CK-12 Biology I - Honors

by CK-12 Foundation

  Achondroplasia

  Whereas cystic fibrosis, Tay-Sachs, and phenylketonuria are all autosomal recessive disorders, achondroplasia is an autosomal dominant disorder. Achondroplasia is the most common cause of dwarfism. Achondroplasia is a result of an autosomal dominant mutation in the fibroblast growth factor receptor gene 3 (FGFR3), which causes an abnormality of cartilage formation. FGFR3 normally has a negative regulatory effect on bone growth. In achondroplasia, the mutated form of the receptor is constitutively active (constantly “turned on”) and this leads to severely shortened bones. Individuals with achondroplasia are heterozygous for the mutation (one mutant copy, one normal copy). Homozygous for the achondroplasia mutation is lethal prior to birth or shortly after birth.

  For autosomal dominant disorders, a person with the disorder has a 50% chance of passing on the gene to their offspring. For achondroplasia, this means there will be a 50% chance that each child will have achondroplasia. Since two copies are fatal, if two people with achondroplasia have a child, there is a 25% chance of the child dying shortly after birth, a 50% chance the child will have achondroplasia, and a 25% chance the child will have a normal phenotype. However, in 3 out of 4 cases, people with achondroplasia are born to parents who don't have the condition. This is the result of a new mutation. New achondroplasis mutations are associated with increasing paternal age (over 35 years). Studies have demonstrated that new gene mutations are exclusively inherited from the father and occur during spermatogenesis. More than 98% of achondroplasia is caused by a G to A point mutation at nucleotide 1138 of the FGFR3 gene, which causes a glycine to arginine substitution. This makes this particular nucleotide one of the most, if not the most, mutable base in the human genome.

  There are three other syndromes with a genetic basis similar to achondroplasia: hypochondroplasia, thanatophoric dysplasia, and SADDAN Dysplasia (severe achondroplasia, developmental delay, acanthosis nigricans (a skin condition)). Each of these disorders is also caused by a mutation in the FGFR3 gene. Each of the conditions results in a distinct difference in the degree of severity of the phenotype, with hypochondroplasia having the mildest phenotype. Other genes in which mutations cause a phenotypic spectrum of disease include the collagen genes among others.

  Sex-Linked Traits

  Traits controlled by genes located on the sex chromosomes (X and Y) are called sex-linked traits (Figure below). Remember, females have two X chromosomes and males have a X and a Y chromosome. Therefore, any recessive allele on the X chromosome of a male will not be masked by a dominant allele. X-linked traits include the hemophilia and color blindness. Hemophilia is the name of a family of hereditary genetic illnesses that impair the body's ability to control coagulation. Color Blindness, or color vision deficiency, in humans is the inability to perceive differences between some or all colors that other people can distinguish.

  Figure 9.10

  X-linked recessive inheritance. As boys have only one X-chromosome, if they inherit the mutant allele from their mother, they will possess the phenotype that results from that allele.

  Hemophilia is a group of diseases in which blood does not clot normally. Factors in blood are involved in clotting. Hemophiliacs lacking the normal Factor VIII are said to have Hemophilia A, the most common form. England's Queen Victoria was a carrier for this disease. The allele was passed to two of her daughters and one son. Since royal families in Europe commonly intermarried, the allele spread, and may have contributed to the downfall of the Russian monarchy.

  Genetic red-green color blindness affects men much more often than women, because the genes for the red and green color receptors are located on the X chromosome. Females are red-green color blind only if both of their X chromosomes carry the defective gene, whereas males are color blind if their single X chromosome carries the defective gene. As males have only the one X-chromosome, the gene for red-green color blindness is transmitted from a color blind male to all his daughters, who are usually heterozygous carriers and therefore unaffected. Subsequently, this carrier woman has a fifty percent chance of passing on a X chromosome with a defective gene to each of her male offspring. The sons of an affected male will not inherit the trait from him, since they receive his Y chromosome and not his X chromosome. Should an affected male have children with a carrier or colorblind woman, their daughters may be colorblind by inheriting a X chromosome with the mutant gene from each parent.

  Muscular dystrophy is a term encompassing a variety of muscle wasting diseases. The most common type, Duchenne Muscular Dystrophy (DMD), affects cardiac and skeletal muscle, as well as some mental functions. DMD is an X-linked recessive disorder occurring in 1 in 3,500 newborns. Most affected individuals die before their 20th birthday.

  Complex Traits

  So far we have discussed traits inherited in a simple Mendelian pattern. Either the trait is dominate or recessive. The trait is affected by only one gene. But this is not the case for many genes; rarely is inheritance that simple. More complex patterns of inheritance are common. These were introduced in the chapter titled Mendelian Genetics.

  Mendel’s pea plants showed complete dominance of one allele over the other. The offspring always completely looked like one of the parents – there was never any phenotype “in between” the two parents. The heterozygous individuals were indistinguishable from the homozygous dominant individuals. Is it possible for both alleles to be dominant, or neither to be completely dominant? The answer to both of these questions is yes.

  Codominance

  Codominance is when two alleles are both expressed in the heterozygous individual; that is, they both affect the phenotype in separate and distinguishable ways (Figure below). The A, B alleles of the ABO blood group system are a classic example, and these have been discussed in the chapter titled Mendelian Genetics. The A and B alleles are codominant with each other. When a person has both an A and a B allele, the person has type AB blood. When two persons with AB blood type have children, the children can be type A, type B, or type AB. There is a 1A:2AB:1B phenotype ratio instead of the 3:1 phenotype ratio found when one allele is dominant and the other is recessive.

  Figure 9.11

  Codominant Inheritance. The A and B alleles are codominant. An AB heterozygous individual has type AB blood.

  Incomplete Dominance

  Incomplete dominance is seen in heterozygous individuals with an intermediate phenotype. For example, if Mendel had ever observed a medium stem length plant when a tall and short plant were crossed, that would have suggested incomplete dominance. In incomplete dominant situations, the phenotype expression is dependent on the dosage of the genes. Two copies of the gene result in full expression, while only one copy produces partial expression and an intermediate phenotype.

  Multiple-Allele Traits

  Traits controlled by more than two alleles have multiple alleles. Theoretically, any base change will result in a new allele. In fact, within the human population, it may be safe to say that most human genes have more than 2 alleles. Whereas, we think of base changes, or mutations, as resulting in a new phenotype or disease, many base changes result in alleles that do not cause significant change in phenotypes. This is common in collagen genes, for example. The best characterized example of multiple alleles in humans is the ABO blood groups, discussed in the chapter titled Mendelian Genetics.

  It is easiest to consider situations where each gene affects only one phenotypic characteristic. However, other situations where genes have other effects are common. As mentioned above, multiple alleles resulting in multiple phenotypes are not uncommon.

  Pleiotropy

  Many genes have multiple phenotypic effects, a property called pleiotropy. Thus, a new mutation in the gene will affect all the phenotypes/traits associated with the gene simultaneously. For example, the symptoms associated with sickle-cell disease are due to pleiotropic alleles. Another example is the collagen genes mentioned above. As you will learn later, many bones develop from a cartilage template. This cartilage template is
made out of many proteins, with type II collagen, the predominant protein in the cartilage. The gene for this collagen, COL2A1, when mutated, not only affects the skeletal system, but due to its pleiotropic nature, it may also affect a person’s eyes and hearing.

  Epistasis

  Epistasis is when a gene at one location (locus) alters the phenotypic expression of a gene at another locus. This is seen in the inheritance of coat color in mice. Epistasis takes place when the action of one gene is modified by one or several other genes, which are sometimes called modifier genes. The gene whose phenotype is expressed is said to be epistatic, while the phenotype altered or suppressed is said to be hypostatic.

  Polygenic Traits

  Polygenic traits are due to the actions of more than one gene and often, their interaction with the environment. These usually result in a measurable range in phenotype, such as height, eye color or skin color. These are known as multifactoral or quantitative characteristics. Polygenic inheritance results in an additive effect of the genes on a single phenotype.

  Skin color is a polygenic trait and obviously demonstrates quantitative characteristics. A number of genes factor into determining a person's natural skin color, so modifying only one of those genes changes the color only slightly. It is currently thought that at least three separately inherited genes contribute to skin pigmentation. Let’s call these three genes A, B, and C. A, B, and C are incompletely dominant to a, b, and c, with A, B, and C each contributing a “unit of darkness” to the phenotype. Therefore an AABBCC individual is very dark, darker than an AaBbCc individual, and much darker than a aabbcc individual. A person may have as many as 6 “dark units” to as few as no “dark units,” and any combination in between. This will result in a phenotypic spectrum of color gradation.

  Many disorders with genetic components are polygenic, including autism, certain cancers, diabetes and numerous others. Most phenotypic characteristics are the result of the interaction of multiple genes. The environment plays a significant role in many of these phenotypes. But what happens when multiple genes are either missing or duplicated?

  Changes in Chromosome Number

  So far we have focused on traits due to one gene or several genes. But what about many genes? What would happen if an entire chromosome were missing or duplicated? What if a human had only 45 chromosomes? Or 47? This real possibility is usually due to mistakes during meiosis; the chromosomes do not fully separate from each other during sperm or egg formation. Specifically, nondisjunction is the failure of replicated chromosomes to separate during anaphase II. If a zygote forms from a gamete lacking a chromosome, a viable embryo cannot be produced. Most human abnormal chromosome numbers result in the death of the developing embryo, often before a woman even realizes she is pregnant. Occasionally, a zygote with an extra chromosome can become a viable embryo and develop.

  Trisomy is a state where humans have an extra autosome. That is, they have three of a particular chromosome instead of two. For example, trisomy 18 results from an extra chromosome 18, resulting in 47 total chromosomes. To identify the chromosome number (including an abnormal number), a sample of cells is removed from an individual or developing fetus. Metaphase chromosomes are photographed and a karyotype is produced. A karyotype will display any abnormalities in chromosome number or large chromosomal rearrangements. Trisomy 8, 9, 12, 13, 16, 18, and 21 have been identified in humans. Trisomy 16 is the most common trisomy in humans, occurring in more than 1% of pregnancies. This condition, however, usually results in spontaneous miscarriage in the first trimester. The most common trisomy in viable births is Trisomy 21.

  Figure 9.12

  Trisomy 21 (Down Syndrome) Karyotype. Note the extra chromosome 21.

  Trisomy 21: Down Syndrome

  One of the most common chromosome abnormalities is Down syndrome, due to nondisjunction of chromosome 21 resulting in an extra complete chromosome 21, or part of chromosome 21 (Figure below). Down syndrome is the only autosomal trisomy where an affected individual may survive to adulthood. Individuals with Down syndrome often have some degree of mental retardation, some impairment of physical growth, and a specific facial appearance. With proper assistance, individuals with Down syndrome can become successful, contributing members of society (Figure below). The incidence of Down syndrome increases with maternal age.

  Figure 9.13

  Child with Down syndrome, exhibiting characteristic facial appearance.

  Figure 9.14

  Boy with Down Syndrome assembling a bookcase.

  Abnormal Numbers of Sex Chromosomes

  What about when a person has more than 2 Y chromosomes, or more than 2 X chromosomes? Or a female with only one X chromosome? Sex-chromosome abnormalities may be caused by nondisjunction of one or more sex chromosomes. Many conditions are known in which there are an abnormal number of sex chromosomes. An X chromosome may be missing (XO), or there may be an extra one (XXX or XXY). There may also be an extra Y chromosome (XYY). Any combination of X and Y chromosomes, as long as there is a Y chromosome, will produce a male (up to XXXXY). These individuals can lead relatively normal lives, but they cannot have children. They may also have some degree of mental retardation. These syndromes include Klinefelter’s syndrome, Turner syndrome and trisomy X.

  Klinefelter's syndrome is caused by the presence of one or more extra copies of the X chromosome in a male's cells. Extra genetic material from the X chromosome interferes with male sexual development, preventing the testicles from functioning normally and reducing the levels of testosterone. Triple X syndrome (trisomy X) results from an extra copy of the X chromosome in each of a female's cells. Females with trisomy X have a lower IQ than their siblings. Turner syndrome results when each of a female's cells has one normal X chromosome and the other sex chromosome is missing or altered. The missing genetic material affects development and causes the characteristic features of the condition, including short stature and infertility.

  Diagnosis and Treatment of Genetic Disorders

  If someone has a rare genetic disease in her family, can she still have a baby? Is she predisposed to pass that phenotype along to her child? These are questions for a professional trained in human genetics. A geneticist and genetic counselor are usually involved in the diagnosis and treatment of human genetic disorders. Families with a genetic disease are referred to a genetic counselor, especially when they wish to determine a baby’s likelihood of inheriting a genetic disease.

  Individuals or their families at risk of inheriting a genetic disorder have many questions. What exactly is a genetic disorder? How does a person get it? Can it be passed onto the next generation? Can it be treated? What are the symptoms? Do the symptoms get worse with age? These and many more questions are where a genetic specialist, such as a genetic counselor can help. Genetic counseling is 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 counseling may be necessary at any time throughout life, from before pregnancy to adulthood. Before pregnancy, genetic counseling would be appropriate for at risk individuals who are planning a family, such as when one or both individuals are either carriers or have a certain genetic trait. During pregnancy, genetic counseling is necessary for couples if the woman will be over 35 years of age at the time of delivery, if prenatal testing is recommended for any reason, or if an abnormality is noted on an ultrasound or other test. After birth, genetic counseling is appropriate if a birth defect is detected. During childhood, genetic counseling is appropriate if the child manifests any signs of developmental delay or a genetic syndrome, and in adulthood, genetic counseling is appropriate if signs of an adult onset genetic disorder is detected. During genetic counseling, individuals are advised of the consequences and nature of the disorder, the probability of developing or transmitting the disorder, and the options open to them in management and family planning in order to make appropriate decisions. In terms of the actual diagnosis of the disease, molecular analysis may
be necessary; this will be discussed in the chapter titled Biotechnology.

  Prenatal Diagnosis

  "Is it possible to test the developing baby for potential genetic problems? Do you need to remove some of the baby's DNA? How do you do that?" These questions are appropriate for a geneticist. Sometimes, to make sure the baby is developing properly, prenatal diagnosis is necessary. Prenatal diagnosis refers to the diagnosis of a disease or condition before the baby is born. The reason for prenatal diagnosis is to detect birth defects such as neural tube defects, chromosome abnormalities, genetic diseases and other conditions. It can also be used to determine the sex of the unborn baby, though this can usually be determined by an ultrasonography (ultrasound).

  Diagnostic prenatal testing can be by invasive methods or non-invasive methods. Non-invasive methods are much less risky to the patient. Non-invasive methods can only evaluate the risk of a condition and cannot actually determine if the fetus has a condition. Non-invasive techniques include examinations of the mother's womb through ultrasonography and analysis of maternal serum. If an abnormality is indicated by a non-invasive procedure, a more invasive technique may be employed to gather more information. Amniocentesis and chorionic villus sampling (CVS) are invasive procedures. These involve probes or needles that are inserted into the placenta. Amniocentesis can be done from about 14 weeks up to about 20 weeks of the pregnancy and CVS can be done earlier, between 9.5 and 12.5 weeks, but is slightly more risky to the unborn child.