5.15 Genetic Disorders
Created by: CK-12/Adapted by Christine Miller
Polly Who?
Each hand in the Figure 5.15.1 photo has an extra pinky finger. This is a condition called polydactyly, which literally means “many digits.” People with polydactyly may have extra fingers and/or toes, and the condition may affect just one hand or foot, or both hands and feet. Polydactyly is often genetic in origin and may be part of a genetic disorder associated with other abnormalities.
What Are Genetic Disorders?
Genetic disorders are diseases, syndromes, or other abnormal conditions caused by mutations in one or more genes, or by chromosomal alterations. Genetic disorders are typically present at birth, but they should not be confused with congenital disorders, a category that includes any disorder present at birth, regardless of cause. Some congenital disorders are not caused by genetic mutations or chromosomal alterations. Instead, they are caused by problems that arise during embryonic or fetal development, or during the process of birth. An example of a nongenetic congenital disorder is fetal alcohol syndrome. This is a collection of birth defects, including facial anomalies and intellectual disability, caused by maternal alcohol consumption during pregnancy.
Genetic Disorders Caused by Mutations
Table 5.15.1 lists several genetic disorders caused by mutations in just one gene. Some of the disorders are caused by mutations in autosomal genes, others by mutations in X-linked genes. Which disorders would you expect to be more common in males than females?
| Genetic Disorder | Direct Effect of Mutation | Signs and Symptoms of the Disorder | Mode of Inheritance |
|---|---|---|---|
| Marfan syndrome | Defective protein in connective tissue | Heart and bone defects and unusually long, slender limbs and fingers | Autosomal dominant |
| Sickle cell anemia | Abnormal hemoglobin protein in red blood cells | Sickle-shaped red blood cells that clog tiny blood vessels, causing pain and damaging organs and joints | Autosomal recessive |
| Hypophosphatemic (Vitamin D-resistant) rickets | Lack of a substance needed for bones to absorb minerals | Soft bones that easily become deformed, leading to bowed legs and other skeletal deformities | X-linked dominant |
| Hemophilia A | Reduced activity of a protein needed for blood clotting | Internal and external bleeding that occurs easily and is difficult to control | X-linked recessive |
Very few genetic disorders are controlled by dominant mutant [pHypophosphatemicb_glossary id=”2119″]alleles[/pb_glossary]. A dominant allele is expressed in every individual who inherits even one copy of it. If it causes a serious disorder, affected people may die young and fail to reproduce. Therefore, the mutant dominant allele is likely to die out of a population.
A recessive mutant allele — such as the allele that causes sickle cell anemia or cystic fibrosis — is not expressed in people who inherit just one copy of it. These people are called carriers. They do not have the disorder themselves, but they carry the mutant allele and their offspring can inherit it. Thus, the allele is likely to pass on to the next generation, rather than die out.
Genetic Disorders Caused by Chromosomal Alterations
Mistakes may occur during meiosis that result in nondisjunction. This is the failure of replicated chromosomes to separate properly during meiosis. Some of the resulting gametes will be missing all or part of a chromosome, while others will have an extra copy of all or part of the chromosome. If such gametes are fertilized and form zygotes, they usually do not survive. If they do survive, the individuals are likely to have serious genetic disorders.
Table 5.15.2 lists several genetic disorders that are caused by abnormal numbers of chromosomes. Most chromosomal disorders involve the X chromosome. The X and Y chromosomes are the only chromosome pair in which the two chromosomes are very different in size. This explains why nondisjunction tends to occur more frequently in sex chromosomes than in autosomes.
| Genetic Disorder | Genotype | Phenotypic Effects |
|---|---|---|
| Down syndrome | Extra copy (complete or partial) of chromosome 21 (see Figure 5.15.3) | Developmental delays, distinctive facial appearance, and other abnormalities (see Figure 5.15.2) |
| Turner syndrome | One X chromosome but no other sex chromosome (XO) | Female with short height and infertility(inability to reproduce) |
| Triple X syndrome | Three X chromosomes (XXX) | Female with mild developmental delays and menstrual irregularities |
| Klinefelter syndrome | One Y chromosome and two or more X chromosomes (XXY, XXXY) | Male with problems in sexual development and reduced levels of the male hormone testosterone |
 |
 |
A karyotype is a picture of a cell’s chromosomes. In Figure 5.15.3, note the extra chromosome 21. In Figure 5.15.2, a young man with Down syndrome exhibits the characteristic facial appearance.
Diagnosing and Treating Genetic Disorders
A genetic disorder that is caused by a mutation can be inherited. Therefore, people with a genetic disorder in their family may be concerned about having children with the disorder. A genetic counselor can help them understand the risks of their children being affected. If they decide to have children, they may be advised to have prenatal (“before birth”) testing to see if the fetus has any genetic abnormalities. One method of prenatal testing is amniocentesis. In this procedure, a few fetal cells are extracted from the fluid surrounding the fetus in utero, and the fetal chromosomes are examined. Down syndrome and other chromosomal alterations can be detected in this way.
The symptoms of genetic disorders can sometimes be treated or prevented. In the genetic disorder called phenylketonuria (PKU), for example, the amino acid phenylalanine builds up in the body to harmful levels. PKU is caused by a mutation in a gene that normally codes for an enzyme needed to break down phenylalanine. When a person with PKU consumes foods high in phenylalanine (including many high-protein foods), the buildup of PKU can lead to serious health problems. In infants and young children, the build-up of phenylalanine can cause intellectual disability and delayed development, along with other serious problems. All babies in Canada and the United States and many other countries are screened for PKU soon after birth. As shown in Figure 5.15.3, the PKU test involves collecting a small amount of blood from the infant, typically from the heel using a small lancet. The blood is collected on a special type of filter paper and then brought to a laboratory for analysis. If PKU is diagnosed, the infant can be fed a low-phenylalanine diet, which prevents the buildup of phenylalanine and the health problems associated with it, including intellectual disability. As long as a low-phenylalanine diet is followed throughout life, most symptoms of the disorder can be prevented.
Curing Genetic Disorders
Cures for genetic disorders are still in the early stages of development. One potential cure is gene therapy. Gene therapy is an experimental technique that uses genes to treat or prevent disease. In gene therapy, normal genes are introduced into cells to compensate for abnormal genes. If a mutated gene causes a necessary protein to be nonfunctional or missing, gene therapy may be able to introduce a normal copy of the gene to produce the needed functional protein.
A gene inserted directly into a cell usually does not function, so a carrier called a vector is genetically engineered to deliver the gene (see Figure 5.15.4 illustration). Certain viruses, such as adenoviruses, are often used as vectors. They can deliver the new gene by infecting cells. The viruses are modified so they do not cause disease when used in people. If the treatment is successful, the new gene delivered by the vector will allow the synthesis of a functioning protein. Researchers still must overcome many technical challenges before gene therapy will be a practical approach to curing genetic disorders.
Feature: Human Biology in the News
Down syndrome is the most common genetic cause of intellectual disability. It occurs in about one in every 700 live births, and it currently affects nearly half a million Americans. Until recently, scientists thought that the changes leading to intellectual disability in people with Down syndrome all happen before birth.
Even more recently, researchers discovered a genetic abnormality that affects brain development in people with Down syndrome throughout childhood and into adulthood. The newly discovered genetic abnormality changes communication between nerve cells in the brain, resulting in slower transmission of nerve impulses. This finding may eventually allow the development of strategies to promote brain functioning in Down syndrome patients, and it may also be applicable to other development disabilities, such as autism. The results of this promising study were published in the March 16, 2016 issue of the scientific journal Neuron.
5.15 Summary
- Genetic disorders are diseases, syndromes, or other abnormal conditions that are caused by mutations in one or more genes, or by chromosomal alterations.
- Examples of genetic disorders caused by single-gene mutations include Marfan syndrome (autosomal dominant), sickle cell anemia (autosomal recessive), vitamin D-resistant rickets (X-linked dominant), and hemophilia A (X-linked recessive). Very few genetic disorders are caused by dominant mutations because these alleles are less likely to be passed on to successive generations.
- Nondisjunction is the failure of replicated chromosomes to separate properly during meiosis. This may result in genetic disorders caused by abnormal numbers of chromosomes. An example is Down syndrome, in which the individual inherits an extra copy of chromosome 21. Most chromosomal disorders involve the X chromosome. An example is Klinefelter’s syndrome (XXY, XXXY).
- Prenatal genetic testing (by amniocentesis, for example) can detect chromosomal alterations in utero. The symptoms of some genetic disorders can be treated or prevented. For example, symptoms of phenylketonuria (PKU) can be prevented by following a low-phenylalanine diet throughout life.
- Cures for genetic disorders are still in the early stages of development. One potential cure is gene therapy, in which normal genes are introduced into cells by a vector such as a virus to compensate for mutated genes.
5.15 Review Questions
- Define genetic disorder.
- Identify three genetic disorders caused by mutations in a single gene.
- Why are single-gene genetic disorders more commonly controlled by recessive than dominant mutant alleles?
- What is nondisjunction? Why can it cause genetic disorders?
- Explain why genetic disorders caused by abnormal numbers of chromosomes most often involve the X chromosome.
- How is Down syndrome detected in utero?
- Use the example of PKU to illustrate how the symptoms of a genetic disorder can sometimes be prevented.
- Explain how gene therapy works.
- Compare and contrast genetic disorders and congenital disorders.
- Explain why parents that do not have Down syndrome can have a child with Down syndrome.
- Hemophilia A and Turner’s syndrome both involve problems with the X chromosome. In terms of how the X chromosome is affected, what is the major difference between these two types of disorders?
- Can you be a carrier of Marfan syndrome and not have the disorder? Explain your answer.
5.15 Explore More
How CRISPR lets you edit DNA – Andrea M. Henle, TED-Ed, 2019.
What you need to know about CRISPR | Ellen Jorgensen, TED, 2016.
The ethical dilemma of designer babies | Paul Knoepfler, TED, 2017.
Attributions
Figure 5.15.1
Polydactyly_ECS by Baujat G, Le Merrer M. on Wikimedia Commons is used under a CC BY 2.0 (https://creativecommons.org/licenses/by/2.0) license.
Figure 5.15.2
Downs/ All the Family [photo] by Nathan Anderson on Unsplash is used under the Unsplash License (https://unsplash.com/license).
Figure 5.15.3
Phenylketonuria_testing by U.S. Air Force photo/Staff Sgt Eric T. Sheler in the US Air Force National Archives on Wikimedia Commons is in the public domain (https://en.wikipedia.org/wiki/Public_domain).
Figure 5.15.4
Gene_therapy by National Institutes of Health (NIH) on Wikimedia Commons is in the public domain (https://en.wikipedia.org/wiki/Public_domain).
Figure 5.15.5
Boy_with_Down_Syndrome by Vanellus Foto on Wikimedia Commons is used under a CC BY-SA 3.0 (https://creativecommons.org/licenses/by-sa/3.0/deed.en) license.
References
Baujat, G., Le Merrer, M. (2007, January 23). Ellis-Van Creveld syndrome. Orphanet Journal of Rare Diseases, 2, 27. https://doi.org/10.1186/1750-1172-2-27
Hecht, M. (2019, June 26). What is polydactyly? [online article]. Healthline. https://www.healthline.com/health/polydactyly
Genetic and Rare Diseases Information Center (GARD). (2016). Hypophosphatemic rickets (previously called vitamin D-resistant rickets) [online article]. NIH. https://rarediseases.info.nih.gov/diseases/6735/hypophosphatemic-rickets [last updated 7/1/2020]
Mayo Clinic Staff. (n.d.). Cystic fibrosis [online article]. MayoClinic.org. https://www.mayoclinic.org/diseases-conditions/cystic-fibrosis/symptoms-causes/syc-20353700
Mayo Clinic Staff. (n.d.). Down syndrome [online article]. MayoClinic.org. https://www.mayoclinic.org/diseases-conditions/down-syndrome/diagnosis-treatment/drc-20355983
Mayo Clinic Staff. (n.d.). Hemophilia [online article]. MayoClinic.org. https://www.mayoclinic.org/diseases-conditions/hemophilia/symptoms-causes/syc-20373327
Mayo Clinic Staff. (n.d.). Klinefelter syndrome [online article]. MayoClinic.org. https://www.mayoclinic.org/diseases-conditions/klinefelter-syndrome/symptoms-causes/syc-20353949
Mayo Clinic Staff. (n.d.). Marfan syndrome [online article]. MayoClinic.org. https://www.mayoclinic.org/diseases-conditions/marfan-syndrome/symptoms-causes/syc-20350782
Mayo Clinic Staff. (n.d.). Phenylketonuria (PKU) [online article]. MayoClinic.org. https://www.mayoclinic.org/diseases-conditions/phenylketonuria/symptoms-causes/syc-20376302
Mayo Clinic Staff. (n.d.). Sickle cell anemia [online article]. MayoClinic.org. https://www.mayoclinic.org/diseases-conditions/sickle-cell-anemia/symptoms-causes/syc-20355876
Mayo Clinic Staff. (n.d.). Turner syndrome [online article]. MayoClinic.org. https://www.mayoclinic.org/diseases-conditions/turner-syndrome/symptoms-causes/syc-20360782
Mayo Clinic Staff. (n.d.). Triple X syndrome [online article]. MayoClinic.org. https://www.mayoclinic.org/diseases-conditions/triple-x-syndrome/symptoms-causes/syc-20350977
National Center on Birth Defects and Developmental Disabilities. (2020). Fetal alcohol spectrum disorders (FASDs): Basics about FASDs [webpage]. Centers for Disease Control and Prevention (CDC). https://www.cdc.gov/ncbddd/fasd/facts.html
TED-Ed. (2019, January 24). How CRISPR lets you edit DNA – Andrea M. Henle. YouTube. https://www.youtube.com/watch?v=6tw_JVz_IEc
TED. (2016, October 24). What you need to know about CRISPR | Ellen Jorgensen. YouTube. https://www.youtube.com/watch?v=1BXYSGepx7Q&feature=youtu.be
TED. (2017, February 10). The ethical dilemma of designer babies | Paul Knoepfler. YouTube. https://www.youtube.com/watch?v=nOHbn8Q1fBM&t=3s
By Christine Miller
DNA Replication: Overview
DNA replication is required for the growth or replication of an organism. You started as one single cell and are now made up of approximately 37 trillion cells! Each and every one of these cells contains the exact same copy of DNA, which originated from the first cell that was you. How did you get from one set of DNA, to 37 million sets, one for each cell? Through DNA replication.
Knowledge of DNA’s structure helped scientists understand DNA replication, the process by which DNA is copied. It occurs during the synthesis (S) phase of the eukaryotic cell cycle. DNA must be copied so that each new daughter cell will have a complete set of chromosomes after cell division occurs.
DNA replication is referred to as "semi-conservative". What this means is when a strand of DNA is replicated, each of the two original strands acts as a template for a new complementary strand. When the replication process is complete, there are two identical sets of DNA, each containing one of the original strands of DNA, and one newly synthesized strand.
DNA replication involves a certain sequence of events. For each event, there is a specific enzyme which facilitates the process. There are four main enzymes that facilitate DNA replication: helicase, primase, DNA polymerase, and ligase.
DNA Replication: The Process
DNA replication begins when an enzyme called helicase unwinds, and unzips the DNA molecule. If you recall the structure of DNA, you may remember that it consists of two long strands of nucleotides held together by hydrogen bonds between complementary nitrogenous bases. This forms a ladder-like structure which is in a coiled shape. In order to start DNA replication, helicase needs to unwind the molecule and break apart the hydrogen bonds holding together complementary nitrogenous bases. This causes the two strands of DNA to separate.
Small molecules called single-stranded binding proteins (SSB) attach to the loose strands of DNA to keep them from re-forming the hydrogen bonds that helicase just broke apart.
Once the nitrogenous bases from the inside of the DNA molecule are exposed, the creation of a new, complementary strand can begin. DNA polymerase creates the new strand, but it needs some help in finding the correct place to begin, so primase lays down a short section of RNA primer (shown in green in Figure 5.4.3). Once this short section of primer is laid, DNA polymerase can bind to the DNA molecule and start connecting nucleotides in the correct order to match the sequence of nitrogenous bases on the template (original) strand.
If we think about the DNA molecule, we may remember that the two strands of DNA run antiparallel to one another. This means that in the sugar-phosphate backbone, one strand of the DNA has the sugar oriented in the "up" position, and the other strand has the phosphate oriented in the "up" position (see Figure 5.4.4). DNA polymerase is an enzyme which can only work in one direction on the DNA molecule. This means that one strand of DNA can be replicated in one long string, as DNA polymerase follows helicase as it unzips the DNA molecule. This strand is termed the "leading strand". The other strand, however, can only be replicated in small chunks since the DNA polymerase replicates in the opposite direction that helicase is unzipping. This strand is termed the "lagging strand". These small chunks of replicated DNA on the lagging strand are called Okazaki fragments.
Take a look at Figure 5.4.5 and find the Okazaki fragments, the leading strand and the lagging strand.
Once DNA polymerase has replicated the DNA, a third enzyme called ligase completes the final stage of DNA replication, which is repairing the sugar-phosphate backbone. This connects the gaps in the backbone between Okazaki fragments. Once this is complete, the DNA coils back into its classic double helix structure.
Semi-Conservative Replication
When DNA replication is complete, there are two identical sets of double stranded DNA, each with one strand from the original, template, DNA molecule, and one strand that was newly synthesized during the DNA replication process. Because each new set of DNA contains one old and one new strand, we describe DNA as being semi-conservative.
Watch this video for a great overview of DNA replication:
https://www.youtube.com/watch?v=Qqe4thU-os8
DNA Replication (Updated), Amoeba Sisters, 2019.
5.4 Summary
- DNA replication requires the action of three main enzymes each with their own specific role:
- Helicase unzips and unwinds the DNA molecule.
- DNA polymerase creates a new complementary strand of DNA on each of the originals halves that were separated by helicase. New nucleotides are added through complementary base pairing: A pairs with T, and C with G.
- Ligase repairs gaps in the sugar-phosphate backbone between Okazaki fragments.
- DNA replication is semi-conservative because each daughter molecule contains one strand from the parent molecule and one new complementary strand.
5.4 Review Questions
2. Why are Okazaki fragments formed?
- Because helicase only unzips DNA in one direction.
- Because DNA is in a double helix.
- Because DNA polymerase only replicates DNA in one direction.
- Because DNA replication is semi-conservative.
3. Drag and drop to label the diagram.
5.4 Explore More
https://www.youtube.com/watch?v=TNKWgcFPHqw
DNA replication - 3D, yourgenome, 2015.
Attributions
Figure 5.4.1
DNA_replication_split.svg by Madprime on Wikimedia Commons is used under a CC0 1.0
Public Domain Dedication license (https://creativecommons.org/publicdomain/zero/1.0/deed.en).
Figure 5.4.2
Helicase and single stranded binding proteins (1) by Christine Miller is used under a CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/) license.
Figure 5.4.3
DNA polymerase and primase by Christine Miller is used under a CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/) license.
Figure 5.4.4
DNA strands run antiparallel by Christine Miller is used under a CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/) license.
Figure 5.4.5
Leading and lagging strand/ DNA Replication/ by yourgenome on Flickr is used under a CC BY-NC-SA 2.0 (https://creativecommons.org/licenses/by-nc-sa/2.0/) license.
References
Amoeba Sisters. (2019, June 28). DNA replication (Updated). YouTube. https://www.youtube.com/watch?v=Qqe4thU-os8&feature=youtu.be
Betts, J. G., Young, K.A., Wise, J.A., Johnson, E., Poe, B., Kruse, D.H., Korol, O., Johnson, J.E., Womble, M., DeSaix, P. (2013, April 25). Figure 3.24 DNA Replication [digital image]. In Anatomy and Physiology. OpenStax. https://openstax.org/books/anatomy-and-physiology/pages/3-3-the-nucleus-and-dna-replication CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/)
yourgenome. (2015, June 26). DNA replication - 3D. YouTube. https://www.youtube.com/watch?v=TNKWgcFPHqw&feature=youtu.be
The smallest particle of an element that still has the properties of that element.
