What if life were just a little bit different?

Epigenetics: The Ultimate Mystery of Inheritance, A Book Review

Written By: Victoria I. Sullivan - Oct• 26•11

DNA methylation

Science writer, Richard C. Francis, provides an entertaining and informative book for lay readers of science, and genetics in particular. For those steeped in the dogma that genes completely control inheritance, Epigenetics: The Ultimate Mystery of Inheritance will require re-evaluation.

Francis explains that most of the information that goes into making us is not there from the outset. “The recipe is written during development, not prior to development. Cells of the liver, muscle, and eye differ in expression of their genes, not in DNA. … differences in gene expression are caused by epigenetic processes.” In the process of differentiation of liver, kidney, heart, lung, tissues, for example, increasing numbers of genes are permanently inactivated and new ones activated through epigenetic processes.

Francis begins chapters with dramatic examples and engages the reader with compelling titles. In “A Grandmother Effect,” Francis relates the surprising epigenetic consequences of famine on unborn children. Babies carried by mothers who endured famine during WWII in western Holland, had low birth weight, and later exhibited significant levels of obesity. In addition, they suffered problems of schizophrenia, depression, and antisocial personality disorders. Later in life, they showed higher incidences of hypertension, heart disease, and type II diabetes. In the blood cells of this Dutch famine group, several genes showed epigenetic changes that have remained for six decades.

Among the epigenetic mechanisms of gene regulation are methylation, histone binding, and microRNA regulation. Methylation of genes coding for the hormone insulin growth factor 2 (IGF2), a gene especially important for growth of the fetus, is under intensive research scrutiny as a causative link to obesity and other disease conditions. The term methylation derives from the methyl group molecule composed of one carbon and three hydrogen atoms (CH3), which attaches to the gene, rendering it completely or partially inactive.

Jose Conseca’s life of excessive use of anabolic steroids, and consequent sexual dysfunction figures into the chapter entitled “What Roids Wrought.” Only cells of certain tissues, including muscles, are sensitive to testosterone, and to anabolic steroids. The latter causes permanent epigenetic changes in expression of genes of these tissues and drastically diminishes the body’s production of testosterone leading to permanent sexual dysfunction.

Francis describes the epigenetic effects of nurturing on offspring. Mice pups deprived of a mother’s frequent licking develop improperly due to epigenetic changes in a pathway of genes and gene regulating factors. Nurturing prepares offspring for success in finding and relating to potential mates, for social integration, and in maintaining social structure. Mothers that were poorly nurtured are poor mothers; thus, this quality is passed down from generation to generation. Although research evidence is from nonhumans, implications of these findings for humans are unavoidable.

Francis describes how stress caused by war and other traumas induces long-term epigenetic changes. Susceptibility may begin in the womb, when mothers endure stress while pregnant. Children of mothers, who suffered posttraumatic stress disorder (PTSD) in Holocaust camps but did not experience the Holocaust, are more likely to develop PTSD.

Gray mule

Despite what we have learned from Mendelian genetics, parental contributions are not always equal. Francis explains the epigenetic parent of origin effect, using mules and hinnies derived from crossbreeding of the donkey and horse, as examples. The larger, stronger mules resemble long legged donkeys. Hinnies are smaller, gentler, and more horse-like. The mule is fathered by a donkey (jackass) and mothered by a horse, whereas the hinny is mothered by a donkey and fathered by a horse.

The differences in physical appearance of mules and hinnies owe to mixing of epigenetic factors from the horse and donkey. When egg and sperm are produced, epigenetic programming is erased, and reestablished in the fertilized egg. In addition, chromosomes are epigenetically imprinted as originating from the male or female parent. In the fertilized, hybrid egg of the horse and donkey cross, the epigenetic paternal or maternal “imprinting” of the chromosomes and genes are hybridized. Whether the egg or sperm parent is a horse or donkey controls epigenetic reprogramming and development.

Paternal and maternal epigenetic imprinting of chromosomes plays out in human diseases. In normal females with a paternal and a maternal X chromosome, one of the X’s is almost totally inactivated by a long strand of RNA and by compacting into a bar-body. Females with Turner syndrome possess only one X and display many genetic problems. Diseases exhibited by the Turner female depend on whether her single X is paternal or maternal. Symptoms include short stature, low hairline, sterility, heart disease, diabetes, visual and hearing impairment, autoimmune disease, cognitive deficits, etc.

Prader-Willi syndrome (PWS) results when a deficient chromosome 15 comes from the father, and victims have various developmental abnormalities including obesity, poor muscle tone, undeveloped gonads, small stature, and mental deficiency. However when a deficient chromosome 15 comes from the mother, Angelman syndrome (AS) results, and the victims have completely different disorders including intellectual and development delays, sleep disturbance, epilepsy, and perpetual smiling facial expression.

Some type 7 plastics may leak bisphenol A.

Environmental factors such as polychlorinated biphenyls (PCB) and bisphenol A used in making plastics, the weed killer atrazine, and fungicides disrupt processes involving hormones. These factors mimic hormones and bind to hormone receptor sites on surfaces of cells sensitive to hormones. The most harmful of these mimic estrogen. In many groups of organisms, exposure leads to epigenetic changes that last for several generations. Human effects include increased rates of prostate cancer, kidney disease, and abnormal testes. Because such chemicals concentrate in water, fish and amphibians especially fall victim. These aquatic-dependent organisms become feminized, rendering populations all-female and/or male sterility.

Francis evaluates two societal controversies from an epigenetic perspective in concluding parts of his book: stem cells and when life begins. He describes the differences between embryonic and somatic stem cells from skin, for example. Somatic stem cells have lost much of the capacities of embryonic stem cells through epigenetic differentiation. In other words, the genes of somatic stem cells have been significantly altered epigenetically in comparison to those of embryonic stem cells, and thus cannot be expected to have the same capacity.

Francis gives an epigenesist’s answer to the question of when human life begins. He writes that a human is not latent in the zygote, but manifests through developmental processes controlled by epigenetics.

Judith Shulevitz compares Francis’ book to Evolution in Four Dimensions: Genetic, Epigenetic, Behavioral, and Symbiotic Variation in the History of Life by Eva Jablonka and Marian J. Lamb. This one is next on my reading list. She mentions Francis’ failure to reference Jean-Batiste Lamarck, who proposed in the early 1800’s that the environment gives rise to changes in animals. Lamarck lacked the tools to explain the mechanisms of such evolutionary changes, and although ridiculed for decades, is somewhat vindicated by epigenetic research.

For an introduction to the importance of epigenetics and to revel in fascinating examples and stories of famous personalities, I highly recommend Francis’ book.

Paying Homage to Barbara McClintock

Written By: Victoria I. Sullivan - Jul• 09•11

The botanist and geneticist, Barbara McClintock would have been the perfect mentor for the fictional Dr. Valerie Smythe, a heroine in my science fiction novel Adoption. Barbara was a brilliant, independent-minded, scientist, who like Valerie suffered her share of discrimination, albeit for different reasons. Unlike Barbara, Valerie is black. For Barbara, gender discrimination was common in science during the early 20th century. However, in time, Barbara’s brilliant contributions to the field of genetics won over her peers, and she remains the only woman to receive an unshared Nobel Peace Prize in the category of Physiology or Medicine.

Barbara developed the technique of staining chromosomes (the location of DNA) with carmine (a red dye) to better visualize those of her research organism, the common corn plant. Her methods subsequently extended to study of chromosomes of other organisms. Advancements in microscopy and work with chromosomes since her days in the lab, would have delighted her.

Karyotype studies of stained chromosomes figure importantly in the fictional discovery of polyploid humans in my novel Adoption. Polyploids are organisms with multiple sets of chromosomes. In humans, a single set of chromosomes numbers 23 and in each of our cells, except sperm and eggs, there are two sets or 46 chromosomes. (Polyploid humans do not exist in real life, however, the fictitious humans in Adoption have four sets of chromosomes.)

Barbara was awarded the Nobel Prize in 1983 for her work toward discovery of “jumping genes” in the 1940s and 1950s. She used her discovery of “jumping genes” to show that genes turn physical features on and off from one generation to the next in corn plants. To explain the array of color changes she observed among corn kernels, she postulated that certain genes move from place to place on chromosomes inside each cell. These genes regulated the colors of a layer in the kernels. Her ideas flew in the face of notions that genes were fixed in one place on chromosomes and were turned off and on, or regulated.

Barbara lectured widely on her research, but her findings were far ahead of their time. Because acceptance of her work met such resistance, she stopped publishing accounts of her research on “jumping genes” after 1953. She felt she risked alienating the scientific mainstream, and in 1973, she wrote: “One must await the right time for conceptual change.” It was only after similar elements were discovered in E. coli many years later, that her work was fully accepted by the scientific community.

The germ of the idea for my novel, Adoption, came from my own botanical research, which depended on Barbara’s pioneering studies in genetics. She probably never anticipated the importance of her work on science fiction writing. Thank you, Barbara.