How Genes Are Controlled

Gene expression (protein production) is carefully regulated Most genes are not simply “on”, but instead are transcribed when needed … and NOT transcribed when not needed

Development of complex organisms must follow a specific and carefully orchestrated script Too much or too little, too early or too late, too short or too long - any of these can cause developmental problems How is this control of gene expression achieved?

Gene Regulation in Bacteria Natural selection has favored bacteria that express only the genes whose products are needed by the cell

Imagine an Escherichia coli bacterium living in your intestines With no lactose present, efficient bacteria will not express the genes to use lactose If you drink a glass of milk, lactose will be present in your digestive tract The environmental conditions have changed for our bacterium In response, E. coli will express three genes for enzymes that enable the bacterium to absorb and digest this sugar After the lactose is gone, these genes are turned off again All three of the genes lie close together and they are all controlled by one control mechanism - they are present in an operon They are coordinately controlled and coordinately expressed There is a single promoter for the operon There is an operator sequence that overlaps the promoter If there is no lactose then a repressor binds to the operator, RNA polymerase cannot bind to the promoter and initiate transcription

If lactose is present, lactose can bind to the repressor and inactivate it, making it so it no longer binds to the operator The RNA polymerase can now bind and initiate transcription

Many operons are present in bacteria Lactose is a nutrient so it can inactivate an active repressor, allowing transcription Products, like amino acids, can activate an inactive repressor When enough of the amino acid is present, the bacterium will shut off its production

Gene Regulation in Eukaryotes Things are more complicated in eukaryotes There are several steps at which regulation can occur DNA Packaging Cells may use DNA packing for long-term inactivation of genes X chromosome inactivation Occurs in female mammals to compensate for differences in gene dosage between males and females takes place in early embryonic development Which X chromosome is inactivated is random in each cell Once an X chromosome is inactivated, that same chromosome will be inactivated in all cells descended from the original cell If a female is heterozygous for any X-linked gene, about half of her cells will express one allele and the other half of her cells will express the other allele

Initiation of Transcription In both prokaryotes and eukaryotes, the initiation of transcription is the most important stage for regulating gene expression Binding of regulatory proteins can turn the transcription of genes on and off

In eukaryotes, there are a lot more proteins involved Repressors are less common in eukaryotes but activators are much more prevalent The “default” setting for most genes appears to be “off”; the binding of activators controls the degree of “on”

RNA Processing Alternative splicing can lead to the production of different proteins from the same gene This can occur in the same cell in response to different signals or in different cell types

Cell Signaling In multicellular organisms, cells of the same type must communicate with each other to coordinately express genes This requires signal molecules

Homeotic Genes Master control genes called homeotic genes regulate groups of other genes that determine what body parts will develop in which locations Mutations in homeotic genes can produce truly bizarre effects Similar homeotic genes help direct embryonic development in nearly every eukaryotic organism examined so far, including yeasts, plants, earthworms, frogs, chickens, mice, and humans

DNA Microarrays DNA microarrays allow the analysis of the expression patterns of thousands of genes at the same time The glass slide has thousands of cells in a grid pattern In each cell, there is a different kind of DNA fragment in each cell, each representing a different gene Cloning Plants and Animals A clone is a genetically identical copy of a biological entity

All body cells contain a complete complement of genes, even if they are not expressing all of them A single differentiated plant cell can undergo cell division and give rise to a complete adult plant

Reproductive cloning using nuclear transplantation is the process of making clones of animals with a defined genotype and phenotype Many mammals have been cloned using this process Dolly the sheep was the first animal cloned using cells from an adult mammal The first cloned cat was named Copy Cat, CC for short The first cloned dog was named Snuppy The adult cells came from a male Afghan named Taj Only one pregnancy out of many gave a successful clone

Therapeutic Cloning and Stem Cells Most cells in the adult human body have undergone commitment, a developmental process that results in cells whose roles are completely determined

Two promising methods exist for generating human cells that are needed to treat victims of accident or disease: Production from embryonic stem cells Production through induced pluripotent stem cells (iPS) Both methods reprogram the cells to give the desired cell type

The purpose of therapeutic cloning is not to produce a living organism but rather to produce embryonic stem cells

In stark contrast, adult stem cells are rare, only found in certain tissues, and only capable of producing one or a few different cell types The Genetics of Cancer Normal cells experience tight cell cycle control Avoiding that tight control involves changes in gene expression Oncogenes Oncogenes are messed-up versions of normal cellular proto-oncogenes The proto-oncogenes are growth factors, responsible for pushing cells through the cell cycle - “gas pedal” genes Tumor-Suppressor Genes Other genes encode proteins that inhibit the division of damaged cells These tumor-suppressor genes prevent uncontrolled cell division – “brake pedal” genes

The Progression of Cancer Nearly 150,000 Americans will be stricken by colon cancer this year Colon cancer, like many cancers, is a gradual process and requires more than one mutation

So malignant tumors result from conversion of proto-oncogene(s) to oncogene(s) and knockout of tumor-suppressor genes

Since cancers are the results of multiple mutations, we can understand why some families are prone to cancer Individuals that inherit one mutation are one step closer to the mutations responsible for cancer

About 15% of colorectal cancers involve inherited mutations There is also evidence that inheritance plays a role in 5–10% of patients with breast cancer, a disease that strikes one out of every ten American women

Cancer is the second leading cause of death (after heart disease) in most industrialized countries Most cancers arise from mutations that are caused by carcinogens, cancer- causing agents found in the environment, including UV radiation and tobacco products