During Amniocentesis a small amount of amniotic fluid, which contains fetal tissues, is extracted from the amnion or amniotic sac surrounding a developing fetus, and the fetal DNA is examined for genetic abnormalities. Amniocentesis is not performed for every pregnancy, but is generally done when an increased risk of genetic defects in the fetus is indicated, by mother's age (over 35 years is common), family history of genetic defects, or other factors.
Chorionic villus sampling (CVS) involves removing a sample of the chorionic villus (placental tissue) and testing it. It is generally carried out only on pregnant women over the age of 35 and those whose offspring have a higher risk of Down syndrome and other chromosomal conditions. The advantage of CVS is that it can be carried out 10-12 weeks after the last period, earlier than amniocentesis.
DNA from the developing baby may be isolated from either an amniocentesis or CVS. A karyotype may be created from fetal chromosomes following either procedure, or a specific mutation may be analyzed. The analysis of specific mutations will be discussed in the chapter titled Biotechnology.
Gene Therapy
So, how do you treat genetic disorders? If medically possible, each manifestation can be treated separately. But is there a way to use genetics to treat the root cause of the disease – that is, to fix the mistake in the DNA?
Gene therapy is the insertion of a new gene into an individual’s cells and tissues to treat a disease, replacing a mutant disease-causing allele with a normal, non-mutant allele. Although the technology is still in its early stages of development, it has been used with some success.
There are a number of mechanisms used to replace or repair a defective gene in gene therapy.
A normal gene may be inserted into a nonspecific location within the genome to replace a nonfunctional gene. This approach is most common.
An abnormal gene could be replaced by a normal gene through homologous recombination.
The abnormal gene could be repaired through selective reverse mutation, which returns the gene to its normal, non-mutant state.
The regulation (the degree to which a gene is turned on or off) of a particular gene could be altered.
As stated above, the most common gene therapy approach is to replace a disease-causing allele with a normal allele. To deliver the new allele to the appropriate cells, a carrier, called a vector, must be used. Currently, the most common type of vectors are viruses that have been genetically altered to carry normal human DNA, and not to result in any phenotypes associated with the virus. As viruses have evolved a robust method of delivering their viral genes to human cells, scientists have tried to develop (and are continuing to develop) methods to take advantage of this process, and have these vectors insert human DNA into target cells. Scientists have manipulated the viral genome to remove disease-causing genes and insert therapeutic human genes (Figure below). For obvious reasons, this is currently a field of intense biomedical research.
Figure 9.15
Gene Therapy using a viral vector. The new gene is inserted into the viral genome, the virus binds to the cell membrane and enters the cell by endocytosis. The viral genome, containing the new gene is injected into the cell nucleus, where the viral DNA is transcribed, starting the process of protein synthesis.
A patient's target cells, such as liver or lung cells are infected with the genetically altered virus. The vector then unloads its genetic material containing the therapeutic human gene into the target cell. The generation of a functional protein product from the therapeutic gene should restore the target cell to a normally functioning phenotype. To date, this process has had limited success, but who can say what will happen in the future.
Severe Combined Immunodeficiency
Severe Combined Immunodeficiency, or SCID, is a heritable immunodeficiency - a genetic disorder that cripples the immune system. It is also known as the ‘bubble boy’ disease, named after David Vetter, SCID’s most famous patient who lived for over 12 years in a sterilized environment, just like living inside a “bubble.” SCID affects about 1 in 100,000 live births. These babies, if untreated, usually die within one year due to severe, recurrent infections. Treatment options have improved considerably and include bone marrow transplants and gene therapy. Children no longer have to live inside a bubble as did David Vetter, who was placed inside his sterile bubble about 10 seconds after birth. He died 15 days after he left his sterile environment, due to an undetected virus in the bone marrow transplant. David was one of the first bone marrow recipients.
More recently gene therapy has proved successful in treating SCID. Insertion of the correct gene into cells of the immune system should correct the problem. Trials started in 1990, and in 1999, the first SCID patients were detected with functional immune systems. Due to some complications these trials had to be stopped, but these issues seem to have been resolved. Gene therapy in individuals with SCID have been human genetics only gene therapy success stories. Since 1999, gene therapy has restored the immune systems of at least seventeen children with the disorder. This raises great hope for other genetic disorders. In your lifetime, it is definitely possible that many genetic disorders may be “cured” by gene therapy. As was mentioned earlier, no one can say what will happen in the future, and no one knows what lies ahead.
Lesson Summary
In humans, whereas many genetic disorders are inherited in a recessive manner, simple dominant inheritance accounts for many of a person’s physical characteristics.
Genetic diseases may also be dominantly inherited, such as with achondroplasia.
Genetic diseases may be due to specific mutations within a gene or to large chromosomal abnormalities.
Traits controlled by genes located on the sex chromosomes (X and Y) are called sex-linked traits.
Any recessive allele on the X chromosome of a male will not be masked by a dominant allele.
Codominance is when two alleles are both expressed in the heterozygous individual.
Incomplete dominance is seen in heterozygous individuals with an intermediate phenotype.
Traits controlled by more than two alleles have multiple alleles.
Many genes have multiple phenotypic effects, a property called pleiotropy.
Epistasis is when a gene at one location (locus) alters the phenotypic expression of a gene at another locus.
Polygenic traits are due to the actions of more than one gene and often, their interaction with the environment.
Trisomy is a state where humans have an extra autosome; they have three of a particular chromosome instead of two.
The most common trisomy in viable births is Trisomy 21 (Down Syndrome).
Prenatal diagnosis refers to the diagnosis of a disease or condition before the baby is born.
Amniocentesis and choronic villus sampling are invasive methods involved in prenatal diagnosis.
Gene therapy is the insertion of a new gene into an individual’s cells and tissues to treat a disease, replacing a mutant disease-causing allele with a normal, non-mutant allele.
Review Questions
What is a genetic disease?
Discuss the main difference between autosomal and sex-linked.
Why is variation within the human genome important?
Why is it more common for males to have X-linked disorders?
Describe how a mutation can lead to a genetic disease.
Discuss how a new mutation can become a new dominant allele.
How are autosomal traits usually inherited? Give examples of traits.
How are genetic diseases usually inherited? Are there exceptions? Give examples.
Discuss the difference between codominance and incomplete dominance. Give examples.
What is meant by trisomy? (Beginning) How can trisomy phenotypes be detected?
What is the most common viable trisomy disorder?
List conditions involving an abnormal number of sex chromosomes.
Why is genetic counseling important?
What is gene thera
py?
Describe the most common approach to gene therapy.
Further Reading / Supplemental Links
The National Human Genome research Institute:
http://www.genome.gov
The Dolan DNA Learning Center:
http://www.dnalc.org/home_alternate.html
DNA Interactive:
http://www.dnai.org/
A Science Odyssey: DNA Workshop:
http://www.pbs.org/wgbh/aso/tryit/dna/
Kimball’s Biology Pages:
http://users.rcn.com/jkimball.ma.ultranet/BiologyPages
http://en.wikipedia.org
Vocabulary
achondroplasia
An autosomal dominant disorder; the most common cause of dwarfism.
amniocentesis
A prenatal diagnostic procedure in which a small amount of amniotic fluid, which contains fetal tissues, is extracted from the amnion or amniotic sac surrounding a developing fetus, so that the fetal DNA is examined for genetic abnormalities.
autosomal dominant disorder
A disorder in which only one mutated allele is needed for a person to be affected.
autosomal recessive disorder
A disorder in which both copies of the gene must be mutated for a person to be affected.
autosome
Any chromosome other than a sex chromosome.
chorionic villus sampling (CVS)
A prenatal diagnostic procedure which involves removing a sample of the chorionic villus (placental tissue) and testing it.
codominance
When two alleles are both expressed in the heterozygous individual; both alleles affect the phenotype in separate and distinguishable ways.
cystic fibrosis (CF)
A recessive inheritable disorder caused by a mutation in a gene called the cystic fibrosis transmembrane conductance regulator (CFTR).
Duchenne muscular dystrophy (DMD)
The most common type of muscular dystrophy; an X-linked recessive disorder.
epistasis
When a gene at one location (locus) alters the phenotypic expression of a gene at another locus.
gene therapy
The insertion of a new gene into an individual’s cells and tissues to treat a disease, replacing a mutant disease-causing allele with a normal, non-mutant allele.
genetic counseling
The process by which individuals or their families who are at risk of an inherited disorder are counseled on many different aspects of the disorder.
genetic counselor
An individual trained in human genetics and counseling.
hemophilia
A group of diseases in which blood does not clot normally.
incomplete dominance
Occurs in heterozygous individuals with an intermediate phenotype; neither allele is dominant over the other.
Klinefelter's syndrome
Caused by the presence of one or more extra copies of the X chromosome in a male's cells.
multiple allele traits
Traits controlled by more than two alleles.
muscular dystrophy
A term encompassing a variety of muscle wasting diseases.
mutation
A change in the nucleotide sequence of DNA or RNA.
nondisjunction
The failure of replicated chromosomes to separate during anaphase II of meiosis.
pedigree
A chart which shows all of the known individuals within a family with a particular phenotype; a representation of genetic inheritance.
Phenylketonuria (PKU)
An autosomal recessive genetic disorder characterized the inability to metabolize the amino acid phenylalanine.
pleiotropy
Having multiple phenotypic effects.
polygenic traits
Traits that are due to the actions of more than one gene and often, their interaction with the environment.
prenatal diagnosis
The diagnosis of a disease or condition in a developing baby; done before the baby is born.
Severe Combined Immunodeficiency (SCID)
A heritable immunodeficiency; a genetic disorder that cripples the immune system.
sex chromosomes
Specify an organism's genetic sex; in humans, the X and Y chromosomes.
sex-linked traits
Traits controlled by genes located on the sex chromosomes (X and Y).
Tay-Sachs disease
An autosomal recessive genetic disorder that is fatal in early childhood; results from the accumulation of harmful quantities of fat in the nerve cells of the brain.
trisomy
A state where humans have an extra autosome, having 47 chromosomes instead of 46. For example, trisomy 16 results in a third chromosome 16.
trisomy 21
Down syndrome; individuals often have some degree of mental retardation, some impairment of physical growth, and a specific facial appearance.
trisomy X
Triple X syndrome; results from an extra copy of the X chromosome in each of a female's cells.
X-linked disorder
A disorder caused by a mutation in a gene on the X chromosome; may be dominant or recessive, though the majority of X-linked disorders are recessive.
Y-linked disorder
A disorder caused by a mutation in a gene on the Y chromosome; only affects males.
Points to Consider
In this chapter, we discussed human genetics as involved in human health. In the next chapter, we will discuss biotechnology. With gene therapy, we can see how biotechnology will play a significant role in society’s future.
Can you speculate on the role of biotechnology in our future?
What other roles for biotechnology do you envision?
Why is biotechnology important?
Chapter 10: Biotechnology
Lesson 10.1: DNA Technology
Lesson Objectives
What is meant by DNA technology?
What is the Human Genome Project?
Describe the goals of the Human Genome Project.
Describe gene cloning and the processes involved.
What is PCR?
Describe the processes involved in PCR.
Introduction
Is it really possible to clone people? Another question is, should we clone people? Are scientific fantasies, such as depicted on TV shows such as Star Trek or in the movie GATTACA, actually a possibility? Who can really say? How, really, will science affect our future? The answers partially lie in the field of biotechnology.
Biotechnology is technology based on biological applications. These applications are increasingly used in medicine, agriculture and food science. Biotechnology combines many features of biology, including genetics, molecular biology, biochemistry, embryology, and cell biology. Many aspects of biotechnology center around DNA and its applications, otherwise known as DNA technology. We could devote a whole textbook to current applications of biotechnology; in this chapter, however, we will focus on the applications towards medicine and the extension into the forensic sciences. First, though, we need to understand DNA technology.
DNA Technology
What is DNA technology? Is it using and manipulating DNA to help people? Is it using DNA to make better medicines and individualized treatments? Is it analyzing DNA to determine predispositions to genetic diseases? The answers to these questions, and many more, is yes. And the answers to many of these issues begin with the Human Genome Project.
The Human Genome Project
If we are all 99.9% genetically identical, what makes us different? How does that 0.1% make us tall or short, light or dark, develop cancer or not? To understand that 0.1%, we also need to understand the other 99.9%. Understanding the human genome is the goal of The Human Genome Project (HGP). This project, publicly funded by the United States Department of Energy (DOE) (Figure below); and the National Human Genome Research Institute (NHGRI), part of the National Institutes of Health
(NIH), may be one of the landmark scientific events of our lifetime. Our Molecular Selves video discusses the human genome, and is available at http://www.genome.gov/25520211.
Figure 10.1
The Human Genome Project logo of the DOE.
The goal of the HGP is to understand the genetic make-up of the human species by determining the DNA sequence of the human genome (Figure below);and the genome of a few model organisms. However, it is not just determining the 3 billion bases; it is understanding what they mean. Today, all 3 billion base pairs have been sequenced, and the genes in that sequence are in the process of being identified and characterized. A preliminary estimate of the number of genes in the human genome is around 22,000 to 23,000.
Figure 10.2
A depiction of DNA sequence analysis. Note the 4 colors utilized, each representing a separate base.
The sequence of the human DNA is stored in databases available to anyone on the Internet. The U.S. National Center for Biotechnology Information (NCBI), part of the NIH, as well as comparable organizations in Europe and Japan, maintain the genomic sequences in a database known as Genbank. Protein sequences are also maintained in this database. The sequences in these databases are the combined sequences of anonymous donors, and as such do not yet address the individual differences that make us unique. However, the known sequence does lay the foundation to identify the unique differences among all of us. Most of the currently identified variations among individuals will be single nucleotide polymorphisms, or SNPs. A SNP (pronounced "snip") is a DNA sequence variation occurring at a single nucleotide in the genome. For example, two sequenced DNA fragments from different individuals, GGATCTA to GGATTTA, contain a difference in a single nucleotide. If this base change occurs in a gene, the base change then results in two alleles: the C allele and the T allele. Remember an allele is an alternative form of a gene. Almost all common SNPs have only two alleles. The effect of these SNPs on protein structure and function, and any effect on the resulting phenotype, is an extensive field of study.
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