About 1 out of 150 live newborns has a detectable chromosomal abnormality. Yet even this high incidence represents only a small fraction of chromosome mutations since the vast majority are lethal and result in prenatal death or stillbirth. Indeed, 50 percent of all first-trimester miscarriages and 20 percent of all second-trimester miscarriages are estimated to involve a chromosomally abnormal fetus.
Chromosome disorders can be grouped into three principal categories: (1) those that involve numerical abnormalities of the autosomes, (2) those that involve structural abnormalities of the autosomes, and (3) those that involve the sex chromosomes. Autosomes are the 22 sets of chromosomes found in all normal human cells. They are referred to numerically (e.g., chromosome 1, chromosome 2) according to a traditional sort order based on size, shape, and other properties. Sex chromosomes make up the 23rd pair of chromosomes in all normal human cells and come in two forms, termed X and Y. In humans and many other animals, it is the constitution of sex chromosomes that determines the sex of the individual, such that XX results in a female and XY results in a male.
Numerical abnormalities, involving either the autosomes or sex chromosomes, are believed generally to result from meiotic nondisjunction—that is, the unequal division of chromosomes between daughter cells—that can occur during either maternal or paternal gamete formation. Meiotic nondisjunction leads to eggs or sperm with additional or missing chromosomes. Although the biochemical basis of numerical chromosome abnormalities remains unknown, maternal age clearly has an effect, such that older women are at significantly increased risk to conceive and give birth to a chromosomally abnormal child. The risk increases with age in an almost exponential manner, especially after age 35, so that a pregnant woman age 45 or older has between a 1 in 20 and 1 in 50 chance that her child will have trisomy 21 (Down syndrome), while the risk is only 1 in 400 for a 35-year-old woman and less than 1 in 1,000 for a woman under the age of 30. There is no clear effect of paternal age on numerical chromosome abnormalities.
Although Down syndrome is probably the best-known and most commonly observed of the autosomal trisomies, being found in about 1 out of 800 live births, both trisomy 13 and trisomy 18 are also seen in the population, albeit at greatly reduced rates (1 out of 10,000 live births and 1 out of 6,000 live births, respectively). The vast majority of conceptions involving trisomy for any of these three autosomes are nonetheless lost to miscarriage, as are all conceptions involving trisomy for any of the other autosomes. Similarly, monosomy for any of the autosomes is lethal in utero and therefore is not seen in the population. Because numerical chromosomal abnormalities generally result from independent meiotic events, parents who have one pregnancy with a numerical chromosomal abnormality are generally not at markedly increased risk above the general population to repeat the experience. Nonetheless, a small increased risk is generally cited for these couples to account for unusual situations, such as chromosomal translocations or gonadal mosaicism, described below.
Structural abnormalities of the autosomes are even more common in the population than are numerical abnormalities and include translocations of large pieces of chromosomes, as well as smaller deletions, insertions, or rearrangements. Indeed, about 5 percent of all cases of Down syndrome result not from classic trisomy 21 but from the presence of excess chromosome 21 material attached to the end of another chromosome as the result of a translocation event. If balanced, structural chromosomal abnormalities may be compatible with a normal phenotype, although unbalanced chromosome structural abnormalities can be every bit as devastating as numerical abnormalities. Furthermore, because many structural defects are inherited from a parent who is a balanced carrier, couples who have one pregnancy with a structural chromosomal abnormality generally are at significantly increased risk above the general population to repeat the experience. Clearly, the likelihood of a recurrence would depend on whether a balanced form of the structural defect occurs in one of the parents.
Even a small deletion or addition of autosomal material—too small to be seen by normal karyotyping methods—can produce serious malformations and mental retardation. One example is cri du chat (French: “cry of the cat”) syndrome, which is associated with the loss of a small segment of the short arm of chromosome 5. Newborns with this disorder have a “mewing” cry like that of a cat. Mental retardation is usually severe.
Abnormalities of the sex chromosomes
About 1 in 400 male and 1 in 650 female live births demonstrate some form of sex chromosome abnormality, although the symptoms of these conditions are generally much less severe than are those associated with autosomal abnormalities. Turner syndrome is a condition of females who, in the classic form, carry only a single X chromosome (45,X). Turner syndrome is characterized by a collection of symptoms, including short stature, webbed neck, and incomplete or absent development of secondary sex characteristics, leading to infertility. Although Turner syndrome is seen in about 1 in 2,500 to 1 in 5,000 female live births, the 45,X karyotype accounts for 10 to 20 percent of the chromosomal abnormalities seen in spontaneously aborted fetuses, demonstrating that almost all 45,X conceptions are lost to miscarriage. Indeed, the majority of liveborn females with Turner syndrome are diagnosed as mosaics, meaning that some proportion of their cells are 45,X while the rest are either 46,XX or 46,XY. The degree of clinical severity generally correlates inversely with the degree of mosaicism, so that females with a higher proportion of normal cells will tend to have a milder clinical outcome.
In contrast to Turner syndrome, which results from the absence of a sex chromosome, three alternative conditions result from the presence of an extra sex chromosome: Klinefelter syndrome, trisomy X, and 47,XYY syndrome. These conditions, each of which occurs in about 1 in 1,000 live births, are clinically mild, perhaps reflecting the fact that the Y chromosome carries relatively few genes, and, although the X chromosome is gene-rich, most of these genes become transcriptionally silent in all but one X chromosome in each somatic cell (i.e., all cells except eggs and sperm) via a process called X inactivation. The phenomenon of X inactivation prevents a female who carries two copies of the X chromosome in every cell from expressing twice the amount of gene products encoded exclusively on the X chromosome, in comparison with males, who carry a single X. In brief, at some point in early development one X chromosome in each somatic cell of a female embryo undergoes chemical modification and is inactivated so that gene expression no longer occurs from that template. This process is apparently random in most embryonic tissues, so that roughly half of the cells in each somatic tissue will inactivate the maternal X while the other half will inactivate the paternal X. Cells destined to give rise to eggs do not undergo X inactivation, and cells of the extra-embryonic tissues preferentially inactivate the paternal X, although the rationale for this preference is unclear. The inactivated X chromosome typically replicates later than other chromosomes, and it physically condenses to form a Barr body, a small structure found at the rim of the nucleus in female somatic cells between divisions (seephotograph). The discovery of X inactivation is generally attributed to British geneticist Mary Lyon, and it is therefore often called “lyonization.”
The result of X inactivation is that all normal females are mosaics with regard to this chromosome, meaning that they are composed of some cells that express genes only from the maternal X chromosome and others that express genes only from the paternal X chromosome. Although the process is apparently random, not every female has an exact 1:1 ratio of maternal to paternal X inactivation. Indeed, studies suggest that ratios of X inactivation can vary. Furthermore, not all genes on the X chromosome are inactivated; a small number escape modification and remain actively expressed from both X chromosomes in the cell. Although this class of genes has not yet been fully characterized, aberrant expression of these genes has been raised as one possible explanation for the phenotypic abnormalities experienced by individuals with too few or too many X chromosomes.
Klinefelter syndrome (47,XXY) occurs in males and is associated with increased stature and infertility. Gynecomastia (i.e., partial breast development in a male) is sometimes also seen. Males with Klinefelter syndrome, like normal females, inactivate one of their two X chromosomes in each cell, perhaps explaining, at least in part, the relatively mild clinical outcome.
Trisomy X (47,XXX) is seen in females and is generally also considered clinically benign, although menstrual irregularities or sterility have been noted in some cases. Females with trisomy X inactivate two of the three X chromosomes in each of their cells, again perhaps explaining the clinically benign outcome.
47,XYY syndrome also occurs in males and is associated with tall stature but few, if any, other clinical manifestations. There is some evidence of mild learning disability associated with each of the sex chromosome trisomies, although there is no evidence of mental retardation in these persons.
Persons with karyotypes of 48,XXXY or 49,XXXXY have been reported but are extremely rare. These individuals show clinical outcomes similar to those seen in males with Klinefelter syndrome but with slightly increased severity. In these persons the “n − 1 rule” for X inactivation still holds, so that all but one of the X chromosomes present in each somatic cell is inactivated.
en españolFundamentos de los genes y de las enfermedades genéticas
Have people ever said to you, "It's in your genes"? They were probably talking about a physical characteristic, personality trait, or talent that you share with other members of your family.
We know that genes play an important role in shaping how we look and act and even whether we get sick. Now scientists are trying to use that knowledge in exciting new ways, such as treating health problems.
What Is a Gene?
To understand how genes work, let's review some biology basics. Most living organisms are made up of cells that contain a substance called deoxyribonucleic (pronounced: dee-AHK-see-rye-bow-noo-klee-ik) acid (DNA).
DNA contains four chemicals (adenine, thymine, cytosine, and guanine — called A, T, C, and G for short) that are strung in patterns on extremely thin, coiled strands in the cell. How thin? Cells are tiny — invisible to the naked eye — and each cell in your body contains about 6 feet of DNA thread, for a total of about 3 billion miles of DNA inside you!
So where do genes come in? Genes are made of DNA, and different patterns of A, T, G, and C code for the instructions for making things your body needs to function (like the enzymes to digest food or the pigment that gives your eyes their color). As your cells duplicate, they pass this genetic information to the new cells.
DNA is wrapped together to form structures called chromosomes. Most cells in the human body have 23 pairs of chromosomes, making a total of 46. Individual sperm and egg cells, however, have just 23 unpaired chromosomes. You received half of your chromosomes from your mother's egg and the other half from your father's sperm cell. A male child receives an X chromosome from his mother and a Y chromosome from his father; females get an X chromosome from each parent.
Genes are sections or segments of DNA that are carried on the chromosomes and determine specific human characteristics, such as height or hair color. Because you have a pair of each chromosome, you have two copies of every gene (except for some of the genes on the X and Y chromosomes in boys, because boys have only one of each).
Some characteristics come from a single gene, whereas others come from gene combinations. Because every person has about 25,000 different genes, there is an almost endless number of possible combinations!
Genes and Heredity
Heredity is the passing of genes from one generation to the next. You inherit your parents' genes. Heredity helps to make you the person you are today: short or tall, with black hair or blond, with brown eyes or blue.
Can your genes determine whether you'll be a straight-A student or a great athlete? Heredity plays an important role, but your environment (including things like the foods you eat and the people you interact with) also influences your abilities and interests.
A person can have changes (or mutations) in a gene that can cause many issues for them. Sometimes changes cause little differences, like hair color. Other changes in genes can cause health problems.
Mutations in a gene usually end up causing that particular gene copy to not do its job the way it normally should. Since we have two copies of every gene, typically there's still a "normal" working copy of the gene. In these cases, usually nothing out of the ordinary happens since the body can still do the jobs it needs to do. This is an example of an autosomalrecessive trait.
For someone to have a recessive disease or characteristic, the person must have a gene mutation in both copies of the gene pair, causing the body to not have working copies of that particular gene.
Genes can be either dominant or recessive. Dominant genes show their effect even if there is just one mutation in one copy of that gene pair; the one mutation "dominates" the normal back-up copy of the gene, and the characteristic shows itself.
A person can be born with gene mutations, or they can happen over a lifetime. Mutations can occur when cells are aging or have been exposed to certain chemicals or radiation. Fortunately, cells usually recognize these types of mutations and repair them by themselves. Other times, however, they can cause illnesses, such as some types of cancer.
If the gene mutation exists in egg or sperm cells, children can inherit the gene mutation from their parents. When the mutation is in every cell of the body (meaning a child was born with it), the body is not able to "repair" the gene change.
What Are Genetic Disorders?
Researchers have identified more than 4,000 diseases that are caused by mutations. But having a genetic mutation that may cause a disease or condition doesn't always mean that a person will actually develop that disease or condition.
On average, people probably carry from 5 to 10 genes with mutations in each of their cells. Problems happen when the particular gene is dominant or when a mutation is present in both copies of a recessive gene pair. Problems can also happen when several variant genes interact with each other — or with the environment — to increase susceptibility to diseases.
If a person has a change in a dominant gene that is associated with a particular condition, he or she will usually have features of that condition. And, each of the person's children will have a 1 in 2 (50%) chance of inheriting the gene and developing the same features. Diseases and conditions caused by a dominant gene include achondroplasia (pronounced: ay-kon-druh-PLAY-zhuh, a form of dwarfism), Marfan syndrome (a connective tissue disorder), and Huntington disease (a degenerative disease of the nervous system).
People who have a change in just one copy of a recessive gene are called "carriers." They don't usually have the disease because they have a normal gene copy of that pair that can do the job. When two carriers have a child together, however, the child has a 1 in 4 (25%) chance of getting a gene with a mutation from both parents, which would result in the child having the disease. Cystic fibrosis (a lung disease), sickle cell anemia (a blood disorder), and Tay-Sachs disease (which causes nervous system problems) are caused by recessive mutations from both parents coming together in a child.
With recessive gene mutations on the X chromosome, usually only guys can develop the disease because they have only one X chromosome. Girls have two X chromosomes — since they have a back-up copy of another X chromosome, they don't always show features of X-linked conditions. These include the bleeding disorder hemophilia (pronounced: hee-muh-FIL-ee-uh) and color blindness.
Sometimes when an egg and sperm unite, the new cell gets too many or too few chromosomes, which can cause issues for the child. For example, most children born with have an extra chromosome number 21.
In some cases, people who are concerned that they might carry certain variant genes can have genetic testing so they can learn their children's chances of inheriting a disease. Pregnant women can also have tests done to see if the fetus they are carrying might have certain genetic illnesses. Genetic testing usually involves taking a sample of someone's blood, skin, or amniotic fluid and checking it for genetic changes.
Sometimes scientists alter genes on purpose. For many years, researchers have altered the genes in plants to produce other plants with special characteristics, such as an increased resistance to disease and pests or the ability to grow in difficult environments. We call this genetic engineering.
Gene therapy is a promising new field of medical research. In gene therapy, researchers try to supply copies of healthy genes to cells with variant or missing genes so that the "good" genes will take over. Viruses are often used to carry the healthy genes into the targeted cells because many viruses can insert their own DNA into targeted cells.
But there are problems with gene therapy. Scientists still don't quite know what every gene in the human body does. Huge scientific efforts like The Human Genome Project and related projects have completed a map of the entire human genome (all of the genetic material on a living thing's chromosomes), but it will take many more years to find out what each gene does and how they interact with one another. For most diseases, scientists don't know if and how genes play a role. Plus, there are major difficulties inserting the normal genes into the proper cells without causing problems for the rest of the body.
There are also concerns that people might try changing genes for ethically troubling reasons, such as to make smarter or more athletic children. No one knows what the long-term effects of that kind of change would be.
Still, for many people who have genetic diseases, gene therapy holds the hope that they — or their children — will be able to live better, healthier lives.