HNSC 3162 Biological Concepts in Public Health (Cai)

Learning Objectives:

By the end of this section, you will be able to:

• summarize what determines traits.
• describe the relationship between DNA and genes.
• Summarize what makes up proteins and its general functions.
• Summarize the makeup of chromosomes.
• Define mutation and summarize its consequences.
• recognize the limitations of Mendelian genetics.

Content

Writing the Rules of Heredity

In the mid 1800’s, an Augustinian friar named Gregor Mendel formalized quantitative observations on heredity in the the pea plant. He undertook hybridization experiments that utilized purebred or true breeding plants with specific qualities over many generations to observe the passage of these traits. Some of these physical traits included: seed shape, flower color, plant height and pod shape.

Mendelian genetics cannot fully explain human health and behavior

There was obvious interest in applying Mendel's laws to agriculture. Mendel's ideas were also embraced by the eugenics movement, the goal of which was to improve the human species by better breeding. Eugenicists encouraged marriages between people of "good" genetic stock, and discouraged reproduction of the "genetically unfit."

Eugenicists wrongly used simple dominant/recessive schemes to explain complex behaviors and mental illnesses — which we now know involve many genes. They also failed to account for environmental effects on human development. In the United States, restrictive eugenics legislation reflected political and social prejudices, rather than genetic facts. The eugenic description of human life was finally discredited by the horrible consequences of the Nazi quest for racial purity.

DNA words are three letters long

The genetic code had to be a "language" — using the DNA alphabet of A, T, C, and G — that produced enough DNA "words" to specify each of the 20 known amino acids. Simple math showed that only 16 words are possible from a two-letter combination, but a three-letter code produces 64 words. Operating on the principle that the simplest solution is often correct, researchers assumed a three-letter code called a codon.

Research teams at University of British Columbia and the National Institutes of Health laboriously synthesized different RNA molecules, each a long strand composed of a single repeated codon. Then, each type of synthetic RNA was added to a cell-free translation system containing ribosomes, transfer RNAs, and amino acids. As predicted, each type of synthetic RNA produced a polypeptide chain composed of repeated units of a single amino acid. Several codons are "stop" signals and many amino acids are specified by several different codons, accounting for all 64 three-letter combinations.

A gene is a discrete sequence of DNA nucleotides

Mendel described a gene as a discrete unit of heredity that influences a visible trait. Beadle and Tatum defined a gene as the discrete directions for making a single protein, which influences a metabolic trait. Early sequencing efforts showed that proteins are, in turn, long chains of amino acids arranged in a specific order. The triplet genetic code further refined the definition of a gene as a discrete sequence of DNA encoding a protein — beginning with a "start" codon and ending with a "stop" codon.

Gene analysis took a giant step forward with the discovery of methods to determine the exact sequence of nucleotides that compose a specific gene. DNA sequencing was built upon earlier knowledge of DNA polymerases and cell-free systems for replicating DNA. The chain-termination method, which makes clever use of a "defective" DNA nucleotide, now dominates DNA sequencing technology.

Knowledge Check

Learning Objectives:

By the end of this section, you will be able to:

• define epigenetics.
• describe what makes up the epigenome and what does it do?
• summarize the role of epigenome in inheritance.
• explain what imprinting is.
• recognize factors that change the epigenome.
• recognize the role of epigenome in cancer.

Content

What is the epigenome?

The epigenome is a multitude of chemical compounds that can tell the genome what to do. The human genome is the complete assembly of DNA (deoxyribonucleic acid)-about 3 billion base pairs - that makes each individual unique. DNA holds the instructions for building the proteins that carry out a variety of functions in a cell. The epigenome is made up of chemical compounds and proteins that can attach to DNA and direct such actions as turning genes on or off, controlling the production of proteins in particular cells. When epigenomic compounds attach to DNA and modify its function, they are said to have "marked" the genome. These marks do not change the sequence of the DNA. Rather, they change the way cells use the DNA's instructions. The marks are sometimes passed on from cell to cell as cells divide. They also can be passed down from one generation to the next.

What does the epigenome do?

A human being has trillions of cells, specialized for different functions in muscles, bones and the brain, and each of these cells carries essentially the same genome in its nucleus. The differences among cells are determined by how and when different sets of genes are turned on or off in various kinds of cells. Specialized cells in the eye turn on genes that make proteins that can detect light, while specialized cells in red blood cells make proteins that carry oxygen from the air to the rest of the body. The epigenome controls many of these changes to the genome.

What makes up the epigenome?

The epigenome is the set of chemical modifications to the DNA and DNA-associated proteins in the cell, which alter gene expression, and are heritable (via meiosis and mitosis). The modifications occur as a natural process of development and tissue differentiation, and can be altered in response to environmental exposures or disease.

The first type of mark, called DNA methylation, directly affects the DNA in a genome. In this process, proteins attach chemical tags called methyl groups to the bases of the DNA molecule in specific places. The methyl groups turn genes on or off by affecting interactions between the DNA and other proteins. In this way, cells can remember which genes are on or off.The second kind of mark, called histone modification, affects DNA indirectly. DNA in cells is wrapped around histone proteins, which form spool-like structures that enable DNA's very long molecules to be wound up neatly into chromosomes inside the cell nucleus. Proteins can attach a variety of chemical tags to histones. Other proteins in cells can detect these tags and determine whether that region of DNA should be used or ignored in that cell.

Is the epigenome inherited?

The genome is passed from parents to their offspring and from cells, when they divide, to their next generation. Much of the epigenome is reset when parents pass their genomes to their offspring; however, under some circumstances, some of the chemical tags on the DNA and histones of eggs and sperm may be passed on to the next generation. When cells divide, often much of the epigenome is passed on to the next generation of cells, helping the cells remain specialized.

What is imprinting?

The human genome contains two copies of every gene-one copy inherited from the mother and one from the father. For a small number of genes, only the copy from the mother gets switched on; for others, only the copy from the father is turned on. This pattern is called imprinting. The epigenome distinguishes between the two copies of an imprinted gene and determines which is switched on. Some diseases are caused by abnormal imprinting. They include Beckwith-Wiedemann syndrome, a disorder associated with body overgrowth and increased risk of cancer; Prader-Willi syndrome, associated with poor muscle tone and constant hunger, leading to obesity; and Angelman syndrome, which leads to intellectual disability, as well motion difficulties.

Can the epigenome change?

Although all cells in the body contain essentially the same genome, the DNA marked by chemical tags on the DNA and histones gets rearranged when cells become specialized. The epigenome can also change throughout a person's lifetime.

What makes the epigenome change?

Lifestyle and environmental factors (such as smoking, diet and infectious disease) can expose a person to pressures that prompt chemical responses. These responses, in turn, often lead to changes in the epigenome, some of which can be damaging. However, the ability of the epigenome to adjust to the pressures of life appears to be required for normal human health. Some human diseases are caused by malfunctions in the proteins that "read" and "write" epigenomic marks.

How do changes in the epigenome contribute to cancer?

Changes in the epigenome can switch on or off genes involved in cell growth or the immune response. These changes can lead to uncontrolled growth, a hallmark of cancer, or to a failure of the immune system to destroy tumors.

In a type of brain tumor called glioblastoma, doctors have had some success in treating patients with the drug temozolomide, which kills cancer cells by adding methyl groups to DNA. In some cases, methylation has a welcome secondary effect: it blocks a gene that counteracts temozolomide. Glioblastoma patients whose tumors have such methylated genes are far more likely to respond to temozolomide than those with unmethylated genes.

Changes in the epigenome also can activate growth-promoting genes in stomach cancer, colon cancer and the most common type of kidney cancer. In some other cancers, changes in the epigenome silence genes that normally serve to keep cell growth in check.

To compile a complete list of possible epigenomic changes that can lead to cancer, researchers in The Cancer Genome Atlas (TCGA) Network, which is supported by the National Institutes of Health (NIH), are comparing the genomes and epigenomes of normal cells with those of cancer cells. Among other things, they are looking for changes in the DNA sequence and changes in the number of methyl groups on the DNA. Understanding all the changes that turn a normal cell into a cancer cell will speed efforts to develop new and better ways of diagnosing, treating and preventing cancer.

How are researchers exploring the epigenome?

In a field of study known as epigenomics, researchers are trying to chart the locations and understand the functions of all the chemical tags that mark the genome.

Until recently, scientists thought that human diseases were caused mainly by changes in DNA sequence, infectious agents such as bacteria and viruses, or environmental agents. Now, however, researchers have demonstrated that changes in the epigenome also can cause, or result from, disease. Epigenomics, thus, has become a vital part of efforts to better understand the human body and to improve human health. Epigenomic maps may someday enable doctors to determine an individual's health status and tailor a patient's response to therapies.

As part of the ENCODE (ENCyclopedia Of DNA Elements) project-which aims to catalog the working parts of the genome-the National Human Genome Research Institute is funding researchers to make epigenomic maps of various cell types. Other NIH-supported investigators have developed a number of epigenomic maps from several human organs and tissues. These NIH projects are part of an international effort to understand how epigenomics could lead to better prevention, diagnosis and treatment of disease.

Lick Your Rats

Some mother rats spend a lot of time licking, grooming, and nursing their pups. Others seem to ignore their pups. Highly nurtured rat pups tend to grow up to be calm adults, while rat pups who receive little nurturing tend to grow up to be anxious.

It turns out that the difference between a calm and an anxious rat is not genetic, —it's epigenetic. The nurturing behavior of a mother rat during the first week of life shapes her pups' epigenomes. And the epigenetic pattern that mom establishes tends to stay put, even after the pups become adults.

Nutrition & the Epigenome

Unlike behavior or stress, diet is one of the more easily studied, and therefore better understood, environmental factors in epigenetic change.

The nutrients we extract from food enter metabolic pathways where they are manipulated, modified, and molded into molecules the body can use. One such pathway is responsible for making methyl groups - important epigenetic tags that silence genes.

Familiar nutrients like folic acid, B vitamins, and SAM-e (S-Adenosyl methionine, a popular over-the-counter supplement) are key components of this methyl-making pathway. Diets high in these methyl-donating nutrients can rapidly alter gene expression, especially during early development when the epigenome is first being established.

Epigenetics & the Human Brain

Throughout our lives, the brain remains flexible and responsive. In addition to receiving signals from the outside world, the brain allows us to form memories and learn from our experiences. Many brain functions are accompanied at the cellular level by changes in gene expression. Epigenetic mechanisms such as histone modification and DNA methylation stabilize gene expression, which is important for long-term storage of information.

Not surprisingly, epigenetic changes are also a part of brain diseases such as mental illness and addiction. Understanding the role of epigenetics in brain disease may open the door to being able to influence it. This may lead to the development of new and more effective treatments for brain diseases.

Knowledge Check