There are about five million conceptions in the United States each year, give or take a few hundred thousand. Consider the fate of 10,000 randomly chosen from these five million.

About 800 are chromosomally abnormal.

Of these 800:

Of the 800 chromosomally abnormal conceptions, about 750 will abort spontaneously:

The remaining 50 individuals with chromosomal abnormalities will make it to birth. Among them should be about:

Chromosomal abnormalities are an important component of medical practice. You will see examples of them in your work and your everyday life.


Specific chromosomal abnormalities were very difficult to identify prior to 1956. In that year, Tjio and Levan published their method for visualizing the chromosomes and revolutionized cytogenetics. They made it possible to accurately count the chromosomes and determine in which of 7 groups of chromosomes the error occurred (Groups A through G). Their methods started nearly two decades where research on chromosomal abnormalities was the focus of human genetics. Shortly after their discovery, this intense study led to other advances in techniques that allowed for the identification of individual chromosomes by differential staining, resulting in unique banding patterns for each chromosome. Now even very small regions can be visualized. To identify chromosomes, they are arrested in late prophase or early metaphase of mitosis, when the chromosomes are duplicated and condensed, but the centromere has not yet divided. Each chromosome consists of two chromatids at this stage. They are stained, photographed and arranged in a particular order, from largest to smallest, in what is called a karyotype. An example of the karyotype of a normal male is shown in Figure 4 below. The chromosomes are grouped by size and location of the centromere (metacentric, submetacentric, and acrocentric).


Figure 4. Karyotype.

There is also a standard nomenclature for describing various karyotypic abnormalities. Refer to Gelehrter, Collins, and Ginsburg, 2nd ed., Chapter 8, for ideograms and chromosomal nomenclature. You will be responsible for all of the material in this chapter.

Each chromosome consists of one double-stranded DNA molecule running the length of the chromosome, along with histones and other proteins. The DNA is arranged in chromatin loops that have general gene expression coordination. Two other distinct structures are essential, the centromere and the telomere. The centromere is the site of attachment of the spindle fiber. Without it the chromosome would not move in mitosis and meiosis, would be lost from the nucleus, and would be degraded by cytoplasmic enzymes. The telomeres are distinct structures at each end of the chromosome. They maintain the structural integrity of the chromosomal DNA. When a telomere is missing there is a strong tendency of the chromosomes to join with one another, or with pieces of one another, causing abnormal gene expression and aberrant chromosome structures.


Chromosome replication is different in humans than it is in bacteria, although the method of DNA replication is the same. In bacteria there is one origin of replication, but the polymerase is very fast. In humans the polymerase copies only about 100 to 150 base pairs per second, but there are 20,000 to 100,000 origins of replication along the 46 chromosomes. Most of these origins are functional in embryogenesis when divisions are occurring very rapidly, but many fewer function in the adult. DNA synthesis begins at several origins of replication along a chromosome and moves in each direction until it meets the replicated strands from the next origin.

Chromosome replication

Figure 5. Chromosome replication.

The chromosomes replicate in a predetermined sequence in mitosis, with each member of the homologous pair duplicating at the same time. The exception in somatic cells, not germ line cells, is that one of the X chromosomes of the female is always last of all the chromosomes to replicate. X replication in female somatic cells does not occur simultaneously in each of the homologs.


Several autosomal abnormalities produce such serious changes in the phenotype that they are not compatible with life. Any ploidy (extra copies of all chromosomes, i.e., triploidy, tertaploidy, etc.) higher than diploid results in early death in utero. Trisomy, an extra copy of a single chromosome, except for chromosomes 13, 18, or 21, is not compatible with life. Trisomy 13 and Trisomy 18 each lead to early death, usually in the neonatal period of development if not in utero.

Meiotic nondisjunction, the failure of the chromosomes to disjoin and pass to opposite poles, in either the first or second meiotic division is the major cause of chromosomal abnormalities. The greatest percentage of these (75%) occurs in oogenesis, where the probability of nondisjunction increases with maternal age. Almost 80% occur in the first meiotic division. To understand a possible mechanism for these observations we need to review oogenesis and spermatogenesis.

Events in spermatogenesis

Figure 6. Events in spermatogenesis. (Note the timing.)

Spermatogenesis begins at puberty and continues on a regular pace through the lifetime of the male, although spermatogonia do not divide as rapidly during later life. Males in their eighth decade have been documented fathers. The process from spermatogonium to mature sperm takes about 64 days, with each division evenly spaced at about 16 days, as shown in Figure 6. Spermatogenesis, with its many more cell divisions is more prone to single gene mutations than is oogenesis. There may be as much as a four or five fold increase in the mutation rate for some Mendelian traits in the sperm of older men.

Oogenesis, on the other hand, is not associated with a higher mutation rate for Mendelian diseases as maternal age increases. Increasing maternal age is associated with a higher incidence of chromosomal abnormalities attributed to nondisjunction. The reason for this association is evident from Figure 7 below.


Figure 7. Events in oogenesis.

All of the oocytes that are ever going to develop in the female are present at birth and all have begun the first meiotic division before they are arrested in the dictyotene state for from 12 to 40 years. Then with each menstrual cycle, one oocyte begins to continue on through the first and second meiotic divisions. These divisions occur very rapidly. With an old mitotic apparatus it is very possible that mistakes in chromosomal movement and cell division will occur. In some ways spermatogenesis, with its liability for mutation, and oogenesis, with its liability for chromosomal aberrations, may be thought of as complementary, one protects against mutation while the other protects against chromosomal abnormalities.


Nondisjunction, the failure of the chromosomes to disjoin and move to opposite poles may affect as many as 25% of all ova and 2% of all sperm. Half of these abnormal gametes are nullisomy, half are disomy. Two copies of a chromosome pass into the same gamete, leaving the other gamete as nullisomy. At fertilization the zygote formed from the gamete with nullisomy gets one copy of the chromosome from the gamete of the other parent and becomes monosomic for that chromosome. Monosomy for an autosome is not compatible with life. At fertilization, the zygote formed from the gamete with the two copies of the chromosome gets a third copy from the gamete of the other parent and become trisomic. As discussed earlier, most do not survive to term.

Down syndrome, or trisomy 21, is the classic example of a human disease caused by autosomal nondisjunction where some, but not all, affected individuals do survive. It occurs in about 1/800 live births, which means around 5000 affected individuals are born each year in the United States. The disease occurs in all races and nationalities. Approximately 95% of these 5000 Down syndrome children are the result of meiotic nondisjunction. The error occurred in first meiotic division in about 80% of these individuals; the remaining 20% occurred in second meiotic division. Errors in oogenesis account for 75% of the births while about 25% are of paternal origin. For a more complete discussion of Down syndrome, including the effects of increasing maternal age, see Gelehrter, Collins, and Ginsburg, 2nd ed., Chapter 8.

There are three other causes of Down syndrome besides simple trisomy 21. Mitotic nondisjunction, isochrome formation, and Robertsonian translocation can also produce Down syndrome.


A chimera is an individual that results from the fusing of two cell lines, from two zygotes, during development. Twins can, under extremely rare circumstances, be chimeras. A mosaic individual is one who originated as a single cell line and through some mitotic event develops two different cell lines. Mitotic nondisjunction is one of the events that will produce a mosaic individual. When mitotic nondisjunction of chromosome 21 occurs early in development of a female, two new cell lines develop, 45, XX, -21 and 47, XX, +21, in addition to the 46,XX founding cells. The monosomy 21 cell line does not survive. The karyotype of the mosaic female is written 46, XX/47,XX + 21. Of course there is an equal probability for the mosaic to arise in a male. The severity of affected of mosaic individuals depends upon how early the nondisjunction occurred and what cell lines developed from those early embryonic cells.


About 9% of Down syndrome children born to mothers who are less than 30 years of age will be the result of Robertsonian translocation. Down syndrome mothers under the age of 30 have a relatively low recurrence risk for a second trisomy 21 if the first affected child resulted from either meiotic or mitotic nondisjunction. However, the recurrence risk is much higher if the affected child was the result of a Robertsonian translocation. Robertsonian translocations are limited to the acrocentric chromosomes, chromosomes 13, 14, 15, 21, and 22. These chromosomes all have short arms, the p arms, that largely are made up of the genes for ribosomal RNA. These short arms are usually called satellites. There are many copies of these genes and a person can function quite well if several are lost. These satellites have a great deal of homology from chromosome to chromosome, and they tend to associate during interphase and mitotic division. Occasionally they will exchange parts, and the long arm, the q arm of one chromosome will become attached to the q arm of another, with the loss of the two p arms, or satellites. All that is lost is a centromere and some ribosomal RNA genes. (Small chromosomal structures get lost in mitosis because they do not attach to a spindle fiber.) Two q arms are now attached (translocated) to the same centromere. This is called a Robertsonian translocation. The formation of a Robertsonian translocation is shown in Figure 8 below.

Robertsonian translocation

Figure 8. Robertsonian translocation.

There is no effect on the individual in which this mitotic event occurs. He or she has a normal phenotype in all respects. Mitosis is unaffected. However, if the translocation occurs in a cell that is destined to be in the germ line, then trouble may arise when that cell tries to undergo meiosis. Pairing of homologous chromosomes at metaphase of the first meiotic division may create problems as described in Figure 9 below.

Pairing of homologous chromosomes

Figure 9. Pairing of homologous chromosomes.

Figure 9 shows that pairing at the first meiotic division can occur three ways, with equal chances for all. When it occurs as shown in A, one secondary oocyte or spermatocyte will get the 14q21q translocation chromosome and the other secondary oocyte or spermatocyte will get a normal 14 and a normal 21. When fertilization occurs, with a normal 14 and a normal 21 from the other parent, the zygotes formed from the gametes with pairing as in A will be either 45, XX or XY, -14, -21, +t(14q21q) a phenotypically normal balanced Robertsonian translocation carrier, or be a 46, XX or XY normal individual. When pairing at first meiotic division is as shown in B, one secondary oocyte or spermatocyte will get chromosome 14 only (no chromosome 21) and the other secondary spermatocyte or oocyte will get chromosome 14q21q and chromosome 21. At fertilization, again the zygote will get a normal 21 and a normal 14 from the other parent. When the gamete from B that got only chromosome 14 unites with a normal gamete, there is monosomy for chromosome 21. That results in very early embryonic death and spontaneous abortion. When the gamete from B that got the 14q21q chromosome plus chromosome 21 unites with a normal gamete, one gets the prober dose of necessary genetic information for chromosome 14 (14 from the normal gamete and 14q of the translocation chromosome) but one has three copies of the genetic information of chromosome 21(21 from the normal gamete, and a 21 and a 21q from the translocation). This results in Down syndrome. When, by chance the chromosomes line up as at C, both gametic products are lethal early in development. One will get only chromosome 21 and will be lacking a chromosome 14. Monosomy for chromosome 14 is lethal. One will get a 14 and a 14q21q, resulting in a zygote that will be trisomic for chromosome 14. This trisomy is also lethal.

From a carrier of a Robertsonian translocation there are 6 types of gametes, only three of which will produce a fetus capable of surviving to term. Of these three combinations who may survive, one should be normal, one should be phenotypically normal but be a carrier of the translocation, and one should have Down syndrome. In actual practice, if the mother is the carrier of the translocation only about 11% of the children have Down syndrome, the remaining 89% non-Down syndrome children are equally divided between normals and balanced translocation carriers. Trisomy 21 embryos do not survive as well as those with the normal amount of genetic information. If the father is a carrier of the translocation, only about 2% of the offspring will have Down syndrome, the remaining 98% being equally divided between normal and balanced translocation carriers. Because Robertsonian translocation is responsible for about 9% of the Down syndrome children born to mothers under the age of 30, it is important to karyotype the child to determine if the child is the result of a Robertsonian translocation or simple meiotic nondisjunction. As one can see, the counseling of the parents is entirely different. Robertsonian translocations are passed from generation to generation, and with this type of inheritance Down syndrome may "run in families."


Isochrome, or 21q21q, may result from a Robertsonian translocation between the two 21 chromosomes during mitosis in the germ line, or it may result from an improper mitotic division of the centromere, where the centromere divides transversely rather than longitudinally. Either of these is a rare event, but they do happen. When that happens it produces a karyotype, 45, XX or XY (depending upon the sex of the individual) -21,-21,+I(21q). Both q arms of chromosome 21 are attached to the same centromere. In gametogenesis, the gametes from an isochrome 21 individual get either the isochrome (21q21q) or they are missing chromosome 21 entirely. The zygotes are then either monosomy 21, which is lethal, or they have a normal 21 and a 21q21q chromosome, resulting in Down syndrome. All of the viable offspring of an isochrome 21 individual will have Down syndrome.

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