Genetics might be one of the oldest scientific pursuits. The Bible tells of Jacob breeding only the goats and sheep with valued coat colors (Genesis 30:32-43), and it's generally believed that dogs were domesticated more than 20,000 years ago by mating wolves with tamer dispositions. However, genetics is also a young science since its founding father, Gregor Mendel, performed his groundbreaking work less than 200 years ago. Mendel's work revealed two fundamental truths: that physical traits are determined by factors (now called genes) passed on by both parents, and that these factors are passed in a predictable pattern from one generation to the next (Figure 1). Mendel's contributions are so profound that his ideas are often referred to as Mendel's Laws of Inheritance.
If breeding patterns and inheritance have been of interest since ancient times, why did it take until the mid-1800s to describe the laws that govern them? What was so special about Mendel that motivated him to perform and understand the experiments as he did?
Previous explanations of inherited characteristics
In Mendel's time, there were many explanations for how characteristics were inherited. Because offspring often appear related but not identical to their parents, one theory proposed that physical traits became blended in each new generation, just as paints can be mixed to give new colors. However, even supporters of the "blending" theory had difficulty explaining how traits like blue eyes could reappear, unblended, in later generations.
Another popular theory in Mendel's time proposed that sperm cells held a miniature but fully formed offspring and that the female's egg contributed an "essence," allowing the offspring to grow. This theory explained that pregnant females stopped menstruating because the blood was redirected into the growing fetus, but it could not satisfactorily describe the evolution of new species (Darwin's Origin of Species would not be published until 1859, when Mendel was already collecting data from his genetic experiments. For more information, see our Charles Darwin I module). The "miniature being" theory was debunked with improved light microscopes of the 1830s when researchers could directly observe the subcellular world of plants and animals, and no evidence for preformed offspring could be found.
A few years later, in 1859, Louis Pasteur's experiments dispelled another popular idea referred to as spontaneous generation, which proposed that life arose from a special brew of non-living materials. In this era of failed and failing theories, Mendel began his work.
Gregor Johann Mendel was an Austrian monk who performed experiments in a monastery known for its scientific as well as its religious pursuits. Beginning in 1843, Mendel undertook experiments to understand the particulars of heredity, initially breeding normal and albino mice and then looking at the coat color of the offspring. Mendel's experiments with mice proved unsatisfactory since the mice took too long to breed and bore so few young in each litter. Additionally, they smelled terrible and some people felt animal breeding experiments were carnal and inappropriate work for a monk. Consequently, Mendel began looking at inheritance in plants, using Pisum stavium, the formal name for simple garden peas (Figure 2). Many varieties of this plant existed, peas were inexpensive and could be grown in rows of pots in the monastery garden, and each plant gave Mendel many peas to examine.
Breeding plants was different from breeding mice, but Mendel still had matchmaking work to perform. Flowering plants (Figure 3) have both male and female reproductive parts. The pollen of a flower, found on the flower's anthers, is similar to sperm cells in other organisms; and the flower's egg cells, called ovules, are kept separate from the pollen by hiding them inside a compartment called the carpel. Breezes or bugs can transfer pollen from the anthers of one flower and leave it on the carpel of another ("cross-pollination"). Just as easily, pollen can travel from the anthers to the carpel of the same flower, resulting in self-pollination. Using a paintbrush, Mendel played the part of a selective insect and pollinated particular plants by brushing the powder from the anthers of one variety onto the carpel of another. To avoid any self-pollination, Mendel also "emasculated" the recipient plants, using tweezers to snip off their anthers. Some might have thought that this, too, was odd work for a monk, but Mendel persisted.
Mendel chose seven physical traits (now referred to as phenotypes) to study: flower color and placement, pod color and shape, pea color and shape, and plant size (Figure 4). These were all easily observable properties of the plants and so could be quickly counted. Mendel's goal was to reveal the genetic makeup (now called genotype) underlying each variety of pea plant and to understand how each trait was inherited. Performing his experiments took at least as much patience as skill. Mendel began by making "pure breeding" plants, ones that reliably gave rise to plants of the same physical traits generation after generation. This alone took him two years but gave him confidence in the genetic makeup of his starting plants, which he called the parental generation of his experiment.
Using his paintbrush, Mendel's next step was to cross-pollinate parental plants with different physical traits, yielding offspring that were the hybrid of two different plants. He recorded the appearance of each trait in the hybrid offspring plants, called the first filial generation (or F1 generation), and then followed the inheritance pattern to the next generation by self-pollinating the F1 plants to produce the second filial generation (F2) and carefully recording each variety that arose. Mendel's mathematical approach to the question of inheritance is one of his greatest legacies. In genetics (as in other sciences) it is easy to be misled by the results of a few experiments. Flip two coins and they may both show heads, but flip 1,000 coins and the split of heads to tails will be nearly even. In Mendel's case he examined more than 1,000 plants for their size and more than 8,000 peas for their color.
The first physical trait that Mendel studied extensively was pea shape. He had two pure breeding lines of plants: one that always gave rise to round peas and another that always gave wrinkled ones. He cross-pollinated these two parental lines and found that every F1 hybrid plant had round peas. This may not have been entirely surprising since most varieties of pure breeding plants in Mendel's collection had round peas, so he might have guessed that the round character would dominate and the wrinkled character would recede into the background. Mendel showed that the result was the same whether the pollen from plants with round peas was used to pollinate plants with wrinkled peas, or the other way around. The consistent results from such "reciprocal crosses" led Mendel to the conclusion that is now called Mendel's First Law: Factors that determine physical traits segregate into both egg and sperm cells (collectively called the "gametes" of the organism). Unlike earlier theories that suggested only sperm carried traits, Mendel showed that both egg and sperm carry physical traits to the offspring.
Mendel's next experiment was particularly telling. He self-pollinated each F1 hybrid plant with its own pollen and recorded the pea shape of the next (F2) generation. Despite all the F1 plants having round peas, some F2 plants had round peas and some had wrinkled peas. In other words, traits that had been hidden in the F1 hybrids had reappeared in their offspring. Mendel counted each variety in the F2 generation and observed that 5,474 had round peas and 1,850 had wrinkled ones (Figure 5). The ratio of these two traits, very nearly three round peas for each wrinkled one, turned out to be an important number. Later, when Mendel repeated his experiments looking at pea color rather than shape, he found 6,022 yellow peas and 2,001 green peas in his F2 plants, again a ratio of 3:1. This 3:1 ratio held true in experiments examining flower color, flower position, pod shape, pod color, and plant size. What could explain this constant ratio? One of the strengths of Mendel's work is a hallmark of the scientific process: He put together his observations to form a hypothesis.
Three observations led Mendel to his second important proposal. First, Mendel had observed that both the egg and sperm carry factors to the offspring. Second, he had shown that one trait dominates in the initial cross of mixed hybrids (for example, round peas in the F1 generation). Lastly, he had observed that a trait that recedes into the background in the F1 generation reappears one-fourth of the time in the F2 generation. Working over the mathematics, Mendel realized that both parents carry two copies of each factor and that each parent must donate one copy to the offspring through their egg or sperm cell. Since all of the offspring in the first cross (F1) carry one factor that dominates (round peas) and one factor that recedes (wrinkled), they all have round peas. However, their offspring (F2) could inherit either a round or wrinkled factor from each the egg and sperm. Only those F2 plants that inherit a wrinkled factor from both the egg and sperm had wrinkled peas – exactly a one-fourth ratio. Thus Mendel concluded that two factors must be involved in producing a physical trait; however, only one factor is passed on from parent to offspring in the sperm or egg cell. At the time, Mendel could not explain how the pairs separated into the gametes, or how they rejoined during pollination, but he was correct in thinking that the factors randomly and independently segregated into the plant's gametes, and his idea is now called Mendel's Second Law.
Mendel's notation system
Mendel devised a notation system to follow the inheritance of each trait. As an example, consider Mendel's experiment with plants that were tall (6 feet) or short (6 inches). Mendel had reasoned that each parental plant had a pair of factors that separated during reproduction and that the F1 offspring inherited one factor from each parent. Mendel called the pure breeding ("homozygous") parental plants "TT" if they grew tall (i.e., the homozygous dominant genotype)or "tt" if short (i.e., the homozygous recessive genotype). He could have named the short plants "SS," but instead he used uppercase letters for the trait that dominated in the F1 generation and used the same letter, but lowercase, to describe the recessive trait (the one that disappeared in the F1 generation but reappeared in the F2 generation). Cross-pollinating the TT and tt plants gave hybrids with a mixed (heterozygous) genotype ("Tt"). These hybrids all showed the dominant trait and grew tall.
In his next experiment Mendel self-pollinated plants of the Tt genotype and saw both tall and short plants arise. Mendel correctly concluded that the tall plants had either received two dominant factors ("TT" like the original pure breeding plants), or one dominant and one recessive factor ("Tt" like the F1 generation). However, the short plants must have inherited two recessive versions of the factor and were once again homozygous "tt." Mendel's insight into the genotype of his plants was remarkable given that nothing was known about the physical nature of inherited material. Mendel's "factors" are now known to be genes encoded by DNA, and the variations are called alleles. "T" and "t" are alleles of one genetic factor, the one that determines plant size.
If both the "TT" and "Tt" genotypes give rise to tall plants and only the "tt" genotype gives short plants, shouldn't Mendel have seen two tall plants to every one short? A Punnett square like the one shown shown in Figure 6 is a useful way to calculate products from genetic crosses and can be used here to understand the 3:1 ratio that Mendel saw. Continuing the tall and short plant example, the "TT" and "tt" gametes from each pure breeding plant can be written across the top or along the left side of a four-quadrant box. Within the box, the individual factors are "donated" to the F1 progeny, resulting in a "Tt" genotype in all four quadrants. All these plants would (and did!) grow tall.
A Punnett square for crosses of the F1 plants shows a different outcome. Both sides of the Punnett square in Figure 7 have "T" and "t" to represent the two possible gametes from each heterozygous plant. The genotypes of the offspring are written inside the square at the intersections: "tT," "tt," "TT," and "Tt." Thus, the 3:1 ratio that Mendel observed can be understood by realizing that three intersections have one or more dominant factor (it doesn't matter if it's listed first or second in the Punnett square), and thus all three result in tall plants, and only one square has both recessive factors (tt), resulting in short plants.
Mendel's laws: Violations and variations
The monastery had many varieties of pea plants to study, and perhaps it was luck or perhaps it was intuition, but all seven of the traits Mendel chose to study are inherited in a straightforward pattern. The relationship of DNA and chromosomes to heredity was not known in Mendel's time. Modern analysis has since shown that five of the seven traits that Mendel studied are encoded by genes on distinct chromosomes of the pea plant, and the remaining two are at opposite ends of one chromosome and so are separated by lots of other genes. Had Mendel examined two traits encoded by neighboring genes, he would have observed what Thomas Hunt Morgan found in the early twentieth century from his experiments with fruit flies. Genes that are close to each other (called "linked" genes) have different inheritance patterns than the unlinked genes that Mendel studied.
It was also Mendel's good fortune (or perhaps his genius) to study quantifiable traits determined by only one pair of genes. Pea plants were either tall or short, their peas either green or yellow. There was nothing in between; many genes are now known to show "incomplete dominance," and there are numerous phenotypes (physical traits) that arise from the combined action of many genes. For example, some plants show incomplete dominance in flower color; when pure varieties that have either red (RR) flowers or white (rr) flowers are bred, the hybrid (Rr) offspring have flowers that are pink (Figure 8).
Mendel studied this phenomenon using a bean plant called P. multiflorus and noted that the outcome did not confirm the 3:1 ratio he had seen with the flower color of his pea plants. Mendel corresponded with many colleagues, and one of these, Carl Nageli, a Professor of Botany at the University in Munich, sent Mendel some hawkweed seeds to study. But this plant has an unusual mode of reproduction in which some of the maternal tissue is reused in the offspring, and so the crosses of the pure breeding plants did not show the expected 3:1 ratio. Mendel was reportedly discouraged by this and wondered if his "laws of inheritance" were universal.
Fur color on animals is another good example of a complex phenotype. In labrador retrievers, fur color is determined by two gene pairs. One pair colors the fur brown or black, and another pair gives rise to a yellow coat. Coat color on Siamese cats is even more complex, being influenced by environmental factors as well as genes so that it grows darker around the nose, tail, and paws of these cats where their bodies are colder (Figure 9). For mice, determination of fur color is more complicated, with five gene pairs involved. Fortunately, Mendel abandoned his experiments with mice early and did not pursue any complex traits like these for his experiments.
Mendel presents his findings
Mendel presented his major findings in a two-part lecture in 1865 followed by a paper entitled "Experiments on Plant Hybridization" in 1866. Unlike the furor created a few years earlier by Darwin's publication, Mendel's proposals were essentially ignored, their truth unrecognized for years, even though the prevalent notions of inheritance were clearly insufficient and the intellectual room to accept his ideas was available.
Mendel did what he could to generate interest in his findings by sending reprints of his article to other people studying inheritance, but to his disappointment, Mendel never enjoyed wide readership or even a common understanding of his work in his lifetime. Today, no one disputes the significance of Mendel's contribution, although some have argued that his insights arose more from luck than from genius. Whatever the balance of intellect and fortune, Mendel's impact on modern thought is unquantifiable, unlike the inheritance of traits he studied.
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