Inherited disorders can arise when chromosomes behave abnormally during meiosis. Chromosome disorders can be divided into two categories: abnormalities in chromosome number and chromosomal structural rearrangements. Because even small segments of chromosomes span many genes, chromosomal disorders are characteristically dramatic and often fatal.

Identification of Chromosomes

How does one find out about their genetic make-up?  What diseases, if any, do I have?  What sort of chromosomes do I pass on to my progeny?  One way we can find answers to these and other genetic questions is to have a karyotype.   A karyotype is the number and appearance of chromosomes, including their length, banding pattern, and centromere position. To obtain and view an individual’s karyotype, cytologists take a sample and allow the cells to grow for staining.  Proper arrangement is done so a photograph the chromosomes and then cut and paste each chromosome into a chart, or karyogram, also known as an ideogram (Figure 1).  More details in karyotype preparation follows below in Career Connection.

Figure 1. This karyotype is of a female human. Notice that homologous chromosomes are the same size and have the same centromere positions and banding patterns. A human male would have an XY chromosome pair instead of the XX pair shown. (credit: Andreas Blozer et al)

In a given species, chromosomes can be identified by their number, size, centromere position, and banding pattern. In a human karyotype, autosomes(non-sex) are generally organized in approximate order of size from largest (chromosome 1) to smallest (chromosome 22). The X and Y chromosomes are not autosomes.  During the naming of Down syndrome to trisomy 21, it was discovered that chromosome 21 is actually shorter than chromosome 22.  Not wanting to change the name of this important disease, chromosome 21 retained its numbering, despite being the shortest set of chromosomes. The chromosome “arms” projecting from either end of the centromere may be designated as short or long, depending on their relative lengths. The short arm is abbreviated p (for “petite”), whereas the long arm is abbreviated q (because it follows “p” alphabetically). Each arm is further subdivided and denoted by a number. Using this naming system, locations on chromosomes can be described consistently in the scientific literature.

Disorders in Chromosome Number

Abnormalities in chromosome number are the most obviously identifiable form of a karotype.  Most of these are due to nondisjunction.  Nondisjunction occurs when homologous chromosomes pairs or sister chromatids fail to separate during meiosis. Causes that attribute to nondisjunction are misaligned or incomplete synapsis or a dysfunction of the spindle apparatus, facilitating chromosome migration. Nondisjunction rates increase with parental age.

Nondisjunction can occur during either meiosis I or II, with differing results (Figure 2). If homologous chromosomes fail to separate during meiosis I, the result is two gametes lacking a that particular chromosome and two gametes with two copies of the chromosome. If sister chromatids fail to separate during meiosis II, the result is one gamete lacking that chromosome, two normal gametes with one copy of the chromosome, and one gamete with two copies of the chromosome.

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Figure 2. Nondisjunction occurs when homologous chromosomes or sister chromatids fail to separate during meiosis, resulting in an abnormal chromosome number. Nondisjunction may occur during meiosis I or meiosis II.

Which of the following statements about nondisjunction is true?

1. Nondisjunction only results in gametes with n+1 or n–1 chromosomes.
2. Nondisjunction occurring during meiosis II results in 50 percent normal gametes.
3. Nondisjunction during meiosis I results in 50 percent normal gametes.
4. Nondisjunction always results in four different kinds of gametes.

Aneuploidy

Figure 3. The incidence of having a fetus with trisomy 21 increases dramatically with maternal age.

An individual with the appropriate number of chromosomes for their species is called euploid.   In humans, euploidy corresponds to 22 pairs of autosomes and one pair of sex chromosomes. An individual with an error in chromosome number is described as aneuploid, a term that includes monosomy (loss of one chromosome) or trisomy (gain of an extraneous chromosome). Monosomy zygotes, missing any one copy of an autosome, fail to develop to birth because they lack essential genes.  Most autosomal trisomies fail to develop to birth; however, duplications of some of the smaller chromosomes (13, 15, 18, 21, or 22) can result in offspring that can survive.  Trisomic individuals suffer from  an excess in gene dose. Individuals with an extra chromosome may synthesize an abundance of the gene products encoded by that chromosome. This extra dose of specific genes can lead to a number of functional challenges, often precludes development. The most common trisomy among viable births is that of chromosome 21, or Down Syndrome. Individuals with this inherited disorder are characterized by short stature, stunted digits, facial distinctions including a broad skull and large tongue, and significant developmental delays. The incidence of Down syndrome is correlated with the age of the mother.  Older women are more likely to become pregnant with fetuses carrying the trisomy 21 genotype (Figure 3).

Polyploidy

Figure 4. As with many polyploid plants, this triploid orange daylily (Hemerocallis fulva) is particularly large and robust, and grows flowers with triple the number of petals of its diploid counterparts. (credit: Steve Karg)

An individual with more than the correct number of chromosome sets (two for diploid species) is called polyploid. Fertilization of an abnormal diploid egg with a normal haploid sperm would yield a triploid zygote. Polyploid animals are extremely rare, with only a few examples among the flatworms, crustaceans, amphibians, fish, and lizards. Polyploid animals are sterile because meiosis cannot proceed normally.  Instead, they produce mostly aneuploid daughter cells that cannot yield viable zygotes. Polyploidy is very common in the plant kingdom, where olyploid plants tend to be larger and more robust than euploids of their species (Figure 4).

Sex Chromosomes

What, if anything, can go wrong with the sex chromosomes?  Rather than a gain or loss of autosomes, variations in the number of sex chromosomes are associated with relatively mild effects.  This occurs because of a molecular process called X inactivation. Early in development when female mammalian embryos consist of just a few thousand cells, one X chromosome in each cell inactivates by tightly condensing into a dormant structure called a Barr body. The chance that an X chromosome, from either parent, is inactivated in each cell is random, but once the inactivation occurs, all cells derived from that one will have the same inactive X chromosome or Barr body. By this process, females compensate for their double genetic dose of X chromosome.

Figure 5. In cats, the gene for coat color is located on the X chromosome. In the embryonic development of female cats, one of the two X chromosomes is randomly inactivated in each cell, resulting in a tortoiseshell pattern if the cat has two different alleles for coat color. Male cats, having only one X chromosome, never exhibit a tortoiseshell coat color. (credit: Michael Bodega)

This can be seen in so-called “tortoiseshell” cats where embryonic X inactivation is observed as color variegation (Figure 5).  Heterozygous females for an X-linked coat color gene will express one of two different coat colors over different regions of their body, corresponding to whichever X chromosome is inactivated in the embryonic cell  of that region.

An individual with an abnormal number of X chromosomes will inactivate all but one X chromosome in each of her cells. However, even inactivated X chromosomes continue to express a few genes.  As a result, X-chromosomal abnormalities are associated with mild mental and physical defects and sterility.  Complete absence of the X chromosome prevents an individual from developing in utero.

Several errors in sex chromosome number have been noted.

(1)  Triplo-X female – XXX female; express developmental delays; reduced fertility

(2)   Klinefelter syndrome – XXY male; small testes; enlarged breasts; reduced body hair

(3)  Turner syndrome –  X0 female; (only a single sex chromosome); short stature; webbed skin in neck region; hearing and cardiac impairments; and sterility

Duplications and Deletions

Figure 6. This individual with cri-du-chat syndrome is shown at two, four, nine, and 12 years of age. (credit: Paola Cerruti Mainardi)

In addition to the loss or gain of an entire chromosome, a chromosomal segment may be duplicated or deleted. Duplications and deletions produce offspring that survive but exhibit physical and mental abnormalities. Duplicated chromosomal segments may fuse to existing chromosomes or may be free in the nucleus. Cri-du-chat (from the French for “cry of the cat”) is a syndrome associated with nervous system abnormalities and identifiable physical features that result from a deletion of most of chromosome 5. (Figure 6). Infants with this genotype emit a characteristic high-pitched cry from which the disordered is named.

Structural Chromosome Rearrangements

Scientists have characterized numerous rearrangements in chromosome structure.  The most common of which are chromosome inversions and translocations.  Both are identified during meiosis.  If the genes carried on homologous chromosomes are not oriented correctly, a recombination event could result in a loss of genes from one chromosome and the gain of genes on the other.

Chromosome Inversions

A chromosomal inversion is the detachment with a 180° rotation and reinsertion of a chromosome part.  Unless they disrupt a gene sequence, inversions only change gene orientation.  Altered gene orientation can result in functional changes due to gene regulators being moved out of position with respect to their targets.  Abnormal levels of gene products could result.

An chromosomal inversion can be pericentric, including the centromere, or paracentric, occurring outside of the centromere (Figure 7). A pericentric inversion that is asymmetric can change the relative lengths of the chromosome arms, making these inversions easily identifiable.

Figure 7. Pericentric inversions include the centromere, and paracentric inversions do not. A pericentric inversion can change the relative lengths of the chromosome arms; a paracentric inversion cannot.

When one homologous chromosome undergoes an inversion but the other does not, the individual is described as an inversion heterozygote. To maintain point-for-point synapsis during meiosis, one homologous chromosome must form a loop, while the other molds around it.   This topology can ensure that the genes are correctly aligned but forces stretching and can be associated with regions of imprecise synapsis (Figure 8).

Figure 8. When one chromosome undergoes an inversion but the other does not, one chromosome must form an inverted loop to retain point-for-point interaction during synapsis. This inversion pairing is essential to maintaining gene alignment during meiosis and to allow for recombination.

Translocations

Figure 9. A reciprocal translocation occurs when a segment of DNA is transferred from one chromosome to another, nonhomologous chromosome. (credit: modification of work by National Human Genome Research/USA)

A translocation occurs when a chromosomal segment detaches and reattaches to a different, nonhomologous chromosome. Translocations can be minor or have devastating effects, depending on the altered gene position with respect to regulatory sequences. Specific translocations have been associated with several cancers and with schizophrenia. Reciprocal translocations result from the exchange of chromosome segments between two nonhomologous chromosomes where there is no gain or loss of genetic information (Figure 9).

Section Summary

The number, size, shape, and banding pattern of chromosomes make them easily identifiable in a karyotype and allows for assessment of many chromosomal abnormalities. Disorders in chromosome number, or aneuploidies, are typically lethal to the embryo, although a few trisomic genotypes are viable. Because of X inactivation, Changes in sex chromosomes typically have milder phenotypic effects. Aneuploidies also include instances in which segments of a chromosome are duplicated or deleted. Chromosome structures may also be rearranged, by inversion or translocation, resulting in problematic phenotypic effects.  Inversions and translocations are often associated with reduced fertility due to the likelihood of nondisjunction.