating tale in its own right as it involved nearly all of the giants of twentieth century genetics, years of arduous field and laboratory breeding work, and some of the most elegant mathematics theoretical population genetics has to offer [3, 4, 5, 6, 7, 8].

THE MISUSE OF MENDEL

The rediscovery of Mendel’s laws of segregation and independent assortment set genetics on a sound theoretical footing in the early 20th century. Among those that used that footing to build up a solid edifice of genetic science many have already been mentioned such as Johanson, Correns, and Punnett.

Another group that deserves special mention all worked in the same laboratory at Columbia University in New York. Under the guidance of the great American geneticist Thomas Hunt Morgan (1866-1945), a   group of students that included Herman Joseph Muller (1890-1967), Calvin B. Bridges (1889-1938), and Alfred H. Sturtevant (1891-1970), studied the transmission of phenotypes cataloged by them in the fruit fly Drosophila melanogaster. From this work emerged most of the founding principles of modern genetics including chromosomal linkage and mutation.So powerful were the discoveries of the early years of the 20th century and so compelling were the models built to explain them, that some carried genetic principles to an unfortunate and, ultimately, tragic extreme. A number of scientists and nonscientists alike saw the elegant simplicity of Mendel as the answer to everything.

Ignoring the complications and the exceptions that were piling up as experiments in Mendelian genetics became more sophisticated and the traits being studied more complex, some seized upon very simple models as all that were needed to explain even the most convoluted biological characteristics. Nowhere was this more evident than in the rapidly expanding discipline of human genetics. Attracted by the allure of simplicity, some of the attempts to explain complex human traits with basic Mendelian principles are humorous when viewed from a 21st century perspective. Many of the texts of the period contained family histories that purported to demonstrate simple Mendelian inheritance of artistic ability or musical ability. One extensive pedigree displayed evidence for the inheritance of ship building skill over several generation of a Norwegian family. Another prominently showed that three generations of band directors followed a basic Mendelian pattern. It is often common even today for people to casually note that doctors or lawyers “run in certain families” and, while no one today would seriously believe that medicine or law or music or even ship building is determined by a single Mendelian gene, such comments were taken very seriously in the early 20th century. In fact, such belief was strong enough for a field of scientific inquiry to arise that sought to enhance traits deemed to be beneficial and to eliminate traits held to be deleterious. This science was called eugenics. Eugenics comes from the Greek roots for “good” and “origin” or “generation.” The term was first used to refer to good breeding through selective heredity around 1883. By the 1920s the eugenics movement in the United States and Europe was gaining wide acceptance and was being championed by the respected American geneticist Charles Davenport (1866-1944). Eugenics was being portrayed as a sound mathematical science based upon Mendel’s law that could produce superior offspring via selective mating.

Eugenicists held that desirable traits should be encouraged and numerous societies like the Race Betterment Foundation were established. Contests were held and prizes were awarded to “good families” at fairs and other events (Figure 4).

The other side of the eugenics movement was much darker. The goal of promoting the inheritance of “good” traits was being mirrored by the goal of preventing the inheritance of “bad” traits. Complex human traits like alcoholism, feeblemindedness, criminality, and even poverty were attributed to a simple model of Mendelian transmission. Prevention in the United States took the form of designating certain countries and groups as being prone to these traits and banning immigration. In addition, there was a massive program of involuntary sterilization of those already here. As late as 1942 the ethics of “euthanizing” children with disabilities was seriously debated in the pages of a major medical journal. In all, thousands of American citizens and immigrants were sterilized by court order.

Figure 4. This family was awarded a prize in a eugenics contest at a 1923 Kansas fair. Thousands of similar examples of “good breeding” were recognized during the heyday of the eugenics movement. Source: PBS Science Odyssey.

In Europe the eugenics movement gained equal acceptance but its power was nowhere exceeded than in Germany when it became an official policy of the Nazi Party. There, its precepts were taken to the ultimate extreme when the Nazi Party came to power in the 1930s. Soon, the list of traits to be eliminated grew quite long and “undesirables” were being rounded up and sent to camps. Selective human breeding programs, called the “liebensborn,” were established and “stocked” with young women who, by the criteria established under the Nazis, displayed the desired traits. Eventually the Nazis took this movement to the “final solution” of the question of the unfit and the concentration camps became death camps (Figure 5).

Figure 5. A photo taken at the liberation of one of the many Nazi death camps discovered as WWII came to an end. In all, the Nazis exterminated more than seven million people of whom six million were Jews.

POST MENDEL

In the beginning of the 20th century, scientific community devoted to evolutionary studies was broadly divided in to two groups. One group was the believer of Darwin’s gradualistic approach for evolution and was interested in studying continuously varying traits. Other group was of Mendel’s supporters who emphasized importance of discontinuous variation and supported the role of single mutational step in producing major adaptive changes. It was the contribution from population geneticists working on mathematical models of evolutionary changes and biologists studying populations in the field and in the laboratory that showed not only the compatibility of Mendelian genetics with Darwin’s Natural Selection, but also recognized several other mechanisms of production and redistribution of variation. The theory, thus, developed by reconciling Mendel’s work on mechanism of inheritance and Darwin’s and Wallace’s theory of natural selection is called as “Modern Evolutionary Theory”. The central figures in these early developments included Julian Huxley who is credited with coining the term “Modern Evolutionary Synthesis”, R.A. Fisher, J.B.S. Haldane, Sewall Wright, G.H. Hardy, W. Weinberg, Theodosius Dobzhansky, E.B. Ford, Ernst Mayr, George G. Simpson among many others.

By working out mathematically, Fisher, Haldane, Wright, Hardy, Weinberg among many , established the basic processes that caused populations to change over time i.e. selection, genetic drift, mutation and migration. This played a key part in the formation of the “Neo-Darwinian Synthesis”, and contributed immensely in integrating population genetics with evolutionary studies.

MENDEL IN THE MODERN WORLD

The laws of heredity established by Mendel form the backbone of modern genetics. Nowhere is this more evident than in the ongoing search for genes that cause diseases in humans, animals and plants. The sophisticated, contemporary methods for mapping and, ultimately, identifying individual genes that either increase risk for developing diseases or actually cause them is firmly rooted in Mendelian genetics. Genetic linkage analysis is based upon the co-transmission of genetic material that is physically linked together on the same region of a chromosome. The mathematics of linkage analysis works because of segregation and independent assortment. A genetic marker that displays independent assortment in families relative to a trait of interest such as cystic fibrosis, Huntington’s Disease, Breast Cancer, or Alzheimer’s Disease cannot be physically linked to that trait whereas a marker that segregates along with the trait is likely to be near the gene that causes the illness. Through this method literally hundreds of human, animal and plant genes have been mapped, cloned, and studied. Indeed, while the various genome sequencing projects, including the Human Genome Project, have made this search far easier than it was just a few years ago, the initial genetic maps that were used as the guides for ordering the sequences were made using mathematical and laboratory techniques, like linkage, that are grounded in the application of Mendel’s Laws.

SUMMARY

The history of science includes many famous priority disputes (e.g., Leibniz and Newton about calculus; discovery of the AIDS virus; see Hellman, 1998). Similarly, many important findings have been known but ignored for decades (e.g., Barbara McClintock’s discovery of transposons). Many aspects of the “rediscovery story “of Mendel’s paper are inaccurate. Mendel’s original paper announced no major findings; it was known and acknowledged as “typical” science for its day. When it was “rediscovered,” Mendel’s paper became famous as a result of a priority dispute between de Vries and Correns. This dispute prompted researchers to reinterpret and read importance into Mendel’s paper. Koelreuter noted the basic facts of heredity a century before Mendel. He found that alternative traits segregate in crosses and may mask each other’s appearance. Mendel, however, was the first to quantify his data, counting the numbers of each alternative type among the progeny of crosses. By counting progeny types, Mendel learned that the alternatives that were masked in hybrids (the F1generation) appeared only 25% of the time in the F2 generation. This finding, which led directly to Mendel’s model of heredity, is usually referred to as the Mendelian ratio of 3:1 dominant-to-recessive traits. When two genes are located on different chromosomes, the alleles assort independently. Because phenotypes are often influenced by more than one gene, the ratios of alternative phenotypes observed in crosses sometimes deviate from the simple ratios predicted by Mendel.

REFERENCES

1. Olby RC. (1966) Origins of Mendelism. New York: Schocken Books.
2. Provine WB. (1971) The Origins of Theoretical Population Genetics. Chicago: University of Chicago Press.
3. Bourguet D. (1999) The evolution of dominance. Heredity, 83: 1−4
4. Fisher RA. (1928) The possible modification of the response of the wild type to recurrent mutations. American Naturalist, 62: 115−126
5. Fisher RA. (1930) The Genetical Theory of Natural Selection. Oxford: Clarendon Press.
6. Mayo O and R Bürger. (1997) The evolution of dominance: a theory whose time has passed?Biological Review, 72: 97−110.
7. Wright S. (1929) Fisher’s theory of dominance. American Naturalist, 63: 274−279.
8. Wright S. (1934) Physiological and evolutionary theories of dominance. American Naturalist, 67:24−53.
9. Peters JA (ed.).(1959) Classic Papers in Genetics. Englewood Cliffs, New Jersey: Prentice-Hall.