Introduction and Goals
Gregor Mendel (Figure 1) concluded from his experiments that "hereditary units" transmitted traits from one generation to the next, but at the time of his work (1850-1860's) chromosomes had not yet been observed. Around the turn of the century, two events firmly placed Mendel's name in history. First, three botanists independently rediscovered Mendel's research after conducting studies similar to his. Second, scientists began to notice differences between the behavior of chromosomes (only recently observed) during mitosis and meiosis. For example, they saw that organisms had pairs of homologous chromosomes that separated during meiosis, and that the fusion of two gametes resulted in a zygote with the normal diploid number of chromosomes.
These facts meshed well with Mendel's Laws of Segregation and Independent Assortment, demonstrating that chromosomes contained the "hereditary units" proposed by Mendel. Mendel's work and the discovery of chromosomes and their behavior laid the groundwork for studies which revealed that genes are found in specific locations on chromosomes, and that homologous chromosomes segregate and non-homologous chromosomes independently assort during meiosis. This tutorial will more closely examine the role that chromosomes play in allele segregation. You will learn that genes (and their alleles) on different chromosomes segregate (or assort) independently. If they are on the same chromosome, however, they may or may not exhibit independent segregation.
By the end of this tutorial you should have a basic understanding of:
- How chromosome behavior explains allele segregation
- Gender determination in humans and other organisms
- Inheritance of other sex-linked genes
- Role of X-inactivation in gene expression
Figure 1. Gregor Mendel. (Click image to enlarge)
The Relationship Between Chromosome Behavior and Mendel's Laws
Figure 2 demonstrates the relationship between Mendel's work and the behavior of chromosomes during meiosis. It shows how a dihybrid individual has two different alleles for each gene: here seed color (Y gene) and shape (R gene); the locations of the genes are indicated by lines on the chromosomes. Each gene is located at the same position on each member of the homologous pair. The random assortment of the homologous pairs in meiosis I results in different combinations of alleles for seed color and shape in the gametes. Through random fertilization, these four different gametes will lead to the characteristic 9:3:3:1 ratio observed by Mendel in his dihybrid crosses.
Figure 2. The chromosomal basis of Mendel's laws. (Click image to enlarge)
Linking Genes and Chromosomes
Although the relationship between genes and traits was fairly well accepted by the early 1900's, biologist T. H. Morgan (Figure 3) of Columbia University first mapped a gene to a specific chromosome. One of the early pioneers working with fruit flies in genetic studies, Morgan (and his students) discovered one male fly with white eyes, a trait they had not seen in these flies. The phenotype that is prevalent in natural populations (wild-type) for this character is red eyes, so the individual had a mutant phenotype for this particular character.
Figure 3. Thomas Hunt Morgan from the 1891 Johns Hopkins yearbook of 1891 (Click image to enlarge) Public Domain Image
Nomenclature Used by Drosophila Geneticists
To assist with his work, Morgan and his students developed a nomenclature system for distinguishing between the normal (wild-type) allele and its variants. This system is still used by Drosophila geneticists. The gene for a particular character is named for the first mutant phenotype discovered. In the case of eye color, the allele for white eyes was appropriately designated w, for "white." The wild-type allele uses the same letter but has a superscript + . Therefore, the allele for red eyes is symbolized as w+. The white eye allele is then simply w. The letter identifying the mutant is lowercase if the allele is recessive (as in white eyes), or uppercase for those mutations that are dominant to the wild-type allele. The allele that causes curly wings, a dominant mutation, is symbolized as Cy, and the allele that codes for straight wings (wild type) is identified as Cy+.
To investigate the mutant white eye allele, Morgan mated the white-eyed male fly with a red-eyed (wild type) female. As shown in Figure 4, all of the F1 offspring had red eyes, indicating that the allele for white eyes was recessive. When Morgan bred the F1 generation flies to one another, he observed the classic 3:1 ratio of red:white eyes, however, only males had the mutant trait. All of the females and one-half of the males had the wild-type trait, which led Morgan to hypothesize that the gene that coded for eye color must be related to sex determination.
Figure 4. Sex-linked pattern of inheritance for a recessive trait. (Click image to enlarge)
Like humans, female fruit flies have two X chromosomes (XX) and males have one X and one Y (XY). If the gene for eye color is located on the X chromosome, then this would explain why the trait rarely appears in females (i.e., a female would have to be homozygous for the recessive mutant). However, males would show the mutant trait if they have one copy of the allele because they have only one X chromosome and there is no corresponding gene for eye color on the Y chromosome. This study demonstrated that the gene for eye color in D. melanogaster was located on the X chromosome and provided further evidence for a chromosome theory of heredity. The X and Y chromosomes are called sex chromosomes because they determine the sex of an individual. Genes that are located on these chromosomes are called sex-linked genes. All other chromosomes in a cell (i.e., other than the sex chromosomes) are referred to as autosomes.
Sex Chromosomes and Meiosis
While there are several different systems for sex determination, for simplicity we will focus on the X-Y system of sex determination to examine sex-linked inheritance. During meiosis, the two X chromosomes (found in females) or the X and Y chromosomes (found in males) pair together because they have a small region of homology, but undergo little crossing over. One of these chromosomes then goes to each gamete, so females produce gametes with only X chromosomes, whereas males produce equal numbers of gametes with either an X or Y chromosome. If two gametes with X chromosomes undergo fertilization, the resultant offspring will be female (XX). That is, if an ovum with an X chromosome and a sperm with an X chromosome combine, the resultant offspring will be female. However, if an ovum with an X chromosome and a sperm with a Y chromosome combine, the offspring will be male (XY). While it has long been known that the X chromosome contains a substantial number of genes, researchers have only recently found genes on the Y chromosome, most of which are associated with the development of male gonads, including the testes determining factor (TDF) gene in mammals. Therefore, it appears that a gene (or genes) on the Y chromosome provides the biochemical signal that begins the development of male gonads in embryos.
Not only do sex chromosomes determine the sex of an individual, but the X chromosome also has genes that code for many characters that are not related to sex determination. Sex-linked alleles in an XY chromosome system follow the patterns of inheritance observed in Morgan's studies, in which fathers transmit these genes to their daughters, and mothers can transmit them to either sons or daughters. Females will only express recessive sex-linked traits that are homozygous, but males will express the trait coded for by their one X chromosome. As a result, sex-linked recessive traits are far more frequent in males than in females, although some females do exhibit sex-linked recessive traits. Since males have only one chromosomal location for sex-linked genes, the terms homozygous and heterozygous have little meaning. By convention, males are said to be hemizygous for sex-linked genes because they have half ("hemi") as many alleles as a female.
As with autosomal traits, you can utilize the Punnett square to study the transmission of sex-linked traits. When completing these crosses, the gametes identify the sex chromosomes only. The genes located on the X chromosome are indicated with superscript letters. (We will not examine any cases where we track a Y-linked gene.) As with Mendelian traits, a lowercase letter indicates a recessive allele, while an uppercase letter indicates a dominant allele. When discussing sex-linked traits, carriers (females who are heterozygous for a recessive trait) need to be considered. Figure 5 illustrates several examples of genetic crosses involving sex-linked traits. White boxes represent unaffected individuals, light-colored boxes represent carriers, and dark-colored boxes represent affected individuals.
Figure 5. The transmission of sex-linked recessive traits for different genetic crosses. (Click image to enlarge)
Sex Determination in Other Organisms
Not only did Morgan's work bolster a chromosome theory of heredity, it also initiated the study of sex-linked traits. Although the basis of sex determination in humans and fruit flies is similar (XX = female, XY = male), the same is not true of all organisms. In Figure 6 the numerals represent the number of autosomes. In some insects sex is determined by the X-O system (Fig 6.2), in which females have two copies of the X chromosome and males only one. Therefore, the sex of the offspring will be determined by whether or not an X chromosome is present in the sperm that fertilizes the ovum. The Z-W system occurs in some birds, insects, and fish (Fig 6.3). In this system the chromosomes found in the ovum are variable (Z or W) Note: the figure is incorrect and sperm always contribute a Z chromosome. Here, it is the female (not the male) that determines the sex of the offspring. Bees and ants display a fourth type of sex determination, the haplo-diploid system (Fig. 6.4). Females develop from fertilized eggs and are diploid, whereas males develop from unfertilized eggs and are haploid.
Figure 6. Different systems of sex determination in animals. (Click image to enlarge)
Sex-linked Genes in Humans - Color Blindness
Sex-linked traits are not unique to flies; a great many exist for humans. One example is color blindness, in which affected individuals are not able to distinguish certain colors. The genes for both red and green color perception are X-linked and the mutations are recessive; therefore, color blindness affects far more males than females. Color blindness is diagnosed by showing children images like the one on this page. The orange circle is visible to all, but individuals with one form of red-green color blindness are unable to distinguish the red star from the green background.
Figure 7. Creamer color chart for diagnosing red-green colorblindness. (Click image to enlarge)
At the following Web sites, find the correct answer to the problems. To view an explanation of a problem, select the "TUTORIAL" button. After viewing the correct answer, close the Problem Set window to return to this page. These sites are a part of the Problem Sets provided by The Biology Project at the University of Arizona.
Problem 7 - Red-green color blindness in humans. This problem is a part of the Sex-Linked Inheritance Problem Set.
Problem 1 - Inheritance of an X-linked recessive trait. This problem is a part of the Human Genetics Problem Set.
View this animation to work through another sample problem on red-green colorblindness:
Sex-linked Genes in Humans - Hemophilia
Another sex-linked trait in humans is hemophilia. Hemophiliacs (individuals affected with hemophilia) lack a protein involved in blood clotting, so they can bleed profusely from even a minor abrasion. This disease is of particular interest, given its relatively high frequency in many of the royal houses of Europe. It is thought that the hemophilia gene spontaneously mutated in one of Queen Victoria's (a queen of England in the 1800s) parents, making her a carrier of the trait. She transmitted the hemophilia allele to one son and some of her daughters, and it eventually affected the imperial houses of Prussia, Russia, and Spain through a series of politically arranged marriages. View the pedigree of the royal families, then return to this page. What pattern do you see that is different than the pattern seen in pedigrees of genetic disorders that are autosomal recessive?
Problem 6 - Hemophilia in humans. Find the correct answer to this multiple-choice question. To view an explanation of the problem, select the "TUTORIAL" button. After viewing the correct answer, close the Problem Set window to return to this page. This site is a part of the Sex-Linked Inheritance Problem Set provided by The Biology Project at the University of Arizona.
View this animation to work through another sample problem on hemophilia inheritance:
Females have two X chromosomes, while males have only one; and yet, males undergo normal development. How can this be? The answer lies in an observation that was made by the geneticist Mary Lyon. Female mammals have a dark region located just inside the nucleus, along the nuclear membrane. The object is called a Barr body. The Barr body is an inactivated X chromosome that stays condensed throughout the cell cycle. By inactivated, it is meant that most of the genes on the chromosome are not expressed and cannot be used to make proteins. Therefore, like the cells in males, females have only one functioning X chromosome and they contribute only one dose (copy) of the genes on that chromosome. Inactivation of the X chromosome in females compensates for the extra copy, thereby making the production of proteins in the cells of males and females the same.
How is the X chromosome inactivated in female cells? It is a process that happens early in development, when one of the two X chromosomes in the cells of the embryo becomes inactivated. It appears to be a random process, with about 50% of the cells inactivating the maternal X and 50% inactivating the paternal X. This animation of X-inactivation during development is from the Howard Hughes Medical Institute.
The results of inactivation are easily seen in tortoiseshell and calico cats (Figure 8). The gene for orange fur is on the X chromosome in cats. If a cat is heterozygous for the orange allele (O = orange, o = not orange), then random inactivation of the X chromosomes causes patches of orange and not orange (usually black) fur. This is why male calico cats are so rare. They must have an XXY chromosome complement. (This chromosome complement causes Klinefelter syndrome in humans.) In these males, one of the X chromosomes is inactivated and Barr bodies are found in their cells. Because of the presence of the Y chromosome, however, these individuals are genetically male.
Figure 8. Tasi, a stunning calico cat that shows the results of X inactivation. (Click image to enlarge)
The gene for the inactivation of the X chromosome, called the XIST gene, is located on the X chromosome. This gene does not appear to code for a protein. It is one of the few genes expressed on the inactivated X chromosome. The gene is transcribed, producing many copies of an RNA molecule. These RNAs attach to the DNA on the same X chromosome, inactivating it. Scientists are still researching the phenomenon. For example, it is uncertain how cells determine if an X chromosome should be inactivated or not. There is still a lot to learn about X-inactivation in mammals.
Previously, we considered the expression pattern of genes that are found on different chromosomes (therefore, they independently assort). However, what is the behavior of genes that are located a particular chromosome? What happens to traits that are found on the sex chromosomes?
In many sexually reproducing organisms, sex is determined by genes that are located on dissimilar chromosomes. These dissimilar chromosomes are termed sex chromosomes. Humans possess 23 pairs of chromosomes; 22 of these are similar (autosomes), whereas one pair (the X and Y chromosomes) is dissimilar and possesses the genes responsible for the transmission of character traits that determine sex. If an individual has the XX genotype, the individual is female, while the XY genotype results in males. There are two important facts to remember about sex chromosomes. First, the X chromosome is generally larger and has more genes than the Y chromosome. Second, genes that affect traits other than sex are also found on these chromosomes (for example, a gene that affects tooth enamel in humans is found on both the X and the Y).
With the above two facts in mind, consider the male genotype (XY). Because the X chromosome has more genes than the Y, not all alleles will be found in the heterozygous state. That is, the maternally derived alleles may be expressed as if they were in the homozygous state. (Remember that the male's X chromosome comes from the mother.) Traits that are disproportionately expressed in one gender (typically males) are termed sex-linked traits. That is, sex-linked traits tend to follow (are linked to) the gender from which they're derived.
In the following tutorial, we will examine the relationship of genes that are located on the same autosome.
After reading this tutorial, you should have a working knowledge of the following terms:
Case Study for Chromosome Behavior and Sex Chromosomes
Some forms of retinitis pigmentosa (a disease of the photoreceptors and the pigment epithelium of the eye) are X-linked. You search the web and discover there are instances when females are afflicted with this disorder. Your lab partner tells you this proves the trait cannot be X-linked because it should only appear in boys.
- Explain why your lab partner is incorrect and give a possible reason as to why he misunderstands this mode of transmission.
- What is the probability that a woman with retinitis pigmentosa will have a son with the disease (her partner does not have the disease)? What is the probability she will have a daughter with the disease?
Now that you have read this tutorial and worked through the case study, go to ANGEL and complete the tutorial practice problem to test your understanding. Questions? Either send your instructor a message through ANGEL or attend an online office hour (the times are posted on ANGEL).