Circumcised Labia

consists of half red-eyed and half white-eyed flies of both sexes. Hence in sex linkage, we see examples not only of different ratios in different sexes, but also of differences between reciprocal crosses.

Note that in Drosophila, eye color has nothing to do with sex determination, so we see that genes on the sex chromosomes are not necessarily related to sexual function. The same is true in humans: pedigree analysis has revealed many X-linked genes, yet few are related to sexual function.

The eye color example concerned a recessive abnormal allele, which must have originally arisen by mutation. Dominant mutant alleles of genes on the X also arise. These show the inheritance pattern corresponding to the wild-type allele for red eyes in the example above. However, in such cases the wild-type allele is recessive. The ratios obtained are the same as in the above example.

MESSAGE Sex-linked inheritance regularly shows different phenotypic ratios in the two sexes of progeny, as well as different ratios in reciprocal crosses.

X-linked inheritance of rare alleles in human pedigrees

As in the analysis of autosomal genes, human pedigrees of genes on the X chromosome are generally drawn up to follow the inheritance of some kind of medical disorder. Hence, again we have to bear in mind that the causative allele is usually rare in the population.

PEDIGREE ANALYSIS OF X-LINKED RECESSIVE DISORDERS Let's look at the pedigrees of disorders caused by rare recessive alleles of genes located on the X chromosome. Such pedigrees typically show the following features:

1. Many more males than females show the rare phenotype under study. This is because of the product law: a female will show the phenotype only if both her mother and her father bear the allele (for example, XA Xa X Xa Y), whereas a male can show the phenotype when only the mother carries the allele. If the recessive allele is very rare, almost all persons showing the phenotype are male.

2. None of the offspring of an affected male show the phenotype, but all his daughters are "carriers," who bear the recessive allele masked in the heterozygous condition. Half the sons of these carrier daughters show the phenotype (Figure 2-25). (Note that in the case of phenotypes caused by common recessive X-linked alleles, this pattern might

Linked Recessive Carrier Father
Figure 2-25 Pedigree showing X-linked recessive alleles expressed in males. These alleles are carried unexpressed by daughters in the next generation, to be expressed again in sons. Note that III-3 and III-4 cannot be distinguished phenotypically.

be obscured by inheritance of the recessive allele from a heterozygous mother as well as the affected father.)

3. None of the sons of an affected male show the phenotype under study, nor will they pass the condition to their offspring. The reason behind this lack of male-to-male transmission is that a son obtains his Y chromosome from his father, so he cannot normally inherit the father's X chromosome, too.

In the pedigree analysis of rare X-linked recessives, a normal female of unknown genotype is assumed to be homozygous unless there is evidence to the contrary.

Perhaps the most familiar example of X-linked recessive inheritance is red-green colorblindness. People with this condition are unable to distinguish red from green. The genes for color vision have been characterized at the molecular level. Color vision is based on three different kinds of cone cells in the retina, each sensitive to red, green, or blue wavelengths. The genetic determinants for the red and green cone cells are on the X chromosome. As with any X-linked recessive, there are many more males with the phenotype than females.

Another familiar example is hemophilia, the failure of blood to clot. Many proteins act in sequence to make blood clot. The most common type of hemophilia is caused by the absence or malfunction of one of these proteins, called factor VIII. The most well known cases of hemophilia are found in the pedigree of interrelated royal families in Europe (Figure 2-26). The original hemophilia allele in the pedigree arose spontaneously (as a mutation) in the reproductive cells of either Queen Victoria's parents or Queen Victoria herself. The son of the last czar of Russia, Alexis, inherited the allele ultimately from Queen Victoria, who was the

Royal Family Hemophilia Pedigree

| Hemophilic male © H] Status uncertain

| Hemophilic male © H] Status uncertain

Hemophilia Inheritance Male

Figure 2-26 The inheritance of the X-linked recessive condition hemophilia in the royal families of Europe.

A recessive allele causing hemophilia (failure of blood clotting) arose in the reproductive cells of Queen Victoria, or one of her parents, through mutation. This hemophilia allele spread into other royal families by intermarriage. (a) This partial pedigree shows affected males and carrier females (heterozygotes). Most spouses marrying into the families have been omitted from the pedigree for simplicity. Can you deduce the likelihood of the present British royal family's harboring the recessive allele? (b) A painting showing Queen Victoria surrounded by her numerous descendants. [Part a, after C. Stern, Principles of Human Genetics, 3d ed. Copyright 1973 by W. H. Freeman and Company; part b, Royal Collection, St. James's Palace. Copyright Her Majesty Queen Elizabeth II.]

Figure 2-26 The inheritance of the X-linked recessive condition hemophilia in the royal families of Europe.

A recessive allele causing hemophilia (failure of blood clotting) arose in the reproductive cells of Queen Victoria, or one of her parents, through mutation. This hemophilia allele spread into other royal families by intermarriage. (a) This partial pedigree shows affected males and carrier females (heterozygotes). Most spouses marrying into the families have been omitted from the pedigree for simplicity. Can you deduce the likelihood of the present British royal family's harboring the recessive allele? (b) A painting showing Queen Victoria surrounded by her numerous descendants. [Part a, after C. Stern, Principles of Human Genetics, 3d ed. Copyright 1973 by W. H. Freeman and Company; part b, Royal Collection, St. James's Palace. Copyright Her Majesty Queen Elizabeth II.]

grandmother of his mother Alexandra. Nowadays, hemophilia can be treated medically, but it was formerly a potentially fatal condition. It is interesting to note that in the Jewish Talmud there are rules about exemp tions to male circumcision that show clearly that the mode of transmission of the disease through unaffected carrier females was well understood in ancient times. For example, one exemption was for the sons of women whose sisters' sons had bled profusely when they were circumcised.

Duchenne muscular dystrophy is a fatal X-linked recessive disease. The phenotype is a wasting and atrophy of muscles. Generally the onset is before the age of 6, with confinement to a wheelchair by 12, and death by 20. The gene for Duchenne muscular dystrophy has now been isolated and shown to encode the muscle protein dystrophin. This discovery holds out hope for a better understanding of the physiology of this condition and, ultimately, a therapy.

A rare X-linked recessive phenotype that is interesting from the point of view of sexual differentiation is a condition called testicular feminization syndrome, which has a frequency of about 1 in 65,000 male births. People afflicted with this syndrome are chromosomally males, having 44 autosomes plus an X and a Y, but they develop as females (Figure 2-27). They have female external genitalia, a blind vagina, and no uterus. Testes may be present either in the labia or in the abdomen. Although

Labial Agglutination

Figure 2-27 Four siblings with testicular feminization syndrome (congenital insensitivity to androgens). All four subjects in this photograph have 44 autosomes plus an X and a Y chromosome, but they have inherited the recessive X-linked allele conferring insensitivity to androgens (male hormones). One of their sisters (not shown), who was genetically XX, was a carrier and bore a child who also showed testicular feminization syndrome. [Leonard Pinsky, McGill University.]

Figure 2-27 Four siblings with testicular feminization syndrome (congenital insensitivity to androgens). All four subjects in this photograph have 44 autosomes plus an X and a Y chromosome, but they have inherited the recessive X-linked allele conferring insensitivity to androgens (male hormones). One of their sisters (not shown), who was genetically XX, was a carrier and bore a child who also showed testicular feminization syndrome. [Leonard Pinsky, McGill University.]

many such persons marry, they are sterile. The condition is not reversed by treatment with the male hormone androgen, so it is sometimes called androgen insensitivity syndrome. The reason for the insensitivity is that a mutation in the androgen receptor gene causes the receptor to malfunction, so the male hormone can have no effect on the target organs that contribute to maleness. In humans, femaleness results when the male-determining system is not functional.

PEDIGREE ANALYSIS OF X-LINKED DOMINANT DISORDERS These disorders have the following characteristics (Figure 2-28):

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