CK-12 Biology I - Honors
Page 39
Sex chromosomes specify an organism's genetic sex. Humans have two different sex chromosomes, one called X and the other Y.
Sex-linked genes are located on either the X or Y chromosome, though it more commonly refers to genes located on the X-chromosome.
Early in embryonic development in females, one of the two X chromosomes is randomly inactivated in nearly all somatic cells. This process is called X-inactivation.
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? Research examples.
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
autosome
Any chromosome other than a sex chromosome.
Barr body
The inactive X-chromosome in females.
chromosome
A threadlike molecule of genes and other DNA wound around histone proteins; located in the nucleus of a cell.
genetic counselor
An individual trained in human genetics and counseling.
genetic disease
A phenotype due to a mutation in a gene or chromosome.
geneticist
A medical doctor specializing in genetic disorders.
genetics
The branch of biology that focuses on heredity.
genome
All of the hereditary information encoded in the DNA, including the genes and non-coding sequences.
karyotype
Depicts, usually in a photograph, the chromosomal complement of an individual, including the number of chromosomes and any large chromosomal abnormalities.
linkage
Refers to particular genetic loci or alleles inherited together, suggesting that they are physically on the same chromosome, and located close together on that chromosome.
microsatellite
Short sequences of 100-200 bp, usually due to repeats of 1-6 bp sequences; also known as a STR (Short Tandem Repeat) polymorphism.
minisatellite
Short sequence polymorphisms of 6-10 bp repeats.
proteome
The complete set of proteins expressed by a genome, cell, tissue, or organism.
repetitive sequences
DNA sequences that repeat a number of times; also known as repetitive elements.
sex chromosomes
Specify an organism's genetic sex; in humans, the X and Y chromosomes.
sex-linked disease
A disorder due to a mutation in a gene on the X-chromosome; also called X-linked disorder.
SNPs
Single Nucleotide Polymorphisms; substitutions in individual bases along a gene or chromosome.
SRY
Sex-determining region Y; gene which encodes the testes-determining factor and triggers testis development, thus determining sex; located on the Y chromosome.
VNTR
Variable Number of Tandem Repeat; short nucleotide sequence ranging from 14 to 100 nucleotides long, organized into clusters of tandem repeats, usually repeated in the range between 4 and 40 times per loci.
X-inactivation
The random inactivation of one X-chromosome in females; occurs early in embryonic development.
Points to Consider
How are traits inherited? How about the inheritance of genetic disorders? Are inheritance patterns of traits and disorders similar?
Could simple Mendelian inheritance account for such complex traits with vast phenotypic variation such as height or skin color? What do you think?
Lesson 9.2: Human Inheritance
Lesson Objectives
Describe the difference between a genetic trait and a genetic disease/disorder.
Define the various modes of inheritance, focusing on the differences between autosomal and sex-linked.
Gives examples of dominant and recessive genetic disorders.
Discuss the inheritance of sex-linked traits.
Discuss complex inheritance patterns.
Define codominant alleles and give examples.
Define incomplete dominance.
Give examples of multiple allele traits.
Discuss how a trisomy condition may be detected.
What is Down syndrome?
List some examples of phenotypes due to abnormal numbers of sex chromosomes.
Discuss the importance of gene therapy.
Describe the most common method of gene therapy.
Introduction
What is a genetic trait? Is a genetic disease a trait? The answer to these questions may be debated, but a genetic trait is a characteristic of you encoded in your DNA. Could you say that a genetic disease is encoded in your DNA? Well, by definition, yes you can.
How are traits inherited? Do different traits have different patterns of inheritance? Is it as simple as a one allele – one phenotype relationship? Or is it more complex? Is there a difference if the gene is located on an autosome or a sex chromosome? Can there be traits due to multiple genes? The answer to all of the above questions is a resounding ‘sometimes.’ Sometimes it is as simple as a one allele – one phenotype relationship, sometimes it is more complex. Sometimes there is a difference depending on the location of the gene. Sometimes traits can be due to multiple genes. Human genetics is an exciting aspect of biology and medicine; an aspect of biology that is extremely important to our health and well being.
Autosomal and Sex-Linked Traits: Mutations and Genetic Disorders
Autosomal vs. sex-linked. In terms of genetics, is the location of a gene or trait an important piece of information? Does it make a difference if the gene is located on a sex chromosome or an autosome? It might. Remember from lesson 9.1 that sex chromosomes determine an organism’s sex, so the autosomes are the other chromosomes. Autosomal-linked traits are due to genes on the autosomes; sex-linked traits are due to genes located on the sex chromosomes.
What is the difference between a trait and a genetic disorder? Could a disorder be considered a trait? We tend to think of traits as hair color or skin color and disorders as something that is bad for you. But in terms of genetics, a genetic disorder is a trait. Both may be due to your genes.
Simple Dominant Heredity
How are traits due to genes on autosomes inherited? Autosomal traits due to the effects of one gene are usually inherited in a simple Mendelian pattern. That is, they can be either dominant or recessive. In humans, whereas many genetic disorders are inherited in a recessive manner, simple dominant inheritance accounts for many of a person’s physical characteristics, such as chin, earlobe, hairline and thumb shape. For example, having earlobes that are attached to the head is a recessive trait, whereas heterozygous and homozygous dominant individuals have freely hanging earlobes. If you have a cleft chin, a pointed frontal hairline (called a widow’s peak), or a hitchhiker’s thumb, you have inherited the dominant allele for each characteristic from at least one of your parents. Other dominant traits include the presence of hair on the middle section of your fingers, thick lips, and almond-shaped eyes. A widow's peak and earlobe shape are di
splayed in Figure below and Figure below.
Figure 9.5
A young woman with a widows peak, due to a dominant allele.
Figure 9.6
A diagram showing free (left) and attached (right) earlobes. Attached earlobes is a recessive trait.
Mutations and Genetic Disorders
Mutations, changes in the DNA or RNA sequence, can have significant phenotypic effects or no effects. We have previously discussed various types of mutations. Now, let’s discuss the outcomes of some of those mutations. As mentioned at the beginning of this chapter, a genetic disorder is a condition caused by abnormalities, such as mutations, in your genes or chromosomes. Genetic disorders are usually present from conception. These disorders include chromosomal abnormalities, in which the individual has too few or too many chromosomes or chromosomes with large alterations, or diseases due to a mutation in a specific gene. These defective genes are usually inherited from the parents, hence the term hereditary disease or genetic disorder. Genetic disorders can be inherited in a dominant or recessive manner (Figure below and Figure below). Recessive disorders require the inheritance of a defective gene from each parent. The parents are usually unaffected and are healthy carriers of the defective gene.
Figure 9.7
Autosomal Dominant Inheritance. Only one affected allele is necessary to result in the affected phenotype. For a genetic disease inherited in this manner, only one mutant allele is necessary to result in the phenotype. Achondroplasia (discussed later) is an example of a dominant disorder. Both homozygous and heterozygous individuals will show the phenotype.
Figure 9.8
Autosomal Recessive inheritance. For a genetic disease inherited in this manner, two mutant alleles are necessary to result in the phenotype. Tay-Sachs Disease (discussed later) is an example of a recessive disorder. Notice that both parents are unaffected carriers of the mutant allele. These unaffected carriers allow the allele to be maintained in the gene pool - the complete set of a population's genes. Even if the allele is lethal in the homozygous recessive condition, the allele will be maintained through heterozygous individuals.
How can you, or a geneticist, determine the inheritance pattern of a phenotype? A pedigree, which is essentially a representation of genetic inheritance, is helpful. A pedigree is a chart, much like a family tree, which shows all of the known individuals within a family with a particular phenotype (Table below). Pedigrees have been discussed in the chapter titled Mendelian Genetics. Examples of autosomally inherited disorders include cystic fibrosis, Tay-Sachs disease, phenylketonuria, and achondroplasia.
Autosomal and Sex-linked Inheritance Patterns Inheritance Pattern Description Example
Autosomal Dominant Only one mutated allele is needed for a person to be affected by an autosomal dominant disorder. Each affected person usually has one affected parent. There is a 50% chance that a child will inherit the mutated gene. Huntingtons disease, Achondroplasia, Neurofibromatosis 1, Marfan Syndrome, Hereditary nonpolyposis colorectal cancer
Autosomal Recessive Both copies of the gene must be mutated for a person to be affected by an autosomal recessive disorder. An affected person usually has unaffected parents who each carry a single copy of the mutated gene (and are referred to as carriers). Cystic fibrosis, Sickle cell anemia, Tay-Sachs disease, Spinal muscular atrophy
X-linked Dominant X-linked dominant disorders are caused by mutations in genes on the X chromosome. Only a few disorders have this inheritance pattern.
X-linked Recessive X-linked recessive disorders are also caused by mutations in genes on the X chromosome. Males are more frequently affected than females. The sons of a man with an X-linked recessive disorder will not be affected, and his daughters will carry one copy of the mutated gene. A woman who carries an X-linked recessive disorder has a 50% chance of having sons who are affected and a 50% chance of having daughters who carry one copy of the mutated gene. Hemophilia A, Duchenne muscular dystrophy, Color blindness
Y-Linked Y-linked disorders are caused by mutations on the Y chromosome. Only males can get them, and all of the sons of an affected father are affected. Y-linked disorders only cause infertility, and may be circumvented with the help of some fertility treatments. Male Infertility
Cystic Fibrosis
Cystic fibrosis (CF) is a recessive inheritable disorder caused by a mutation in a gene called the cystic fibrosis transmembrane conductance regulator (CFTR). The product of this gene is a chloride ion channel important in creating sweat, digestive juices, and mucus. Although most people without CF have two working copies of the CFTR gene, only one is needed to prevent cystic fibrosis. CF develops when individuals have a mutation in both copies of the gene, such that neither gene product works normally. CF is one of the most common life shortening diseases. Diagnosis is usually made in childhood. In the United States, approximately 1 in 3,900 children is born with CF (Figure below). One in 22 people of European descent are carriers of a mutated CFTR gene. CF mainly affects the lungs and digestive system, causing difficulty breathing due to thick mucus production, progressive disability, and for some individuals, premature death.
Individuals can be diagnosed prior to birth by genetic testing. Because development of CF in the fetus requires each parent to pass on a mutated copy of the CFTR gene and because CF testing is expensive, testing is often initially performed on just one parent. If that parent is found to be a carrier of a CFTR gene mutation, the other parent is then tested to calculate the risk that their children will have CF. CF can result from more than a thousand different mutations; currently it is not possible to test for each one. As new DNA testing methodologies are developed, testing for more mutations will become more common and less expensive. Testing analyzes DNA for the most common mutations, such as a deletion of amino acid 508 (phenylalenine, also known as ΔF508). If a family has a known uncommon mutation, specific screening for that mutation can be performed. However, it must be noted that because there may be other not yet identified mutations that result in CF, and as not all known mutations are found on current tests, a negative screen does not guarantee that a child will not have CF.
Figure 9.9
A young cystic fibrosis patient undergoing breathing treatment. Cystic fibrosis is a recessively inherited genetic disorder.
Tay-Scahs Disease
Tay-Sachs disease is a genetic disorder that is fatal in its most common variant, known as Infantile Tay-Sachs disease. Tay-Sachs is an autosomal recessive disorder, requiring the inheritance of a defective gene from each parent. The disease results from the accumulation of harmful quantities of fat in the nerve cells of the brain. Tay-Sachs results from mutations in the HEXA gene located on chromosome 15, which encodes the alpha-subunit of the lysosomal enzyme beta-N-acetylhexosaminidase A, which normally breaks down the fat. More than 90 mutations, including substitutions, insertions, deletions, splice site mutations, and other more complex patterns have been characterized in this gene, and new mutations are still being reported. Each of these mutations alters the protein product, inhibiting the function of the enzyme.
Tay-Sachs disease is a rare disease. Unaffected carriers of a Tay-Sachs allele may not know they have the allele. Other autosomal disorders such as cystic fibrosis and sickle cell anemia are far more common. The importance of Tay-Sachs lies in the fact that an inexpensive enzyme assay test was developed. The automation of this analysis has provided one of the first "mass screening" tools in medical genetics. Two unaffected carriers can have a child homozygous for a Tay-Sachs allele, resulting, currently, in a lethal phenotype. Tay-Sachs alleles are maintained in a population through these unknowing heterozygous carriers.
The analysis and screening for Tay-Sachs has became a research and public health model for understanding and preventing all autosomal genetic disorders. Another genetic disease that is easily analyzed in phenylketonuria.
Phenylketonuria
Phenylketonuria (PKU) is an autosomal recessive genetic disorder characterized the inability to metabolize t
he amino acid phenylalanine. PKU is due to a deficiency in the enzyme phenylalanine hydroxylase (PAH). When PAH is deficient, phenylalanine accumulates and is converted into phenylketones, which can be detected in the urine. Left untreated, this condition can cause problems with brain development, leading to progressive mental retardation and seizures. However, PKU can be treated with a specific diet, one low in phenylalanine. A diet low in phenylalanine and high in tyrosine can bring about a nearly total cure.
The incidence of PKU is about 1 in 15,000 live births. In the United States PKU is screened at birth as part of a national biochemical screening program, for every baby born in a hospital. Babies born at home may not be screened. If PKU is diagnosed early enough, an affected newborn can grow up with normal brain development, but only by eating a special diet low in phenylalanine for the rest of his or her life. In essence, this is a protein-free diet. This requires severely restricting or eliminating foods high in protein content (containing phenylalanine), such as breast milk, meat, chicken, fish, nuts, cheese and other dairy products. Starchy foods such as potatoes, bread, pasta, and corn must also be monitored. Many diet foods and diet soft drinks that contain the sweetener aspartame must also be avoided, as aspartame consists of two amino acids: phenylalanine and aspartic acid. Supplementary infant formulas are used in these patients to provide the amino acids and other necessary nutrients that would otherwise be lacking in their diet. Since phenylalanine is required for the synthesis of many proteins, it is necessary to have some of this amino acid, but levels must be strictly controlled. In addition, tyrosine, which is normally derived from phenylalanine, must also be supplemented.