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Nov 14, 2008

Introduction to Genetics

Alternative Names
Homozygous; Inheritance; Heterozygous; Inheritance patterns; Heredity and disease; Heritable; Genetic markers

Definition
Genetics is the study of heredity, the process in which a parent passes certain genes onto their children. A person's appearance -- height, hair color, skin color, and eye color -- are determined by genes. Other characteristics affected by heredity:

Likelihood of getting certain diseases
Mental abilities
Natural talents

An abnormal trait (anomaly) passed down through families (inherited) may:

Have no effect on your health or well being -- for example, it may just involve a white patch of hair or an extended earlobe
Be of minor consequence -- for example, color blindness
Have a dramatic effect on your quality or length of life

For most genetic disorders, genetic counseling is advised. Many people may also want to seek prenatal diagnosis.
The terms anomaly, abnormality, disorder, defect, disease, and syndrome are not used consistently, and do not have precise definitions.

Information
Human beings have cells with 46 chromosomes -- 2 sex chromosomes and 22 pairs of non-sex (autosomal) chromosomes. Males are "46, XY" and females are "46, XX". The chromosomes are made up of strands of genetic information, called DNA.

Genes are sections of DNA. The location of the gene is called the locus. Most genes carry information that is necessary to make a protein.

The pairs of autosomal chromosomes (one from the mother and one from the father) carry basically the same information. That is, each has the same genes. However, there may be slight variations of these genes. These slight differences occur in less than 1% of the DNA sequence and produce variants of a particular gene, called alleles.

If a gene is abnormal, it may lead to an abnormal protein or an abnormal amount of a normal protein. Since the autosomal chromosomes are paired, there are two copies of each gene, one from each parent. If one of these genes is defective, the other may make enough protein so that no disease is seen. This is called a recessive disease, and the gene is said to be inherited in a recessive pattern.

However, if only one abnormal gene is needed to produce a disease, it's called a dominant hereditary disorder. In the case of a dominant disorder, if one abnormal gene is inherited from mom or dad, the child will likely show the disease.

A person with one abnormal gene is termed HETEROZYGOUS for that gene. If a child receives an abnormal recessive disease gene from both parents, the child will show the disease and will be

HOMOZYGOUS for that gene.
If two parents each have one copy of a recessive disease gene, then each child has a 25% (1 in 4) chance of showing the disease. If one parent has two copies of the disease gene and the other has one copy, then each child has a 50% (1 in 2) chance of being homozygous.

GENETIC DISORDERS
Almost all diseases have a genetic component. However, the importance of that component varies. Disorders in which genes play an important role (genetic diseases) can be classified as:

Single-gene defects
Chromosomal disorders
Multifactorial

A single gene disorder (also called Mendelian disorder) is caused by a defect in one particular gene. Single gene defects are rare. But since there are about 18,000 known single gene disorders, their combined impact is significant.

Single-gene disorders are characterized by how they are passed down in families. There are six basic patterns of single gene inheritance:

Autosomal dominant
Autosomal recessive
X-linked dominant
X-linked recessive
Y-linked inheritance
Maternal (mitochondrial) inheritance

The observed effect of a gene (the appearance of a disorder) is called the phenotype.

People with one copy of a recessive disease gene are called carriers. Carriers usually don't show the disease. However, the gene can often be found by sensitive laboratory tests.

In AUTOSOMAL DOMINANT INHERITANCE, the abnormality or abnormalities usually appear in every generation. Each affected child of an affected parent has a 50% chance of inheriting the disease.

In AUTOSOMAL RECESSIVE INHERITANCE, the parents of an affected individual may not show the disease. On average, the chance of an affected child's brothers or sisters having the disease are 1 in 4. Males and females are equally likely to be affected. For a child to have symptoms of an autosomal recessive disorder, the child must receive the defective gene from BOTH parents.
Because most recessive disorders are rare, a child is at increased risk of a recessive disease if the parents are related. Related individuals are more likely to have inherited the same rare gene from a common ancestor.

In X-LINKED RECESSIVE INHERITANCE, the incidence of the disease is much higher in males than females. Since the abnormal gene is carried on the X chromosome, males do not transmit it to their sons. However, they do transmit it to their daughters.

The presence of one normal X chromosome masks the effects of the X chromosome with the abnormal gene. So, almost all of the daughters of an affected man appear normal, but they are all carriers of the abnormal gene. The sons of these daughters then have a 50% chance of receiving the defective gene.

In X-LINKED DOMINANT INHERITANCE, the presence of the defective gene appears in females even if there is also a normal X chromosome present. Since males pass the Y chromosome to their sons, affected males will not have affected sons. All of their daughters will be affected, however. Sons or daughters of affected females will have a 50% chance of getting the disease.

EXAMPLES OF SINGLE GENE DISORDERS

Autosomal recessive:

ADA deficiency (sometimes called the "boy in a bubble" disease)
Alpha-1-antitrypsin (AAT) deficiency
Cystic fibrosis (CF)
Phenylketonuria (PKU)
Sickle cell anemia
X-linked recessive:
Duchenne muscular dystrophy
Hemophilia A

Autosomal dominant:

Familial hypercholesterolemia
Huntington's disease
X-linked dominant:
Only a few, very rare, disorders are X-linked dominant. One of these is hypophosphatemic rickets, also called vitamin D -resistant rickets.

CHROMOSOMAL DISORDERS

In chromosomal disorders, the defect is due to an excess or lack of the genes contained in a whole chromosome or chromosome segment.
Chromosomal disorders include:

Down syndrome
Klinefelter syndrome
Turner syndrome

MULTIFACTORIAL DISORDERS

Many of the most common diseases involve interactions of several genes and the environment (for example illnesses in the mother and medications). These include:

Cancer
Coronary heart disease
Hypertension
Stroke

MITOCHONDRIAL DNA-LINKED DISORDERS

Mitochondria are small organisms found in most of the body's cells. They are responsible for energy production inside cells. Mitochondria contain their own private DNA.

In recent years, more than 60 hereditary disorders have been shown to result from changes (mutations) in mitochondrial DNA. Because mitochondria come only from the female egg, most mitochondria-related disorders are passed down only from the mother.

Mitochondrial disorders can appear at any age. They have a wide variety of symptoms and signs. These disorders may cause:

Blindness
Developmental delay
Gastrointestinal problems
Hearing loss
Heart rhythm problems
Metabolic disturbances
Short stature

References
Goldman L, Ausiello D. Cecil Textbook of Medicine. 23rd ed. Philadelphia, Pa: Saunders Elsevier; 2007.

Update Date: 5/20/2008 （Source：NIH）

Updated by: Diana Chambers, MS, EdD, Certified Genetics Counselor (ABMG), Charter Member of the American Board of Genetic Counseling, University of Tennessee, Memphis, TN. Review provided by VeriMed Healthcare Network. Also reviewed by David Zieve, MD, MHA, Medical Director, A.D.A.M., Inc.

Nov 7, 2008

Gene Therapy for Cancer: Questions and Answers

Key Points
Gene therapy is an experimental treatment that involves introducing genetic material into a person's cells to fight or prevent disease (see Question 2).

Researchers are studying gene therapy for cancer through a number of different approaches (see Question 3).

A gene can be delivered to a cell using a carrier known as a “vector.” The most common types of vectors used in gene therapy are viruses (see Question 4).

The viruses used in gene therapy are altered to make them safe; however, some risks still exist with gene therapy (see Questions 5 and 6).

A clinical trial using gene therapy must be approved by at least two review boards at the scientists’ institution, as well as by the U.S. Food and Drug Administration and the National Institutes of Health Recombinant DNA Advisory Committee (see Questions 9 and 10).

The Ethical, Legal, and Social Implications (ELSI) Research Program was established in 1990 to identify, analyze, and address the implications of human genetics research (see Questions 11 and 12).

What are genes? Genes are the biological units of heredity. Genes determine obvious traits, such as hair and eye color, as well as more subtle characteristics, such as the ability of the blood to carry oxygen. Complex characteristics, such as physical strength, may be shaped by the interaction of a number of different genes along with environmental influences.

Genes are located on chromosomes inside cells and are made of deoxyribonucleic acid (DNA), which is a type of biological molecule. Humans have between 30,000 and 40,000 genes. Genes carry the instructions that allow cells to produce specific proteins, such as enzymes.

To make proteins, a cell must first copy the information stored in genes into another type of biological molecule called ribonucleic acid (RNA). The cell's protein synthesizing machinery then decodes the information in the RNA to manufacture specific proteins. Only certain genes in a cell are active at any given moment. As cells mature, many genes become permanently inactive. The pattern of active and inactive genes in a cell and the resulting protein composition determine what kind of cell it is and what it can and cannot do. Flaws in genes can result in disease.

What is gene therapy?

Advances in understanding and manipulating genes have set the stage for scientists to alter a person's genetic material to fight or prevent disease. Gene therapy is an experimental treatment that involves introducing genetic material (DNA or RNA) into a person's cells to fight disease. Gene therapy is being studied in clinical trials (research studies with people) for many different types of cancer and for other diseases. It is not currently available outside a clinical trial.

How is gene therapy being studied in the treatment of cancer?

Researchers are studying several ways to treat cancer using gene therapy. Some approaches target healthy cells to enhance their ability to fight cancer. Other approaches target cancer cells, to destroy them or prevent their growth. Some gene therapy techniques under study are described below.

In one approach, researchers replace missing or altered genes with healthy genes. Because some missing or altered genes (e.g., p53) may cause cancer, substituting “working” copies of these genes may be used to treat cancer. Researchers are also studying ways to improve a patient's immune response to cancer. In this approach, gene therapy is used to stimulate the body's natural ability to attack cancer cells. In one method under investigation, researchers take a small blood sample from a patient and insert genes that will cause each cell to produce a protein called a T-cell receptor (TCR). The genes are transferred into the patient's white blood cells (called T lymphocytes) and are then given back to the patient. In the body, the white blood cells produce TCRs, which attach to the outer surface of the white blood cells. The TCRs then recognize and attach to certain molecules found on the surface of the tumor cells. Finally, the TCRs activate the white blood cells to attack and kill the tumor cells.

Scientists are investigating the insertion of genes into cancer cells to make them more sensitive to chemotherapy, radiation therapy, or other treatments. In other studies, researchers remove healthy blood-forming stem cells from the body, insert a gene that makes these cells more resistant to the side effects of high doses of anticancer drugs, and then inject the cells back into the patient. In another approach, researchers introduce “suicide genes” into a patient's cancer cells. A pro-drug (an inactive form of a toxic drug) is then given to the patient. The pro-drug is activated in cancer cells containing these “suicide genes, ” which leads to the destruction of those cancer cells.

Other research is focused on the use of gene therapy to prevent cancer cells from developing new blood vessels (angiogenesis).

How are genes transferred into cells so that gene therapy can take place?

In general, a gene cannot be directly inserted into a person's cell. It must be delivered to the cell using a carrier, or “vector.” The vectors most commonly used in gene therapy are viruses. Viruses have a unique ability to recognize certain cells and insert genetic material into them. In some gene therapy clinical trials, cells from the patient's blood or bone marrow are removed and grown in the laboratory. The cells are exposed to the virus that is carrying the desired gene. The virus enters the cells and inserts the desired gene into the cells’ DNA. The cells grow in the laboratory and are then returned to the patient by injection into a vein. This type of gene therapy is called ex vivo because the cells are grown outside the body. The gene is transferred into the patient's cells while the cells are outside the patient's body.

In other studies, vectors (often viruses) or liposomes (fatty particles) are used to deliver the desired gene to cells in the patient's body. This form of gene therapy is called in vivo, because the gene is transferred to cells inside the patient's body.

What types of viruses are used in gene therapy, and how can they be used safely?

Many gene therapy clinical trials rely on retroviruses to deliver the desired gene. Other viruses used as vectors include adenoviruses, adeno-associated viruses, lentiviruses, poxviruses, and herpes viruses. These viruses differ in how well they transfer genes to the cells they recognize and are able to infect, and whether they alter the cell's DNA permanently or temporarily. Thus, researchers may use different vectors, depending on the specific characteristics and requirements of the study.

Scientists alter the viruses used in gene therapy to make them safe for humans and to increase their ability to deliver specific genes to a patient's cells. Depending on the type of virus and the goals of the research study, scientists may inactivate certain genes in the viruses to prevent them from reproducing or causing disease. Researchers may also alter the virus so that it better recognizes and enters the target cell.

What risks are associated with current gene therapy trials?

Viruses can usually infect more than one type of cell. Thus, when viral vectors are used to carry genes into the body, they might infect healthy cells as well as cancer cells. Another danger is that the new gene might be inserted in the wrong location in the DNA, possibly causing harmful mutations to the DNA or even cancer.

In addition, when viruses or liposomes are used to deliver DNA to cells inside the patient's body, there is a slight chance that this DNA could unintentionally be introduced into the patient's reproductive cells. If this happens, it could produce changes that may be passed on if a patient has children after treatment.

Other concerns include the possibility that transferred genes could be “overexpressed,” producing so much of the missing protein as to be harmful; that the viral vector could cause inflammation or an immune reaction; and that the virus could be transmitted from the patient to other individuals or into the environment. Scientists use animal testing and other precautions to identify and avoid these risks before any clinical trials are conducted in humans.

What major problems must scientists overcome before gene therapy becomes a common technique for treating disease?

Scientists need to identify more efficient ways to deliver genes to the body. To treat cancer and other diseases effectively with gene therapy, researchers must develop vectors that can be injected into the patient and specifically focus on the target cells located throughout the body. More work is also needed to ensure that the vectors will successfully insert the desired genes into each of these target cells.

Researchers also need to be able to deliver genes consistently to a precise location in the patient's DNA, and ensure that transplanted genes are precisely controlled by the body's normal physiologic signals.

Although scientists are working hard on these problems, it is impossible to predict when they will have effective solutions.

The first disease approved for treatment with gene therapy was adenosine deaminase (ADA) deficiency. What is this disease and why was it selected?

ADA deficiency is a rare genetic disease. The normal ADA gene produces an enzyme called adenosine deaminase, which is essential to the body's immune system. Patients with ADA deficiency do not have normal ADA genes and do not produce functional ADA enzymes. ADA-deficient children are born with severe immunodeficiency and are prone to repeated serious infections, which may be life-threatening. Although ADA deficiency can be treated with a drug called PEG-ADA, the drug is extremely costly and must be taken for life by injection into a vein.

ADA deficiency was selected for the first approved human gene therapy trial for several reasons: The disease is caused by a defect in a single gene, which increases the likelihood that gene therapy will succeed.

The gene is regulated in a simple, “always-on” fashion, unlike many genes whose regulation is complex. The amount of ADA present does not need to be precisely regulated. Even small amounts of the enzyme are known to be beneficial, while larger amounts are also tolerated well.

How do gene therapy trials receive approval?

A proposed gene therapy trial, or protocol, must be approved by at least two review boards at the scientists’ institution. Gene therapy protocols must also be approved by the U.S. Food and Drug Administration (FDA), which regulates all gene therapy products. In addition, trials that are funded by the National Institutes of Health (NIH) must be registered with the NIH Recombinant DNA Advisory Committee (RAC). The NIH, which includes 27 Institutes and Centers, is the Federal focal point for biomedical research in the United States.

Why are there so many steps in this process?

Any studies involving humans must be reviewed with great care. Gene therapy in particular is potentially a very powerful technique, is relatively new, and could have profound implications. These factors make it necessary for scientists to take special precautions with gene therapy.

What are some of the social and ethical issues surrounding human gene therapy?

In large measure, the issues are the same as those faced whenever a powerful new technology is developed. Such technologies can accomplish great good, but they can also result in great harm if applied unwisely.

Gene therapy is currently focused on correcting genetic flaws and curing life-threatening disease, and regulations are in place for conducting these types of studies. But in the future, when the techniques of gene therapy have become simpler and more accessible, society will need to deal with more complex questions.

One such question is related to the possibility of genetically altering human eggs or sperm, the reproductive cells that pass genes on to future generations. (Because reproductive cells are also called germ cells, this type of gene therapy is referred to as germ-line therapy.) Another question is related to the potential for enhancing human capabilities—for example, improving memory and intelligence—by genetic intervention. Although both germ-line gene therapy and genetic enhancement have the potential to produce benefits, possible problems with these procedures worry many scientists. Germ-line gene therapy would forever change the genetic makeup of an individual's descendants. Thus, the human gene pool would be permanently affected. Although these changes would presumably be for the better, an error in technology or judgment could have far-reaching consequences. The NIH does not approve germ-line gene therapy in humans.

In the case of genetic enhancement, there is concern that such manipulation could become a luxury available only to the rich and powerful. Some also fear that widespread use of this technology could lead to new definitions of “normal” that would exclude individuals who are, for example, of merely average intelligence. And, justly or not, some people associate all genetic manipulation with past abuses of the concept of “eugenics,” or the study of methods of improving genetic qualities through selective breeding.

What is being done to address these social and ethical issues?

Scientists working on the Human Genome Project (HGP), which completed mapping and sequencing all of the genes in humans, recognized that the information gained from this work would have profound implications for individuals, families, and society. The Ethical, Legal, and Social Implications (ELSI) Research Program was established in 1990 as part of the HGP to address these issues. The ELSI Research Program fosters basic and applied research on the ethical, legal, and social implications of genetic and genomic research for individuals, families, and communities. The ELSI Research Program sponsors and manages studies and supports workshops, research consortia, and policy conferences on these topics. More information about the HGP and the ELSI Research Program can be found on the National Human Genome Research Institute (NHGRI) Web site at http://www.genome.gov on the Internet.

You and Your Genes

You and your genes.

Play the DNA - The Double Helix Game (Nobel Foundation) - Requires Flash Player

DNA - The Double Helix

In the beginning of the 1950s, biologists knew that DNA carried the hereditary message. But how? The DNA molecule looks like a spiral ladder where the rungs are formed by base molecules, which occur in pairs. These sequences of base pairs represent the genetic information. In the game below, you can make copies of DNA molecules and find out which organism the genetic material belongs to!

Play the DNA - The Double Helix Game

Stool DNA and Occult Blood Testing to Screen for Colorectal Neoplasia

7 October 2008 | Volume 149 Issue 7 | Page I-20
Summaries for Patients are a service provided by Annals to help patients better understand the complicated and often mystifying language of modern medicine.

Summaries for Patients are presented for informational purposes only. These summaries are not a substitute for advice from your own medical provider. If you have questions about this material, or need medical advice about your own health or situation, please contact your physician. The summaries may be reproduced for not-for-profit educational purposes only. Any other uses must be approved by the American College of Physicians.
The summary below is from the full report titled "Stool DNA and Occult Blood Testing for Screen Detection of Colorectal Neoplasia." It is in the 7 October 2008 issue of Annals of Internal Medicine (volume 149, pages 441-450). The authors are D.A. Ahlquist, D.J. Sargent, C.L. Loprinzi, T.R. Levin, D.K. Rex, D.J. Ahnen, K. Knigge, M.P. Lance, L.J. Burgart, S.R. Hamilton, J.E. Allison, M.J. Lawson, M.E. Devens, J.J. Harrington, and S.L. Hillman.

What is the problem and what is known about it so far?

Colorectal cancer arises from the lining of the colon. It causes more deaths than any other type of cancer except lung cancer, but it is curable if detected and removed before it spreads to other organs. Fortunately, colon cancer develops from growths called polyps, which do not spread to other organs but are detectable by imaging tests, such as radiography; inspecting the surface of the colon through a flexible tube (colonoscopy); and testing the stool for substances released from polyps and cancers. Polyps take 5 to 10 years to become cancerous. Abnormalities in DNA from cells in a polyp cause the cells to lose control of division, which allows the polyp to become larger. Additional DNA abnormalities occur that allow cancer cells to invade the rest of the body. Polyps and cancer constantly shed cells into the stool, and it is possible to detect the mutations that cause polyps to grow and become malignant. The tests are called stool DNA tests.

Why did the researchers do this particular study?

To see whether stool DNA tests detected more polyps and cancers than did tests for blood in the stool, a well-proven colon cancer screening test.

Who was studied?

3764 healthy adults with an average risk for colon cancer.

How was the study done?

The study participants collected samples of stool at home and sent them to a laboratory that tested for hidden blood. Another laboratory tested the stool to see whether it contained DNA abnormalites associated with polyps or cancer. The laboratory used 2 tests, which were designed to detect different gene abnormalities. Everybody had colonoscopy, the most reliable test for colon polyps and cancer.

What did the researchers find?

The best test for blood in the stool detected 21% of the cases of cancer and most worrisome types of polyps. The older of the 2 stool DNA tests (called SDT-1) detected 20% of cases of cancer. The newer stool DNA test (called SDT-2) detected 40% of the cases of cancer and most worrisome types of polyps.

What were the limitations of the study?

The researchers did not measure the frequency of positive SDT-2 tests in all patients who did not have worrisome polyps or cancer (false-positive results).

What are the implications of the study?

Testing stool for DNA abnormalities that control cell growth is a promising way to screen for colon polyps and cancer.

Related articles in Annals:
Articles
Stool DNA and Occult Blood Testing for Screen Detection of Colorectal Neoplasia
David A. Ahlquist, Daniel J. Sargent, Charles L. Loprinzi, Theodore R. Levin, Douglas K. Rex, Dennis J. Ahnen, Kandice Knigge, M. Peter Lance, Lawrence J. Burgart, Stanley R. Hamilton, James E. Allison, Michael J. Lawson, Mary E. Devens, Jonathan J. Harrington, AND Shauna L. Hillman
Annals 2008 149: 441-450. [ABSTRACT][SUMMARY][Full Text]

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Nov 22, 2008

Advances in DNA (Gene) -2

Advances in DNA (Gene) -1

Nov 14, 2008

Introduction to Genetics

Nov 7, 2008

Gene Therapy for Cancer: Questions and Answers

You and Your Genes

Play the DNA - The Double Helix Game (Nobel Foundation) - Requires Flash Player

Stool DNA and Occult Blood Testing to Screen for Colorectal Neoplasia

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