An X-linked recessive trait generally is more prevalent in males than females. Other situations, however, can affect gene expression in the sexes differently.
6.4 X Inactivation
Females have two alleles for every gene on the X chromo- somes, whereas males have only one. In mammals, a mecha- nism called X inactivation balances this apparent inequality in the expression of genes on the X chromosome.
Equaling Out the Sexes
By the time a female embryo consists of 8 cells, about 75 percent of the genes on one X chromosome in each cell are inactivated, and the remaining 25 percent are expressed to different degrees in different women. Which X chromosome is mostly turned off in each cell—the one inherited from the mother or the one from the father—is usually random. As a result, a female mammal expresses the X chromosome genes inherited from her father in some cells and those from her mother in others. She is, therefore, a mosaic for expression of most genes on the X chromosome ( figure 6.11 ).
By studying rare human females who have lost a small part of one X chromosome, researchers identified a specific region, the X inactivation center, that shuts off much of the chromosome. Genes in the PARs and some other genes escape inactivation. A gene called XIST controls X inactivation. It encodes an RNA that binds to a specific site on the same (inac- tivated) X chromosome. From this point out to the chromosome tip, the X chromosome is inactivated.
Once an X chromosome is inactivated in one cell, all its daughter cells have the same X chromosome inactivated.
Because the inactivation occurs early in development, the adult female has patches of tissue that differ in their expression of
Sex-Limited Traits
A sex-limited trait affects a structure or func- tion of the body that is present in only males or only females. Such a gene may be X-linked or autosomal.
Understanding sex-limited inheritance is important in animal breeding. For example, a New Zealand cow named Marge, who has a mutation that makes her milk very low in saturated fat, is found- ing a commercial herd. Males play their part by transmitting the mutation, even though they do not make milk. In humans, beard growth is sex-limited.
A woman does not grow a beard because she does not manufacture the hormones required for facial hair growth. She can, however, pass to her sons the genes specifying heavy beard growth.
An inherited medical condition that arises during pregnancy is obviously sex-limited, but the male genome contributes to the development of supportive structures, such as the placenta.
This is the case for preeclampsia, a sudden rise in blood pressure late in pregnancy. It kills 50,000 women worldwide each year. A study of 1.7 mil- lion pregnancies in Norway found that if a man’s first wife had preeclampsia, his second wife had
double the risk of developing the condition, too. Another study found that women whose mothers-in-law developed preeclampsia when pregnant with the womens’ husbands had approximately twice the rate of developing the condi- tion themselves. Perhaps a gene from the father affects the placenta in a way that elevates the pregnant woman’s blood pressure.
Sex-Influenced Traits
In a sex-influenced trait, an allele is dominant in one sex but recessive in the other. Such a gene may be X-linked or auto- somal. The difference in expression can be caused by hormonal differences between the sexes. For example, an autosomal gene for hair growth pattern has two alleles, one that produces hair all over the head and another that causes pattern baldness. The baldness allele is dominant in males but recessive in females, which is why more men than women are bald. A heterozygous male is bald, but a heterozygous female is not. A bald woman is homozygous recessive. Even a bald woman tends to have some wisps of hair, whereas an affected male may be completely hairless on the top of his head.
Key Concepts
1. A sex-limited trait affects body parts or functions present in only one gender.
2. A sex-influenced allele is dominant in one sex but recessive in the other.
Maternal X Fertilized ovum
Early cell division
X chromosome inactivation
Mitosis
Paternal X
Barr body
Normal skin Skin lacking normal sweat glands
Figure 6.11 X inactivation. A female is a mosaic for expression of genes on the X chromosome because of the random inactivation of either the maternal or paternal X in each cell early in prenatal development. In anhidrotic ectodermal dysplasia, a woman has patches of skin that lack sweat glands and hair. (Colors distinguish cells with the inactivated X, not to depict skin color.)
enzyme. Affected boys are deaf, mentally retarded, have dwarf- ism and abnormal facial features, heart damage, and enlarged liver and spleen. In contrast, in Fabry disease (MIM 301500, also called alpha-galactosidase A deficiency), the enzyme is not easily released from cells, so a female who is a heterozygote may have cells in the affected organs that lack the enzyme. She may develop mild symptoms of this disorder that causes skin lesions, abdominal pain, and kidney failure in boys.
A familiar example of X inactivation is the coat colors of tortoiseshell and calico cats. An X-linked gene confers brownish-black (dominant) or yellowish-orange (recessive) color. A female cat heterozygous for this gene has patches of each color, forming a tortoiseshell pattern that reflects differ- ent cells expressing either of the two alleles ( figure 6.12 ). The earlier the X inactivation, the larger the patches, because more cell divisions can occur after the event, producing more daugh- ter cells. White patches may form due to epistasis by an auto- somal gene that shuts off pigment synthesis. A cat with colored patches against such a white background is a calico. Tortoise- shell and calico cats are nearly always female. A male can have these coat patterns only if he inherits an extra X chromosome.
In humans, X inactivation can be used to identify car- riers of some X-linked disorders. This is the case for Lesch- Nyhan syndrome (MIM 300322), in which an affected boy has cerebral palsy, bites his fingers, shoulders, and lips to the X-linked genes. With each cell in her body having only one
active X chromosome, she is roughly equivalent to the male in terms of gene expression.
X inactivation can alter the phenotype (gene expression), but not the genotype. It is not permanent, and is reversed in germline cells destined to become oocytes. Therefore, a fertil- ized ovum does not have an inactivated X chromosome.
X inactivation is an example of an epigenetic change—
one that is passed from one cell generation to the next but that does not alter the DNA base sequence. We can observe X inactivation at the cellular level because the turned-off X chromosome absorbs a stain much faster than the active X.
This differential staining occurs because inactivated DNA has chemical methyl (CH 3 ) groups that prevent it from being tran- scribed into RNA and also enable it to absorb stain.
X inactivation can be used to check the sex of an indi- vidual. The nucleus of a cell of a female, during interphase, has one dark-staining X chromosome called a Barr body. A cell from a male has no Barr body because his one X chromosome remains active.
In 1961, English geneticist Mary Lyon proposed that the Barr body is the inactivated X chromosome and that it is turned off in early development. Checking for Barr bodies has been done in the Olympics to identify athletes competing as the wrong gender.
Effect on the Phenotype
The consequence of X inactivation on the phenotype can be interesting. For homozygous X-linked genotypes, X inactivation has no effect. No matter which X chromosome is turned off, the same allele is left to be expressed. For heterozygotes, however, X inactivation leads to expression of one allele or the other. This doesn’t affect health if enough cells express the functional gene product. However, some traits reveal the X inactivation. The swirls of skin color in incontinentia pigmenti (IP) patients reflect patterns of X inactivation in skin cells (see fig. 6.9b). Where the normal allele for melanin pigment is shut off, pale swirls develop.
Where pigment is produced, brown swirls result.
A female who is heterozygous for an X-linked recessive gene can express the associated condition if the normal allele is inactivated in the tissues that the illness affects. Consider a carrier of hemophilia A. If the X chromosome carrying the nor- mal allele for the clotting factor is turned off in the liver, then the woman’s blood will clot slowly enough to cause mild hemo- philia. (Luckily for her, slowed clotting time also greatly reduces her risk of cardiovascular disease caused by blood clots block- ing circulation.) A carrier of an X-linked trait who expresses the phenotype is called a manifesting heterozygote.
Whether or not a manifesting heterozygote results from X inactivation depends upon how adept cells are at sharing.
Consider two lysosomal storage disorders, which are deficien- cies of specific enzymes that normally dismantle cellular debris in lysosomes. In Hunter syndrome (MIM 309900, also called mucopolysaccharidosis II), cells that make the enzyme readily send it to neighboring cells that do not, essentially correcting the defect in cells that can’t make the enzyme. Carriers of Hunter syndrome do not have symptoms because cells get enough
Figure 6.12 Visualizing X inactivation. X inactivation is obvious in a calico cat. X inactivation is rarely observable in humans because most cells do not remain together during development, as a cat’s skin cells do.
that lack the enzyme have turned off the X chromosome that carries the normal allele; the hair cells that manufacture the normal enzyme have turned off the X chromosome that carries the disease-causing allele. The woman is healthy because her brain has enough HGPRT, but each son has a 50 percent chance of inheriting the disease. Reading 6.2 discusses another syn- drome affected by X inactivation.
point of mutilation, is mentally retarded, and passes painful urinary stones. Mutation results in defective or absent HGPRT, an enzyme. A woman who carries Lesch-Nyhan syndrome can be detected when hairs from widely separated parts of her head are tested for HGPRT. (Hair is used for the test because it is accessible and produces the enzyme.) If some hairs con- tain HGPRT but others do not, she is a carrier. The hair cells
Before the age of the Internet, identifying and describing a new syndrome could take years, or even decades. This was the case for Rett syndrome, a neurological condition that affects nearly always females.
In 1954, Austrian pediatrician Andreas Rett and his nurse noticed that their practice included eight little girls who did strange things with their hands—uncontrollably (figure 1). They’d tap objects, clap, repeatedly put their hands in their mouths, and most commonly, wring their hands. The girls shared other symptoms. All had been developing normally but then gradually lost muscle tone.
Growth of their heads slowed. As time went on, seizures began, they lost the ability to speak, and the girls became completely disabled (table 1).
Dr. Rett filmed the girls and went around Europe looking for other cases. Meanwhile, other pediatricians were noting the symptoms in their patients, independently. Although Dr. Rett published his observations in European journals, they did not attract the attention of the medical mainstream until 1983, when a Swedish researcher published in the Annals of Neurology and, finally, others noticed. He named the condition Rett syndrome.
In 1999, Ruthie Amir, at the Baylor College of Medicine in Texas, discovered the gene behind the disorder—MECP2, for methyl-CpG- binding protein 2 (MIM 312750), on the X chromosome. The syndrome is pleiotropic, causing symptoms in several organ systems, because the gene adds methyl groups to other genes, silencing them.
Rett syndrome is dominant.
In 99 percent of cases, it is not passed from parent to child but arises anew. This is not surprising, because affected parents of either sex would be too ill to have children.
The disease arises in either of two ways: The gene may mutate in an X-bearing sperm cell; alternatively, an affected girl’s mother might indeed have the syndrome, but due to skewed X inactivation, the X chromosome carrying the mutation is turned off in most brain cells. The mother’s case might be so mild as to be undetected—hence, her passing it to her daughter would appear as a sporadic (noninherited) case.
Reading 6.2
Rett Syndrome—A Curious Inheritance Pattern
Figure 1 Rett syndrome affects girls. One sign of Rett syndrome is holding and wringing the hands.
Table 1 Stages and Symptoms of Rett Syndrome
Stage Onset Symptoms
I 6–18 months Minor slowing of development; loss of eye contact and interest in objects.
II 1–4 years Loss of ability to speak; autistic behavior;
breathing irregularities; unsteady gait; head growth slows; mental retardation.
III 2–10 years Seizures and loss of motor skills, but behavior may improve and autistic features fade; this stage can last a lifetime.
IV adolescence Severe motor problems, including rigidity, weakness, adulthood and spasticity; walking impaired, but cognition and communication skills remain.
for the heterozygote to be more severely affected than the homozygous recessive individual.) An explanation is that the encoded protein is part of a signal transduction pathway that controls the bone fusion, and when two forms of that protein are made in the female heterozygote, the signal is disrupted in a way that blocks the cells that form the sutures of the skull from joining cleanly.
Key Concepts
1. In female mammals, X inactivation compensates for differences between males and females in the numbers of gene copies on the X chromosome.
2. Early in development, one X chromosome in each cell of the female is turned off.
3. The effects of X inactivation can be noticeable when heterozygous alleles are expressed in certain tissues.
6.5 Genomic Imprinting
In Mendel’s pea experiments, it didn’t matter whether a trait came from the male or female parent. For certain genes in mammals, however, parental origin does influence the phe- notype. These genes are said to be imprinted. In genomic imprinting, methyl (CH 3 ) groups cover a gene or several linked genes and prevent them from being accessed to synthesize pro- tein ( figure 6.14 ).
For a particular imprinted gene, the copy inherited from either the father or the mother is always covered with methyls, even in different individuals. The result of this gene cloaking is that a disease may be more severe, or different, depending upon which parent transmitted the mutant allele. That is, a par- ticular gene might function if it came from the father, but not if it came from the mother, or vice versa.
Subtle Effects of X Inactivation
Theoretically, X inactivation evens out the sexes for expres- sion of X-linked genes. In actuality, however, a female may not be equivalent, in gene expression, to a male because she has two cell populations, whereas a male has only one. One of a female’s two cell populations has the X she inherited from her father active, and the other has the X chromosome she inherited from her mother active. For heterozygous X-linked genes, she would have some cells that manufacture the protein encoded by one allele, and some cells that produce the protein encoded by the other allele. Although most heterozygous genes have the alleles about equally represented, sometimes X inactivation can be skewed. That is, most cells express the X inherited from the same parent. This can happen if one of the X chromosomes includes an expressed allele that confers a greater rate of cell division than the different allele from the other parent, giving certain cells a survival advantage.
Another way that X inactivation makes a female differ- ent from a male is seen when the proteins encoded by different alleles interact. This can be beneficial or harmful. A benefi- cial example of dual expression of alleles occurs in certain types of monkeys in which an X-linked visual pigment gene has two alleles. Females who are homozygous for this gene and males have 2-color vision, but lucky female monkeys who are heterozygous for this gene enjoy 3-color vision.
A situation in which being a heterozygote for an X-linked gene is harmful is craniofrontonasal syndrome (MIM 304110) (figure 6.13 ). Males and homozygous females have asymmetri- cal facial features. However, heterozygous females have a much more severe phenotype, with very abnormal faces resulting from abnormal fusing of the skull bones. (It is highly unusual
Figure 6.13 Craniofrontonasal syndrome is more severe in females because of an unusual detrimental effect of expressing
both alleles of an X-linked gene. Figure 6.14 Methyl (CH3) groups (red) “silence” certain genes.
and the female pronucleus degenerates, an abnormal growth of placenta-like tissue called a hydatidiform mole forms. If a fertilized ovum contains only two female genomes but no male genome, a mass of random differentiated tissue, called a tera- toma, grows. A teratoma, which means “monster cancer,” may consist of a variety of tissues in a bizarre mix. With either a hydatidiform mole or a teratoma, no embryo results, although a pregnancy test may be positive, because the pregnancy hor- mone (hCG) may be produced.
Genomic imprinting can explain incomplete penetrance, in which an individual is known to have inherited a genotype associated with a particular phenotype, but has no signs of the
Silencing the Contribution From One Parent
Imprinting is an epigenetic alteration. It is a layer of meaning stamped upon a gene without changing its DNA sequence. The imprinting pattern is passed from cell to cell in mitosis, but not from individual to individual through meiosis. When silenced DNA is replicated dur- ing mitosis, the pattern of blocked genes is exactly placed, or imprinted, on the new DNA, covering the same genes as in the parental DNA ( figure 6.15 ). In this way, the “imprint”
of inactivation is perpetuated, as if each such gene “remembers” which parent it came from.
In meiosis, however, imprints are removed and reset. As oocyte and sperm form, the CH 3 groups shielding their imprinted genes are stripped away, and new patterns are set down, depending upon whether the fertilized ovum chromosomally is male (XY) or female (XX).
In this way, women can have sons and men can have daughters without passing on their sex- specific parental imprints.
The function of genomic imprinting isn’t well understood, but because many imprinted genes take part in early development, particularly of the brain, it may be a way to finely regulate the abundance of key proteins in the embryo.
The fact that some genes lose their imprints after birth supports this idea of early importance. Also, imprinted genes are in clusters along a chromo- some, and are controlled by other regions of DNA called imprinting centers. Perhaps one gene in a cluster is essential for early development, and the others become imprinted simply because they are nearby—a bystander effect.
Genomic imprinting has implications for understanding early human development. It sug- gests that for mammals, two opposite-sex parents are necessary to produce a healthy embryo and placenta. This apparent requirement for opposite- sex parents was discovered in the early 1980s, through experiments on early mouse embryos
and examination of certain rare pregnancy problems in humans.
Researchers created fertilized mouse ova that contained two male pronuclei or two female pronuclei, instead of one from each. Results were strange. When the fertilized ovum had two male genomes, a normal placenta developed, but the embryo was tiny and quickly stopped developing. A zygote with two female pronuclei, on the other hand, developed into an embryo, but the placenta was grossly abnormal. Therefore, the male genome controls placenta development, and the female genome, embryo development.
The mouse results were consistent with abnormalities of human development. When two sperm fertilize an oocyte
Oocyte
Homolog 1 Homolog 2
Sperm
Zygote
Female Male
Somatic cell
Germ cell
Old imprints erased
New imprints made
Oocytes Sperm
Figure 6.15 Genomic imprinting. Imprints are erased during meiosis, then reinstituted according to the sex of the new individual.