McGraw-Hill Answers| Sex Linkage and Pedigree Analysis

By Hyde, D.R.

Edited by Paul Ducham


Two significant inheritance patterns are observed for X-linked recessive alleles. First, males will preferentially exhibit the recessive X-linked phenotype. This expression pattern of primarily affecting males is shown in figure 4.1.
     Because females have two X chromosomes, they can produce phenotypically normal offspring that have either homozygous or heterozygous allelic combinations. Males, with only one copy of the X chromosome, are neither homozygous (two copies of the same allele) nor heterozygous (two different alleles). Instead, males are hemizygous, which describes genes that are present in only one copy, like the X-linked genes in males.
     When only a single copy of a gene is present, a single recessive allele can determine the phenotype in a phenomenon called pseudodominance. Thus, a male fly with one recessive w allele is white-eyed, with the w allele acting like a dominant allele to confer the whiteeyed phenotype. This demonstrates that expression of a recessive phenotype is not dependent upon the presence of two recessive alleles, but rather the absence of a dominant allele.
     The second major inheritance pattern observed with X-linked genes and the corresponding phenotypes is a crisscross pattern of inheritance. Figure 4.1d demonstrates this pattern as the male parent passes his dominant trait (such as wild-type eyes, fig. 4.1d) to his female offspring, and the female parent passes her recessive phenotype (white eyes) to her male offspring. If we examine the reciprocal cross, we do not observe the crisscross pattern (fig. 4.1a). Thus, the crisscross pattern of phenotypic inheritance is not always observed for X-linked genes.
     Because males do not transmit their X chromosome to their male offspring, a recessive X-linked phenotype such as color blindness in humans is never normally transmitted from father to son. However, the male will transmit his X chromosome to his daughter (fig. 4.1a). The daughter of an affected male will be heterozygous if she is phenotypically normal. We call this heterozygous individual a carrier, as she possesses the recessive allele. Thus, the transmission of the X chromosome from the male parent to only his female offspring to produce carriers, along with the pseudodominance of X-linked recessive alleles in males, combine to produce the crisscross pattern of inheritance.

Deviation from Mendelian Patterns
Notice that the two different crosses (see fig. 4.1a and 4.1d) produced different phenotypes in the F1progeny. These differences are not consistent with the Mendelian pattern of inheritance that we described in chapter 2. In figure 4.1a, the recessive white-eyed phenotype is lost in the F1 generation as expected, but in the reciprocal cross it is present in half the progeny (fig. 4.1d).
     This does not suggest that Mendel’s laws are incorrect, but rather it demonstrates another level of complexity that Mendel did not observe in his pea crosses. In this case, the increased complexity is due to the two different sex chromosomes and the hemizygous nature of the male. It is comforting that as we uncover the cause of the increased complexity, we see how Mendel’s laws still apply, through the pairing of the X and Y chromosome during meiosis in the male. This observation demonstrates that Mendel’s laws are actually more fundamental than we had expected.
     In the following chapter, we will explore other examples of deviations from Mendel’s patterns.

Y-Linked Traits
Because both the X and the Y are sex chromosomes, two different patterns of sex-linked inheritance are possible. The terms sex-linked and X-linked usually refer to loci found only on the X chromosome. The term Y-linked refers to loci found only on the Y chromosome, which controls holandric traits (traits found only in males).
     There are 1,098 genes that are located on the human X chromosome, whereas 171 genes are known to be on the Y chromosome. The small number of loci on the Y chromosome makes the identification of Y-linked phenotypes difficult. In humans, the best example of a Y-linked trait is a form of retinitis pigmentosa, which results in night blindness that progresses into complete blindness. Retinitis pigmentosa has many different genetic causes, some of which are autosomal and others are sex-linked.
     This particular form of retinitis pigmentosa was first described in a four-generation Chinese family. In this family, only males were affected. Furthermore, all of the sons, and none of the daughters, of an affected male were also affected. All of the daughters of an affected male also failed to produce an affected child. This transmission from father to all of his sons and no affected females is consistent with the trait being inherited in a Y-linked manner.
     For many years, hairy ear rims was believed to be a Y-linked trait (fig. 4.2) because of the description that it was inherited only in fathers and their sons. NIH’s database, the Online Mendelian Inheritance in Man (OMIM) describes recent data that strongly suggests that hairy ear rims result either from more than one locus on the Y chromosome, with one of the loci located in the pseudoautosomal region, or it is not Y linked at all.




Aside from X-linked and Y-linked inheritance, two additional inheritance patterns show a bias in the phenotypic expression between the two sexes. However, the genes controlling these traits are located on the autosomes rather than either of the sex chromosomes.
     Sex-limited traits are expressed in only one gender, although the genes are present in both. In women, breast development and milk production are sex- limited traits, as are facial hair distribution and sperm production in men. Nonhuman examples of sexlimited traits include plum age patterns in birds—in many species, the male is brightly colored—and horns found in male, but not female, elk (fig. 4.3).
     Sex-influenced traits appear in both genders, but are recessive in one and dominant in the other. One potential example of a sex-influenced trait in humans is a heart condition called long QT syndrome (LQTS). This syndrome is characterized by a prolonged QT interval on the electrocardiograph, ventricular arrhythmias, potential seizure, and sudden death. LQTS appears to affect more adult females than adult males, suggesting that a sex-related difference is present. However, the mutation associated with LQTS has been mapped to the voltage-gated potassium channel-1 gene (KCNQ1 gene), which is located on chromosome 11.
     The autosomal location of the gene suggests that males and females would be equally affected by LQTS. However, the predominance of this autosomal-linked phenotype in females confers the sex-influenced nature on LQTS. The reason that women preferentially exhibit LQTS remains unclear, although hormonal differences between the sexes is one possibility.



In 1910, Morgan described the pattern of sex-linked inheritance in Drosophila. He isolated a white-eyed mutant male in a culture of wild-type (red-eyed) flies (fig. 4.5). When this male was crossed with a wildtype female, all the F1 progeny were wild-type (see fig. 4.5). The loss of the white-eyed phenotype in these F1progeny suggested that the white-eyed phenotype was recessive to the wild-type phenotype.
     When these F1 individuals were crossed with each other, both white-eyed and red-eyed progeny were produced (see fig. 4.5). However, the phenotypes were not equally distributed between both sexes. All the females and half the males were red-eyed, whereas the remaining half of the males were white-eyed.
     Because the female possessed two X chromosomes and the male only one X chromosome, we can redraw the crosses to include the sex chromosomes (fig. 4.6). Furthermore, the X chromosome contains the white gene locus, but the Y chromosome does not. We denote the white allele as w and the wild-type allele as +.
     Morgan then performed the reciprocal cross, which involved switching the phenotypes of the parents (fig. 4.7). In contrast to all the F1 progeny having the dominant wild-type phenotype (see fig. 4.6), the reciprocal cross produced white-eyed F1 males and red-eyed F1 females (see fig. 4.7). This is a crisscross pattern of inheritance, in which the male passes his phenotype to his daughters and the female passes her phenotype to her sons. Crossing two F1 individuals produced both white-eyed flies (half the males and half the females) and red-eyed flies (half the males and half the females).
     The inheritance of the white-eyed phenotype from Morgan’s crosses was consistent with the eye color phenotype being associated with the X chromosome. However, he was unable to provide conclusive proof of the chromosomal theory of inheritance. This proof was left to one of Morgan’s students, Calvin Bridges.





Bridges repeated Morgan’s cross of red-eyed males (X+Y) and white-eyed females (XwXw) in very large numbers (fig. 4.8). The F1 progeny consisted of white-eyed males and red-eyed females to observe the crisscross pattern of inheritance. However, 1 in approximately every 2000 males were red-eyed, and 1 in every 2000 females were white-eyed (see fig. 4.8). Bridges called these rare F1 individuals primary exceptional progeny. Although the primary exceptional males were sterile, the primary exceptional females were fertile.
     Bridges then crossed the white-eyed primary exceptional females with red-eyed males and again found the majority of the progeny were white-eyed males and redeyed females (see fig. 4.8). Now, however, approximately 1 in 200 males were red-eyed and an equivalent ratio of females were white-eyed. Bridges called these unusual F2 progeny secondary exceptional progeny. Unlike the primary exceptional males, the secondary exceptional males and females were both fertile.
     Bridges used the knowledge of Drosophila sex determination (see section 4.3) and the fact that the white gene was on the X chromosome to construct a model to explain this data. Bridges knew that Drosophila males only have one X chromosome, and that males lacking a Y chromosome were sterile. Therefore, the sterile primary exceptional males must have been X0. The X chromosome in these males must have been inherited from their male parent, as this parent possessed the only X chromosome with the wild-type eye color allele.
     How did the male pass his X chromosome on to a male offspring? Normally, an X chromosome from the male parent would be passed to female offspring. Therefore, a male fly having a paternal X chromosome can occur only if the female parent produced an egg that lacks an X chromosome. The result is that the primary exceptional male receives the X chromosome from the male parent and no sex chromosome (0) from the female parent (see fig. 4.9). According to genic balance in Drosophila, the offspring’s X:A ratio would be 0.5, and the fly would be male.
     Then how does the female produce an egg that lacks an X chromosome? This occurs as a result of nondisjunction, in which the chromosomes failed to segregate during either meiosis I or meiosis II (see fig. 4.10). Thus, sperm that contained an X chromosome could fertilize an egg lacking an X chromosome to produce an X0 male (see fig. 4.9). Cytology of these primary exceptional males confirmed Bridges’ hypothesis that they were X0.
     The white-eyed primary exceptional females must be XwXw to account for their gender. The white-eyed phenotype suggested that both X chromosomes must contain the recessive w allele. Because the male parent contained an X chromosome with the wild-type allele (X+), both X chromosomes in the primary exceptional females must have been inherited from their female parent (see fig. 4.9). Thus, the female parent must have produced an egg from nondisjunction that contained two Xw chromosomes (see fig. 4.10).
     These XwXw eggs could have been fertilized with sperm lacking a sex chromosome to produce the primary exceptional females; however, this result would require nondisjunction to also have occurred in the male parent. The likelihood of producing an individual from two gametes that both experienced nondisjunction would be significantly less than that of the single nondisjunction event that produced the primary exceptional males.
     Because the primary exceptional males and females were found at the same frequency, they both must be produced by a nondisjunction event in only one parent. Thus, the primary exceptional females were generated from XwXw eggs that were fertilized with a sperm containing the Y chromosome to produce XwXwY females (see fig. 4.9). Bridges knew that the Y chromosome would not change the gender of the XXY female because of genic balance, and his cytological analysis confirmed that the primary exceptional females were XXY.





The ultimate proof of the chromosomal theory of inheritance came when Bridges examined the secondary exceptional progeny. The white-eyed primary exceptional females possessed an odd number of sex chromosomes. As these germ cells entered meiosis, only two of the three sex chromosomes could pair during meiosis I.
     The preferred synapsis would occur between the two X chromosomes (fig. 4.11 left), because they contain more sequences in common than exist between the X and Y pseudoautosomal regions. When the two X chromosomes paired, two types of gametes were produced: Xw and XwY (see figs. 4.9 and 4.11). In the rarer cases when an X and Y synapsed in meiosis I (see fig. 4.11), the two types of gametes produced are XwXw and Y (see figs. 4.9 and 4.11).
     The Punnett square in figure 4.9 shows the various products resulting from these four primary exceptional female gametes and the two different wild-type male gametes. Again, secondary exceptional progeny are produced, namely the white-eyed female (XwXwY) and wild-type male (X+Y). However, the secondary exceptional males would be fertile because they carry a Y chromosome (see fig. 4.9).
     Bridges’ predictions on what sex chromosomes would be present in flies expressing each phenotype was again confirmed by cytology. The ability to predict the correct combination of sex chromosomes that corresponded to a specific eye color provided compelling proof that the chromosomes were tightly associated with the genetic units that conferred a given phenotype.



You are probably already familiar with the XY system. Human females have 46 chromosomes arranged in 23 homologous pairs, including the two X chromosomes. Because females have two copies of the same sex chromosome, all of their gametes contain the same sex chromosome. For this reason, they are termed the homogametic sex. Males, with the same number pairs (autosomes) and one heterologous pair, the XY pair (fig. 4.12). Males are termed the heterogametic sex because they produce gametes with either an X or a Y sex chromosome.
     The Y chromosome, which is known to encode approximately 171 genes (fig. 4.13), contains a single gene that determines if a developing mammal will be male. This Y chromosome gene, which is called either the testis-determining factor (TDF) or sex- determining region Y (SRY) gene, acts as a sex switch to initiate male development in mammals (see chapter 21). The role of the SRY gene in determining maleness has been conclusively shown in mice, where mice that contain two X chromosomes and the SRY gene inserted in an autosome develop as males. Additionally, mice containing one X chromosome and a Y chromosome, with the SRY gene deleted, will develop as females. Thus, it is not two X chromosomes that determine femaleness nor a Y chromosome that determines maleness, but rather the presence of the SRY gene that determines maleness, and the absence of SRY that determines femaleness.
     Although most mammals use this XY system for gender determination, there are a few exceptions. Notably, the platypus utilizes a compound sex chromosome system that we will discuss later in this chapter.
     Drosophila also utilizes the XY system. As with humans, the female flies are the homogametic sex, with six autosomes and two X chromosomes. Males, which are the heterogametic sex, contain six autosomes, one X chromosome and one Y chromosome. The Drosophila Y chromosome does not encode an SRY gene that determines maleness; however, the Y chromosome is known to carry at least six genes that are essential for male fertility. These fertility genes encode proteins needed during spermatogenesis. For example, kl-5 encodes part of the dynein motor needed for sperm flagellar movement. We will discuss how Drosophila gender is determined in the next section.
     The Y chromosome in both humans and flies contains two regions, one at either end of the chromosome, that are homologous to the X chromosome (see fig. 4.13). These regions are termed pseudoautosomal, and they permit the Y chromosome to pair with the X chromosome during meiosis in males to allow for their proper segregation.
     Because both human and Drosophila females normally have two X chromosomes, and males have an X and a Y chromosome it seems impossible to know whether maleness is determined by the presence of a Y chromosome or by the absence of a second X chromosome. One way to resolve this problem would be to isolate individuals with unusual numbers of chromosomes. In chapter 8, we will examine the causes and outcomes of anomalous chromosome numbers. Here, we consider two facts from that chapter.
     First, in rare instances, individuals can have extra sets of chromosomes, although they are not necessarily viable. These individuals are referred to as polyploids (triploids with 3n, tetraploids with 4n, etc.).
     Second, also infrequently, individuals have more or fewer than the normal number of any one chromosome. These aneuploids usually result when a pair of chromosomes fails to separate properly during meiosis, an occurrence called nondisjunction (fig. 4.14). Thus, nondisjunction can produce gametes that either contain an extra copy of a chromosome or lack a chromosome. After fertilization, the gamete with an extra copy of a chromosome will produce an individual that has three copies, and the gamete lacking a copy of a chromosome will yield an individual that only has one copy.
     The existence of polyploid and aneuploid individuals makes it possible to test whether the Y chromosome is male determining. For example, the gender of a human or a fruit fly that has the expected number of autosomes (44 in human beings, 6 in Drosophila), but only a single X without a Y would answer the question. If the Y is absolutely required in determining a male, then this X0 individual should be female. However, if the sexdetermining mechanism is a result of the number of X chromosomes, this individual should be a male.
     In humans, a single X chromosome (X0) results in a female. However, this female is not completely normal, a condition called Turner syndrome. Alternatively, humans with an extra sex chromosome, XXY, are male. Similar to the X0 condition, the XXY individuals are not completely normal, a condition called Klinefelter syndrome. (Details of both these conditions are described in chapter 8.) Because the sex of a Turner syndrome individual is female, it must be the presence of the Y chromosome and not a single X chromosome that determines maleness. Similarly, the sex of a Klinefelter syndrome individual reveals that a single Y chromosome determines maleness, regardless of the number of X chromosomes.
     Although Drosophila also utilizes the XY system for sex determination, the Y chromosome does not determine maleness. Using polyploids and aneuploids, a different sex determination mechanism was revealed in the fruit fly (see following section).
     You might wonder about an individual that does not contain an X chromosome. These Y0 individuals have not been identified in either mammals or Drosophila. This suggests that the X chromosome, unlike the Y chromosome, is essential for the viability of the organism.





In 1921, geneticist Calvin Bridges, working with Drosophila, crossed a triploid female (3n) with a normal male (2n). He observed many combinations of autosomes and sex chromosomes in the offspring (table 4.1). From his results, Bridges suggested that sex in Drosophila is determined by the balance between (ratio of) autosomes that favor maleness and X chromosomes that favor femaleness. He calculated a ratio of X chromosomes to autosomal sets to see if this ratio would predict the sex of a fly. An autosomal set (A) in Drosophila consists of one chromosome from each autosomal pair, or three chromosomes. Thus, a diploid would have two autosomal sets.
     Bridges’ genic balance theory of sex determination was essentially correct. When the X:A ratio is 1.00, as in a normal female (XX), or greater than 1.00, the organism is a female. When this ratio is 0.50, as in a normal male (XY), or less than 0.50, the organism is a male. At 0.67, the organism is an intersex, which means that it possesses characteristics of both sexes. Metamales (X: A = 0.33) and metafemales (X:A = 1.50) are usually very weak and sterile. The metafemales usually do not even emerge from their pupal cases and die.



Analogous to the XY chromosome system, the ZW system also utilizes two different chromosomes to determine gender. Males, which have two copies of the Z chromosome, are the homogametic sex (table 4.2). Females are the heterogametic sex, with one Z chromosome and one W chromosome. The ZW system occurs in birds, some fishes, and moths.
     Unlike the relatively small pseudoautosomal region that is shared between the X and Y chromosomes, the Z and W chromosomes share a relatively large pseudoautosomal region. In some species, the Z and W chromosomes are nearly indistinguishable. This suggests that the Z and W chromosomes evolved from a pair of homologous autosomes and are unrelated to the X and Y sex chromosomes in origin.
     Regardless of their origin, the Z and W chromosomes evolved into the sex chromosomes in a variety of organisms. Rather than using a gene that is related to the mammalian Y chromosome’s SRY gene to determine maleness, the ZW system appears to employ at least two different genes in gender determination.
     The Z chromosome contains the DMRT1 gene, which appears to be important in determining the male gender. Although the DMRT1 gene seems to be unrelated to the mammalian SRY gene, it may function in an analogous manner to control the formation of the male testis. However, this mechanism is more complicated than the SRY determination process in the XY system because both males and females contain a Z chromosome, and therefore, a DMRT1 gene. The two Z chromosomes in the male ostensibly produce more DMRT1 protein than the single copy in the female. Thus, maleness may be controlled by the amount of DMRT1 protein compared with the presence or absence of the SRY protein in the XY system. The DMRT1 gene, which is present in human chromosome 9, must be present in two copies for normal testis differentiation in males.
     The W chromosome also contains a gene, ASW or Wpkci, which is thought to be important in determining the female gender. In addition to activating the expression of genes that must be expressed in females, the Wpkci protein may also help prevent the expression of genes that must be expressed in males.



In the X0 system, which is observed in a variety of insects, only a single type of sex chromosome is designated the X chromosome (see table 4.2). This X chromosome should not be confused with the X chromosome in the XY system. In the X0 system, the female usually has two X chromosomes (XX) and the male a single X chromosome (X0). Whereas the X0 male is sterile in the XY system due to the absence of the Y chromosome, the X0 male in the X0 system is fertile. The number of X chromosomes appears to be all that is required for determining the gender of the individual, which is analogous to the number of Z chromosomes determining gender.
     The nematode Caenorhabditis elegans, which is a popular genetic model, also uses the X0 system. As described earlier, an individual with a single X chromosome (X0) will be a male. However, a C. elegans individual with two X chromosomes (XX) will be a hermaphrodite, which is an individual with both sex organs (ovaries and testis). There are no females. In this case, the hermaphrodite can either self-fertilize or mate with a male to produce offspring. It is hypothesized that the X chromosome:autosome ratio, similar to that described for Drosophila, determines the gender of the individual. An X:A ratio of 1.0 would produce a hermaphrodite, and a ratio of 0.5 would yield a male.


The most common example of the haplo-diploid system is found in bees. In this system, there is no sex chromosome. Instead, males (drones) are haploid, and females (workers and the queen) are diploid (see table 4.2). During meiosis, the queen produces haploid eggs. If those eggs are not fertilized, they will develop into males. If they are fertilized, they will become either workers or a queen.


In the compound chromosome case, several X and Y chromosomes combine to determine sex. Compound chromosomal systems tend to be complex, with the precise mechanism of gender determination unclear. For example, the nematode Ascaris incurva has eight X chromosomes and one Y. The species has 26 autosomes. Males have 35 chromosomes (26A + 8X + Y), and females have 42 chromosomes (26A + 16X). During meiosis, the X chromosomes unite end to end and behave as one unit. Thus, the male produces gametes that contain either eight X chromosomes or a single Y chromosome. Females produce gametes that contain eight X chromosomes.
     The duck-billed platypus (Ornithorhynchus anatinus) is a monotreme, an egg-laying mammal. Unlike other mammals that utilize the XY system, the platypus employs a compound chromosome system. Only in the last 2 years has the sex chromosome composition been determined in the platypus.
     The five different X chromosomes in the platypus (X1, X2, X3, X4, X5) differ in their size and gene composition. It also has five different Y chromosomes (Y1, Y2, Y3, Y4, Y5). The male contains all five X and Y chromosomes and the female contains 10 X chromosomes, which are composed of two copies of each X chromosome (see table 4.2). Cells that are undergoing meiosis in a male arrange their X and Y chromosomes in a long chain in a specific order (X1 Y1 X2 Y2 X3 Y3 X4 Y4 X5 Y5). It is thought that this chromosome chain is held together by homologous sequences that are shared between specific pairs of X and Y chromosomes.
     Although the number and arrangement of the sex chromosomes have been determined in the platypus, the genetic basis of sex determination remains unknown. Unlike other mammals, the SRY gene is not present on any of the five Y chromosomes. However, the X5 chromosome does possess a DMRT1 gene, which is present in one copy in the male platypus and two copies in the female. This is surprising because the DMRT1 gene, which determines maleness in the ZW system, is present in two copies in the male and one copy in the female. Furthermore, two copies of the DMRT1 gene are required for testis development in other male mammals. The actual genetic basis of gender determination remains unknown in the platypus, but the identification of the sex chromosome composition will greatly speed the discovery of the critical gene(s).


Sex chromosomes are not the only determinants of an organism’s gender. Environmental sex determination (ESD) is an alternative mechanism that controls the gender of individuals. One mechanism of ESD depends on the substrate where some marine worms and gastropods develop. The environmental temperature during egg development also plays a major role in gender determination in turtles, lizards, crocodiles, and alligators.
     The effect of temperature on gender determination varies from species to species (fig. 4.15). At low temperatures, some organisms develop only as males, but other organisms develop only as females. At the high temperature, development is directed into the other gender. It is the temperatures that lie between the two extremes that allow both males and females to develop. However, some species develop as only females at both the low and high temperatures (see fig. 4.15). At the intermediate temperatures, the percentage of individuals that develop as males increases and may even reach 100%.
     Although ESD is controlled by environmental conditions and not the presence of specific sex chromosomes, it is clear that the environment must act on a metabolic or physiological process in the developing embryo. The processes controlled by the environment are unclear, but they likely involve steroid biosynthesis. Two potential target enzymes are reductase and aromatase, which control the conversion of testosterone into either dihydrotestosterone or estradiol, respectively.
     Consistent with a potential role in ESD, levels of aromatase were increased in eggs that were incubated at female-producing temperatures, but not at male-producing temperatures. To test the potential role of aromatase and reductase, aromatase inhibitors were injected into eggs that were incubated at femaleproducing temperatures and primarily males were produced. Injection of reductase inhibitors into eggs that were incubated at male-producing temperatures yielded mostly females.
     It also appears that temperature is affecting the expression of the aromatase and reductase genes either directly or indirectly. At female-producing temperatures, the expression of aromatase is increased and reductase remains low. At male-producing temperatures, reductase is expressed at higher levels and aromatase remains low. Thus, ESD is mediated through the regulation of gene expression, as it is in other mechanisms of sex determination.



In fruit flies, the X-linked genes in the male are hypertranscribed relative to the female. By increasing the transcription of the X-linked genes approximately twofold in males, the males and females express roughly equivalent levels of the gene products.
     This increased transcription in males requires four proteins that are encoded by the maleless and malespecific lethal-1, -2, and -3 genes. Mutations in any of these four genes result in the male dying early in development because it cannot express the X-linked genes at a high enough level for survival.
     The proteins encoded by these four genes form a complex called the dosage compensation complex. This complex also requires at least two different RNAs that are encoded by the rox1 and rox2 genes. The dosage compensation complex can be detected bound to the X chromosome in males, but not in females (fig. 4.16).



In mammals, dosage compensation is achieved when the X chromosome undergoes X chromosome inactivation. In this process, all of the X chromosomes in a cell, except one, are modified so that they are transcriptionally inactive. The result is that normal females (XX), males (XY), and Klinefelter males (XXY) all exhibit approximately the same level of expression for X-linked genes. The inactive X chromosomes, called Barr bodies (fig. 4.17), are named after Murray Barr who first identified them. Both a normal female and a Klinefelter male have one Barr body in each nucleus.
     It should be noted that only part of the X chromosome is inactivated. Approximately nine genes in the pseudoautosomal regions of the X chromosome and several other genes scattered along the X chromosome remain active in the Barr body. All the pseudoautosomal genes are present on both the X and Y chromosome. Thus, the female has two copies of each of these genes (one on each X chromosome) and the male also has two copies of each of these genes (one on the X and the other on the Y chromosome). By not inactivating these particular genes on the Barr body, both the normal female and male transcribe two copies of each of these genes.
     What determines which X chromosome will be inactivated? In marsupials, the paternal X chromosome is specifically inactivated. In all other mammals, the selection of the X chromosome that will be inactivated appears to be random. In humans, the selection point occurs when the embryo is composed of approximately 500–1000 cells. Once the inactivation decision is made in one cell, all of the cells descended from that cell exhibit the same inactive X chromosome (fig. 4.18a).
     This random inactivation leads to mosaic females that possess different patches, or regions, that have an active paternal X chromosome and other patches that have an active maternal X chromosome. These random patches can be seen in the Calico cat (see fig. 4.18b), where the orange and black patches are due to the inactivation of different X chromosomes during early development.
     The mechanism by which X inactivation takes place is described in chapter 21.




Think of the difficulties Mendel would have faced had he decided to work with human beings instead of pea plants. Human geneticists face the same problems today. Humans take a long time to reach reproductive maturity, and the number of offspring that result from two parents are not large—rarely over single-digit numbers in the lifetime of the mother. And of course, it is unethical to “arrange” matings between individuals with desired genotypes to suit the geneticist’s wishes. Under these circumstances, it is unlikely that Mendel would have observed his standard ratios in human families.
     To determine the inheritance pattern of many human traits, geneticists often have little more to go on than a family history that many times does not include critical mating combinations. This family history can be diagrammed as a pedigree, which represents all the individuals in the family and their phenotypes. Frequently, uncertainties and ambiguities plague human genetic analysis. In chapter 5, we will discuss particular phenomena (penetrance and expressivity) that can further increase the difficulty in elucidating human inheritance patterns. In the following sections, we assume for the sake of discussion that the simplest explanations are correct.
     One assumption often made in pedigree analysis is that the trait being examined is rare. This simplifies the pedigree because the presence of the mutant allele will also be rare. In these cases, it is assumed that someone marrying into the pedigree lacks the rare allele, unless evidence exists to the contrary.
     The NIH’s OMIM database contains information on a large number of human genes and genetic diseases. As of 2007, OMIM contains information on 11,823 human genes and 6,195 human traits and diseases, including autosomal dominant, autosomal recessive, and sex-linked genes. Pedigrees are useful in deducing both the mode of inheritance and the genotypes of individuals. Genotype information is important in determining the probability that a couple will have a child that suffers from a particular trait.
     To review, humans have 23 pairs of chromosomes. One pair is called the sex chromosomes because they determine the gender and secondary sexual characteristics of the individual. The rest are autosomes. In the following sections, we will differentiate the dominant from the recessive patterns of inheritance as well as distinguishing patterns associated with the sex chromosomes from those connected to the autosomes.


One way to examine a pattern of inheritance is to draw a pedigree. Figure 4.19 defines some of the symbols used in constructing a pedigree. Circles represent females, and squares represent males. Filled symbols represent individuals who exhibit the trait under study. These individuals are said to be affected when the trait being studied is an inherited disease. The open symbols represent those who do not exhibit the trait (unaffected).
     A horizontal line connecting two individuals (one male, one female) is called a marriage or mating line, and a double horizontal line represents a consanguineous mating, which is a mating between related individuals. Offspring (children) are attached to a mating line by a vertical line. All the brothers and sisters (siblings or sibs) from the same parents are connected by a horizontal line above their symbols.
     Figure 4.20, which is a pedigree for the trait polydactyly (having more than 10 fingers or toes), shows other conventions. Siblings are numbered below their symbols according to birth order, and generations are numbered on the left in Roman numerals. When the sex of a child is unknown, the symbol is diamondshaped (for example, the children of III-1 and III-2 in fig. 4.20). A number within a symbol represents the number of siblings not separately listed.
     Individuals IV-7 and IV-8 in figure 4.20 are fraternal (dizygotic or nonidentical) twins: they originate from the same point. Individuals III-5 and III-6 are identical (monozygotic) female twins: they originate from the same short vertical line and their lines are connected by a horizontal line.
     When other symbols occur in a pedigree, they are usually defined in the legend. Individual V-5 in figure 4.20 is identified as the proband or propositus (female, proposita) by the arrow pointing to his symbol. The proband is the individual that is first identified with the trait, usually by a physician or clinical investigator, and the pedigree is usually constructed by assembling the ancestors of that individual.
     On the basis of the information in a pedigree, geneticists attempt to determine the mode of inheritance of a trait. Two types of questions might be answered through pedigree analysis. First, do patterns occur within the pedigree that are consistent with a particular mode of inheritance? Second, are patterns present that are not consistent with a particular mode of inheritance? Often, it is impossible to determine the mode of inheritance of a trait with certainty.



Looking again at the pedigree in figure 4.20, several points become apparent. First, polydactyly, (shown in fig. 4.21), occurs in every generation. Every affected child has an affected parent—no generations are skipped. This pattern suggests dominant inheritance.
     Second, the trait occurs about equally in both sexes; there are eight affected males and six affected females in the pedigree. This equal ratio of affected genders indicates autosomal rather than sex-linked inheritance. Because of this, we would categorize polydactyly as an autosomal dominant trait.
     Note that individual IV-13 (see fig. 4.20), a male, passed on the trait to two of his three sons. This inheritance from father to son would rule out X-linked dominant inheritance, because a male gives his X chromosome to all of his daughters and none of his sons. Consistency in many such pedigrees has confirmed that an autosomal dominant gene causes polydactyly.



Figure 4.22 shows a pedigree with a different pattern of inheritance for hypotrichosis (lack of hair growth). Unlike the autosomal dominant pedigree, affected individuals are not found in each generation of this pedigree. Also, the affected daughters, identical triplets, come from unaffected parents. They represent, in fact, the first appearance of the trait in three generations.
     A telling point for the pattern of inheritance in hypotrichosis is that the parents of the triplets are first cousins, that is, they represent a consanguineous mating. Consanguineous matings often produce offspring that have rare recessive, and often deleterious, traits. The reason this occurs is that through common ancestry, a rare allele that is heterozygous in a single common ancestor can be passed on to both sides of the pedigree and produce a homozygous child. In this case, the parents share a common set of grandparents. Because of the danger of combining deleterious alleles, marriage between first cousins is prohibited in 30 states.
     Although the appearance of a trait in a consanguineous pedigree is often good evidence for an autosomal recessive mode of inheritance, all modes of inheritance appear in consanguineous pedigrees, and recessive inheritance is not confined to consanguineous pedigrees. It is possible that two unrelated individuals may carry a recessive allele for the same gene. Although not shown in this pedigree, all the children of two affected individuals (homozygous recessive) must also be affected to demonstrate an autosomal recessive trait.



Figure 4.23 is a pedigree with yet a different pattern of inheritance. The phenotype under consideration is the distribution of low blood phosphorus levels, which is one characteristic of vitamin-D-resistant rickets. This pedigree suggests a dominant mode of inheritance because the trait does not skip generations.
     Unlike the autosomal dominant pedigree in figure 4.20, this pedigree shows affected males passing the trait on to all their daughters, but not to their sons. This pattern is consistent with the transmission of the X chromosome, which fathers pass on to all of their daughters and none of their sons. Therefore, this likely represents a sex-linked dominant trait.
     Although this pedigree is consistent with a sexlinked dominant mode of inheritance, it does not rule out autosomal dominant inheritance. An instance of transmission of the trait from father to son, however, would eliminate the X-linked mode of inheritance as a possibility.
     In figure 4.23, a slight possibility exists that the trait is recessive. This could be true if individuals I-2, II-6, and II-10 were all heterozygotes. But because this is a rare trait, the possibility that all three of these individuals are heterozygous is small. For example, if 1 person in 50 (0.02) is a heterozygote, then the probability of three heterozygotes mating within the same pedigree is (0.02)sup>3, or 8 in 1 million. The rareness of this event further supports the hypothesis of dominant inheritance.



Figure 4.24 is the pedigree of Queen Victoria of England and the expression of the blood clotting disorder hemophilia. Through her children, hemophilia was passed on to many of the royal houses of Europe.
     Several interesting aspects of this pedigree help to confirm the method of inheritance. First, the hemophilia trait skips generations, which suggests a recessive mode of inheritance. Although Alexis (1904–18) was a hemophiliac, his parents, grandparents, great-grandparents, and great-great-grandparents in this pedigree were unaffected. This pattern of affected individuals having unaffected parents occurs in several other places in the pedigree. From this and other pedigrees, and from the biochemical nature of the defect, scientists confirmed that hemophilia is a recessive trait.
     Second, all the affected individuals are males, strongly suggesting sex linkage. Because males are hemizygous for the X chromosome, more males than females should have the sex-linked recessive phenotype because of pseudodominance.
     Third, the trait is never passed from father to son in this pedigree. This result would defy the route of inheritance of an affected X chromosome. We can conclude from the pedigree, therefore, that hemophilia is an X-linked recessive trait.
     It is important to realize that many human diseases exhibit similar symptoms, but are due to mutations in different genes. This suggests that different pedigrees for the same clinical disease (described on the basis of symptoms) may show different patterns of inheritance. For example, several different inherited forms of hemophilia are known, each of which is deficient in one of the steps in the pathway that forms fibrinogen, the blood clot protein. Two of these forms, “classic” hemophilia A and hemophilia B, are sex-linked. Other hemophilias are autosomal.
     We can make several predictions about the pedigree in figure 4.24, if it indeed reveals an X-linked recessive trait. First, because all males get their X chromosomes from their mothers, affected males should be the offspring of carrier (heterozygous) females. A female must be a carrier if her father had the disease, as the father passes his X chromosome to all of his daughters. However, a female has a 50% chance of being a carrier if her brother has the disease and her father is unaffected. In that case, her mother is a carrier.
     It is also possible for a woman to be homozygous for this condition—that is, her father would be affected, and her mother would be a carrier. Because both the father and mother must have the recessive allele to have an affected daughter, X-linked recessive traits are less common in females than males; where only the mother must be a carrier. Hemophilia in a woman, however, could be fatal with the start of menses, and childbirth would be extremely dangerous. Such a situation is not found in the pedigree in figure 4.24.



The following lists summarize the major points of the four patterns of inheritance that we discussed. Keep in mind that a pedigree showing all of the features associated with one pattern does not necessarily eliminate other patterns. The other patterns may simply be less likely, as you saw with an autosomal recessive inheritance mode in figure 4.24. The only way to conclusively eliminate a pattern of inheritance is to identify a part of the pedigree that is inconsistent with that pattern.

Autosomal Dominant Inheritance
   1. Trait should not skip generations (unless the trait lacks full penetrance, see Chapter 5).
   2. When an affected person mates with an unaffected person, approximately 50% of their offspring should be affected (indicating also that the affected individual is heterozygous).
   3. The trait should appear in almost equal numbers between males and females.

Autosomal Recessive Inheritance
   1. Trait often skips generations.
   2. An almost equal number of males and females will be affected.
   3. Traits are often found in the offspring of consanguineous matings.
   4. If both parents are affected, all children should be affected.
   5. In most cases when an unaffected individual mates with an affected individual, all the children will be unaffected. When at least one child is affected (indicating that the unaffected parent is heterozygous), approximately half the children should be affected.
   6. Most affected individuals have unaffected parents who are carriers.

Sex-Linked Dominant Inheritance
   1. The trait does not skip generations.
   2. Affected males must come from affected mothers.
   3. Approximately half the children, both sons and daughters, of an affected heterozygous female are affected.
   4. Affected females may have either affected mothers or fathers.
   5. All the daughters, but none of the sons, of an affected father are affected (if the mother is unaffected).

Sex-Linked Recessive Inheritance
   1. Most affected individuals are male.
   2. All the daughters of an affected male will be carriers and all of the sons will be unaffected.
   3. Affected females have affected fathers and affected or carrier mothers.
   4. All the sons of affected females should be affected. 5. Approximately half the sons of carrier (heterozygous) females should be affected.


Once a pedigree is generated and the mode of inheritance for the observed trait is determined, we can then calculate the probability of a particular genotype for any individual in the pedigree. We can also calculate the probability that an offspring produced from the pedigree will possess a specific genotype or phenotype. These calculations require the sum and product rules we first discussed in chapter 2.
     Let’s look at the pedigree in figure 4.25. This pedigree represents a recessive trait because two individuals (III-2 and III-5) are both affected but have unaffected parents. Because both of these affected individuals are females and the majority of the affected individuals are not males, this is likely an autosomal recessive trait.
     For this autosomal recessive trait, we can assign genotypes to several individuals: I-1 would be homozygous dominant (RR) and I-2 would be homozygous recessive (rr). Individuals II-2 and II-3 must therefore be heterozygotes based on their parents’ genotypes. Individuals II-1, II-5, and II-6 must be heterozygotes to produce the affected daughters III-2 and III-5. If this trait is rare, then individual II-4 would likely be homozygous dominant (RR).
     The genotypes of these individuals can be conclusively deduced, but two individuals have ambiguous genotypes. There is a 50% chance that the female III-3 is a heterozygote, based on her parents’ genotypes (Rr × RR). Individual III-4 is phenotypically normal and the son of two heterozygotes, which means that his genotype could be either RR or Rr.
     We know that a child from a monohybrid cross (which is II-5 × II-6 in this pedigree) has a 25% chance of being homozygous dominant, 50% of being heterozygous, and 25% chance of being homozygous recessive. We know that individual III-4 is not homozygous recessive because he does not express the recessive trait. Of the possible genotypes that exhibit the dominant phenotype, being heterozygous is twice as likely as being homozygous. Thus, there is a 66.7% chance that individual III-4 is heterozygous and a 33.3% chance he is homozygous dominant.
     We can also calculate the probability that individual IV-1 will exhibit the recessive trait. We deduced that the probability of individual III-3 being heterozygous is 50% and individual III-4 being heterozygous is 66.7%. We also know that in a monohybrid cross between two heterozygotes, the probability of the offspring being homozygous recessive is 25%. Using the product rule,

                    P = 50% × 66.7% × 25% = 8.3%

     When studying rare traits in a pedigree, as mentioned earlier, it is assumed that someone marrying into the pedigree lacks the rare allele, unless evidence exists to the contrary. Figure 4.25 shows an example of this. Individual II-4 is assumed to be homozygous dominant, because his offspring show no evidence of possessing the rare recessive phenotype. However, individual II-1 cannot be homozygous dominant, even though he is also marrying into the family, because individual II-1 has an affected daughter. Both parents (II-1 and II-2) must be heterozygotes for an offspring to be affected.