Genetics: Part IV Genetic Disorders

What has gone wrong? What do you see wrong in this picture? The blood cell on the left is sickle shaped, a classic sign of the genetic disorder, sickle cell anemia. We can predict genetic outcomes of many inheritable traits, even those that are detrimental such as sickle cell.

•Huntington’s disease •X-linked color blindness Certain human genetic disorders can be attributed to the inheritance of single gene traits or specific chromosomal changes, such as nondisjunction. illustrative examples: •Sickle cell anemia •Tay-Sachs disease •Huntington’s disease •X-linked color blindness •Trisomy 21/Down syndrome •Klinefelter’s syndrome We will explore some of the genetic disorders listed in the curriculum framework. As we work our way through three chosen examples, think about how each trait can be maintained in a population even though it affects members adversely.

Some traits are determined by genes on sex chromosomes. Illustrative examples Sex-linked genes on sex chromosome (X in humans) In mammals and flies, the Y chromosome is very small and carries few genes

Small change, Big problem A point mutation in the gene for hemoglobin results in the misshapen, sickle cells as shown here. This trait is inheritable. Heterozygotes (said to have sickle-cell trait) are usually healthy but may suffer some symptoms. About one out of ten African Americans has sickle cell trait, an unusually high frequency of an allele with detrimental effects in homozygotes. Heterozygotes are less susceptible to the malaria parasite, so there is an advantage to being heterozygous. The heterozygous advantage afforded by this mutation is that the heterozygotes are resistant to malaria. This advantage results in the maintenance of this trait within a population in a malaria prone area even though the trait is lethal in the homozygous recessive condition.

Sex Linked Traits Traits carried on the sex chromosomes are said to be sex linked. In humans, most sex-linked traits are carried on the X chromosome. Sex-linked traits are expressed more often in human males than females.

Example of Sex Linked Trait: Hemophilia Queen Victoria of England was a carrier of the gene for hemophilia. She passed the harmful allele for this X-linked trait on to one of her four sons and at least two of her five daughters. Her son Leopold had the disease and died at age 30, while her daughters were only carriers. As a result of marrying into other European royal families, the princesses Alice and Beatrice spread hemophilia to Russia, Germany, and Spain. By the early 20th century, ten of Victoria's descendants had hemophilia. All of them were men, as expected.

Probability? What is the probability that the son of a carrier female and a normal male will have hemophilia?

Probability? What is the probability that the son of a carrier female and a normal male will have hemophilia? The answer is ½ or 50% since the question specifically refers to the son. If the question had asked what is the probability of a child born to these parents having hemophilia, then the answer would have been 25%.

Imagine a genetic counselor working with a couple who have just had a child who is suffering from Tay-Sachs disease. Neither parent has Tay-Sachs, nor does anyone in their families. Which of the following statements should this counselor make to this couple? a. “Because no one in either of your families has Tay-Sachs, you are not likely to have another baby with Tay-Sachs. You can safely have another child.” b. “Because you have had one child with Tay-Sachs, you must each carry the allele. Any child you have has a 50% chance of having the disease.” c. “Because you have had one child with Tay-Sachs, you must each carry the allele. Any child you have has a 25% chance of having the disease.” d. “Because you have had one child with Tay-Sachs, you must both carry the allele. However, since the chance of having an affected child is 25%, you may safely have thee more children without worrying about having another child with Tay-Sachs.” Answer: c The intent of the question is to help students understand that Tay-Sachs is a genetic disease caused by a deleterious recessive allele. It also should help students realize that, with independent events, prior events have no effect on subsequent events. Answer a is likely wrong because the fact that the couple had one child with Tay-Sachs indicates that each parent has an allele for Tay-Sachs (the one exception is if a new mutation, a rare event, occurred during the meiotic events leading up to the production of one of the gametes that formed the first child). In answer b, the first sentence is correct but this answer is wrong because each child has a 25% probability of having the disease (it would be 50% if the allele were dominant). Answer c is correct. Answer d is wrong because each conception must be viewed as an independent event. If this rationale were true, every family that had a girl would next have a boy—and we’ve all seen examples of families with two girls or two boys. Answer e is wrong because Tay-Sachs is recessive and a person must have two copies of the allele to have the disease.

Example of Sex Linked Trait: Colorblindness Compare these two spectra to see the difference in normal vision and red/green color blindness.

Color blindness Draw a Punnett Square to show how a color blind male could produce a family containing colorblind females. The image shows one of the 38 plates of the Ishihara color blindness test. This gene is carried on the X chromosome. Draw a Punnett Square to show how a color blind male could produce a family containing colorblind females.

Is your Punnett Square like this one?

Nondisjunction The failure of chromosomes to separate properly during gamete formation can result in genetic disorders. The term used to describe this condition is a double negative and may be confusing to students. Remind them that the normal event is for the chromosomes to separate or “disjoin” so “disjunction” is normal. Therefore the abnormal event above is called nondisjunction.

Nondisjunction Nondisjunction results in too many copies of the same gene inside a newly form zygote. Each subsequent division of that cell repeats the mistaken duplication. All of the cells of the child will bear evidence of the non-disjunction event.

Trisomy 21 A close look at this Karyotype reveals the result of a nondisjunction of chromosome 21. Three copies of chromosome 21 are present. The owner of this set of chromosomes would express the collection of traits known as Down Syndrome.

Down syndrome patients have noticeable traits Flattened nose and face, slanting eyes, single fold in the palm of the hand and wide spread first and second toe. All attributed to the expression chromosome 21. Trisomy 21 is one example of genetic disorders caused by chromosomal nondisjunction. Other disorders include Klinefelters and Turners syndrome.

Which female has sickle cell anemia Which female has sickle cell anemia? (X) Why are there no affected males in this pedigree? (chance. Note that the trait is not sex-linked) What are the chances of female U producing an affected male? (1/8, because there is a ¼ chance of producing a child with sickle cell anemia and a ½ chance that the child will be male)

Huntington’s Disease: A Late-Onset Lethal Disease Huntington’s disease is a degenerative disease of the nervous system The disease has no obvious phenotypic effects until the individual is about 35 to 40 years of age Once the deterioration of the nervous system begins the condition is irreversible and fatal

Lethal Dominant Trait Huntington’s affects people after reproduction age so it continues to be maintained in a population

Envision a family in which the grandfather, age 47, has just been diagnosed with Huntington’s disease. His daughter, age 25, now has a 2-year-old baby boy. No one else in the family has the disease. What is the probability that the daughter will contract the disease? A. 0% B. 25% C. 50% D. 75% E. 100% Answer: C This question begins a series of three questions about Huntington’s disease and seeks to make sure that students understand that the daughter has a 50% probability of inheriting the normal allele (normal phenotype) and a 50% probability of inheriting the Huntington allele (Huntington phenotype). The question will also help students understand the implications of the fact that the Huntington allele is dominant.

Nonnuclear Inheritance

Curriculum Framework Some traits result from nonnuclear inheritance Chloroplasts and mitochondria are randomly assorted to gametes and daughter cells; thus traits determined by chloroplasts and mitochondrial DNA do not follow simple Mendelian rules. In animals, mitochondrial DNA is transmitted by the egg and not by the sperm; as such, mitochondrial-determined traits are maternally inherited.

The 37 genes in the human mitochondria are only passed from the mother to the subsequent generation.

Mitochondrial Inheritance Sometimes referred to as Maternal Inheritance More than 40 known human disorders are attributed to mitochondrial inheritance. Links have been made between mtDNA and diabetes, certain cancers and aging just to name a few.

Illustrative examples Many ethical, social and medical issues surround human genetic disorders. Illustrative examples Reproduction issues Civic issues such as ownership of genetic information, privacy, historical context

Would you want to know? For a growing number of diseases, tests are available that identify carriers and help define the odds more accurately In amniocentesis, the liquid that bathes the fetus is removed and tested In chorionic villus sampling (CVS), a sample of the placenta is removed and tested Other techniques, such as ultrasound and fetoscopy, allow fetal health to be assessed visually in utero