Dec 28 2010

Chutes and Ladders


“The major problem, I think, is chromatin… you can inherit something beyond the DNA sequence. That’s where the real excitement of genetics is now”
—James Watson

Chutes and Ladders is a popular children’s game played board grid of numbered squares; on certain squares on the grid are drawn a number of “ladders” and a number of “chutes” also connecting the squares together. Normally a player roles a die and moves that number of squares. However, landing on the top of a chute or bottom of a ladder results the player moving his or her piece upwards or downwards on the grid.

The game is based on the ancient game of Snakes and Ladders, actually a game of morality, which is believed to date back to ancient India, with bases of the ladders being located on squares representing various types of good and the more numerous snakes signaling evil. The game appealed to 18th century Victorians, who brought the game back to England, substituting the more Victorian values of penitence, thrift and industry for the ladders and indolence, indulgence and disobedience for the chutes. However, they at least equalized the number of ladders and snakes.

Landscapes

“Any landscape is a condition of the spirit.”
— Henri Frédéric Amiel

Conrad Waddington (1905-1975) first coined the term “epigenetics” in 1968. Originally an embryologist, he had studied with Thomas Hunt Morgan, also an embryologist. Waddington had increasingly come to believe that the answers to his questions concerning development lay in genetics. In 1915 Morgan first demonstrated that genes are carried on chromosomes and are the mechanical basis of heredity. Waddington saw the term as a way to describe the integration of epigenesis (the series of occurrences in development with genetics). With it, Waddington helped create the field of developmental genetics.

Waddington described it as “the branch of biology which studies the causal interactions between genes and their products, which bring the phenotype into being.” (2) Epigenetics, in a broad sense, is a bridge between genotype and phenotype—a phenomenon that changes the outcome of a locus or chromosome without changing the underlying DNA sequence. For example, even though the vast majority of cells in a multicellular organism share an identical genotype, organ and tissue development generates a diversity of cell types with disparate, yet stable, profiles of gene expression and distinct cellular functions.

Epigenetics

Epigenetics is the study of reversible heritable changes in gene function that occur without a change in the sequence of nuclear DNA. It is also the study of the processes involved in the unfolding development of an organism. In both cases, the object of study includes how gene regulatory information that is not expressed in DNA sequences is transmitted from one generation to the next – that is “in addition to” the genetic information encoded in the DNA. In its simplest manifestation, epigenetics is defined as any genetic mechanism that results in phenotypic variation without altering the base-pair nucleotide sequence of the genes. (3)

Waddington used an important visual metaphor to describe the development of an individual organism –or part of an organism, such as an organ, tissue or even a specific cell. He likened it to a ball rolling down an undulating, dissected landscape predetermined by the genetic architecture that lay underneath. This he called an epigenetic landscape. This epigenetic landscape is a metaphor for how gene regulation modulates development. One is asked to imagine a number of marbles rolling down a hill towards a wall. The marbles will compete for the grooves on the slope, and come to rest at the lowest points. These points represent the eventual cell fates, that is, tissue types.

Epigenetic landscape I. “The path followed by the ball, as if rolls towards the spectator, corresponds to the developmental history of a particular part of the egg.” (Waddington CW. The Strategy of the Genes. London, Allen and Unwin (1957)

A key theme in this work is that the final form of an organism does not develop entirely and exclusively from a blueprint specified in the genetic program, but rather is a result of the way the genes interact with the environment throughout the developmental process. (4-5)

Waddington suggested that these concurrent interacting influences of genotype and environment could best be conceptualized as an epigenetic landscape, a domain of multiple hills and valleys; and that the growth and development of the organism could be likened to a marble making its way downhill. “Well-worn” or “beaten” paths pathways along which the course of development of an organism normally unfolds were termed chreodes. In the epigenetic landscape, chreodes are the developmental trajectories in the landscape and the epigenetic landscape itself represents the probability distribution of the developmental outcomes. In essence, the balls are much more likely to wind up at the base of a deeper valley, than stuck on some shelf or side valley. As the ball rolls down the landscape, it can be buffered by external or internal influences and perturbations; but it tends to return to the base valley, the chreode. (6,7)

Epigenetic landscape II. “The complex system of interactions underlying the epigenetic landscape. The pegs in the ground represent genes, the strings leading from the chemical tendencies that the genes produce. The modeling of the epigenetic landscape, which slopes down from above one’s head towards the distance, is controlled by the pull of these numerous guy-ropes which are ultimately anchored to the genes.” (Waddington CW. The Strategy of the Genes. London, Allen and Unwin (1957)

The resistance of phenotypic variations to environmental or genetic influences is called canalization. Another way of thinking about it: Canalization is a measure of the ability of a population to produce the same phenotype regardless of variability of its environment or genotype. In Waddington’s epigenetic landscape a canalized trait would be a valley enclosed by high ridges, safely guiding the phenotype to its “fate.” This phenotypic buffering of the developmental systems can produce a “wild-type” phenotype (or what might more accurately be called a phenotypic mean) in the face of various mutations or environmental insults.

In many ways, canalization is the opposite of phenotype plasticity, since it works to insure that phenotypic variation is limited to the degrees that the same phenotype is produced regardless of genotypic or environmental changes. Traits that are highly canalized show little capacity for variation.

Evolution in the epigenetic landscape can occur from:

  • Variation in developmental systems: Certain systems might be more or less sensitive to the effects of canalization than others
  • A shifting in phenotypic mean: The marble’s outcome shifts from its original valley to one with a deeper cut and steeper walls
  • A gradual decrease in variance: Due to natural selection acting on some sort of environmental condition certain alternate traits are winnowed out, leaving the remaining marbles to wear continuous path, deepening a previously shallower valley into a deeper one.

Some authors (8) distinguish between a “genetic” and an “environmental” form of canalization. Genetic canalization refers to distinct genotypes producing the same phenotype, while environmental canalization refers to the same genotype producing the same phenotype in spite of environmental variation.


  1. Watson JD. A conversation with James D. Watson. Sci. Am. 288, 66–69 (2003)
  2. Waddington CH. The Strategy of the Genes; a Discussion of Some Aspects of Theoretical Biology. Allen & Unwin London (1957)
  3. Goldberg AD, Allis CD, Bernstein E. Epigenetics: a landscape takes shape. Cell. Feb 23;128(4):635-8. 2007
  4. Gilbert SF, Epel D. Ecological Developmental Biology. Sinaur Associates. Sunderland USA (2009)
  5. Waddington CH. Genetic assimilation of an acquired character. Evolution 7: 118-126. 1953
  6. Waddington CH. Principles of development and differentiation. Macmillan Company. New York USA (1966)
  7. Waddington CH. The Evolution of an Evolutionist. Edinburgh University Press. Edinburgh (1975)
  8. Jablonka E and Lamb MJ. Evolution in Four Dimensions: Genetic, Epigenetic, Behavioral, and Symbolic Variation in the History of Life. MIT Press. Cambridge MA (2005


Portions excerpted from Fundamentals of Generative Medicine copyright 2010, Drum Hill Publishing, USA.


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