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3-3-3. Chromosomal Basis of Inherited DisordersLearning Objectives
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 can span many genes, chromosomal disorders are characteristically dramatic and often fatal. Identification of ChromosomesThe isolation and microscopic observation of chromosomes forms the basis of cytogenetics and is the primary method by which clinicians detect chromosomal abnormalities in humans. A 
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, Career ConnectionGeneticists Use Karyograms to Identify Chromosomal AberrationsAlthough Mendel is referred to as the “father of modern genetics,” he performed his experiments with none of the tools that the geneticists of today routinely employ. One such powerful cytological technique is karyotyping, a method in which traits characterized by chromosomal abnormalities can be identified from a single cell. To observe an individual’s karyotype, a person’s cells (like white blood cells) are first collected from a blood sample or other tissue. In the laboratory, the isolated cells are stimulated to begin actively dividing. A chemical called colchicine is then applied to cells to arrest condensed chromosomes in metaphase. Cells are then made to swell using a hypotonic solution so the chromosomes spread apart. Finally, the sample is preserved in a fixative and applied to a slide. The geneticist then stains chromosomes with one of several dyes to better visualize the distinct and reproducible banding patterns of each chromosome pair. Following staining, the chromosomes are viewed using bright-field microscopy. A common stain choice is the Giemsa stain. Giemsa staining results in approximately 400–800 bands (of tightly coiled DNA and condensed proteins) arranged along all of the 23 chromosome pairs; an experienced geneticist can identify each band. In addition to the banding patterns, chromosomes are further identified on the basis of size and centromere location. To obtain the classic depiction of the karyotype in which homologous pairs of chromosomes are aligned in numerical order from longest to shortest, the geneticist obtains a digital image, identifies each chromosome, and manually arranges the chromosomes into this pattern (Figure 1). At its most basic, the karyogram may reveal genetic abnormalities in which an individual has too many or too few chromosomes per cell. Examples of this are Down Syndrome, which is identified by a third copy of chromosome 21, and Turner Syndrome, which is characterized by the presence of only one X chromosome in women instead of the normal two. Geneticists can also identify large deletions or insertions of DNA. For instance, Jacobsen Syndrome—which involves distinctive facial features as well as heart and bleeding defects—is identified by a deletion on chromosome 11. Finally, the karyotype can pinpoint During Mendel’s lifetime, inheritance was an abstract concept that could only be inferred by performing crosses and observing the traits expressed by offspring. By observing a karyogram, today’s geneticists can actually visualize the chromosomal composition of an individual to confirm or predict genetic abnormalities in offspring, even before birth. Disorders in Chromosome NumberOf all of the chromosomal disorders, abnormalities in chromosome number are the most obviously identifiable from a karyogram. Disorders of chromosome number include the duplication or loss of entire chromosomes, as well as changes in the number of complete sets of chromosomes. They are caused by 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 that lack 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 that lacks that chromosome, two normal gametes with one copy of the chromosome, and one gamete with two copies of the chromosome. Art Connection
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?
AneuploidyAn individual with the appropriate number of chromosomes for their species is called 
Figure 3: The incidence of having a fetus with trisomy 21 increases dramatically with maternal age. Link to Learning:
Link to Learning
Visualize the addition of a chromosome that leads to Down syndrome in this video simulation. PolyploidyAn individual with more than the correct number of chromosome sets (two for diploid species) is called 
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) Sex Chromosome Nondisjunction in HumansHumans display dramatic deleterious effects with autosomal trisomies and monosomies. Therefore, it may seem counterintuitive that human females and males can function normally, despite carrying different numbers of the X chromosome. Rather than a gain or loss of autosomes, variations in the number of sex chromosomes are associated with relatively mild effects. In part, this occurs because of a molecular process called 
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) An individual carrying 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, and X chromosomes must reactivate for the proper maturation of female ovaries. As a result, X-chromosomal abnormalities are typically associated with mild mental and physical defects, as well as sterility. If the X chromosome is absent altogether, the individual will not develop in utero. Several errors in sex chromosome number have been characterized. Individuals with three X chromosomes, called triplo-X, are phenotypically female but express developmental delays and reduced fertility. The XXY genotype, corresponding to one type of Klinefelter syndrome, corresponds to phenotypically male individuals with small testes, enlarged breasts, and reduced body hair. More complex types of Klinefelter syndrome exist in which the individual has as many as five X chromosomes. In all types, every X chromosome except one undergoes inactivation to compensate for the excess genetic dosage. This can be seen as several Barr bodies in each cell nucleus. Turner syndrome, characterized as an X0 genotype (i.e., only a single sex chromosome), corresponds to a phenotypically female individual with short stature, webbed skin in the neck region, hearing and cardiac impairments, and sterility. Duplications and DeletionsIn addition to the loss or gain of an entire chromosome, a chromosomal segment may be duplicated or lost. Duplications and deletions often 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 5p (the small arm of chromosome 5) (Figure 6). Infants with this genotype emit a characteristic high-pitched cry on which the disorder’s name is based. 
Figure 6: This individual with cri-du-chat syndrome is shown at two, four, nine, and 12 years of age. (credit: Paola Cerruti Mainardi) Chromosomal Structural RearrangementsCytologists have characterized numerous structural rearrangements in chromosomes, but chromosome inversions and translocations are the most common. Both are identified during meiosis by the adaptive pairing of rearranged chromosomes with their former homologs to maintain appropriate gene alignment. If the genes carried on two homologs are not oriented correctly, a recombination event could result in the loss of genes from one chromosome and the gain of genes on the other. This would produce aneuploid gametes. Chromosome InversionsA An inversion can be 
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 homolog must form a loop, and the other homolog must mold around it. Although this topology can ensure that the genes are correctly aligned, it also forces the homologs to stretch 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. Evolution ConnectionThe Chromosome 18 InversionNot all structural rearrangements of chromosomes produce nonviable, impaired, or infertile individuals. In rare instances, such a change can result in the evolution of a new species. In fact, a pericentric inversion in chromosome 18 appears to have contributed to the evolution of humans. This inversion is not present in our closest genetic relatives, the chimpanzees. Humans and chimpanzees differ cytogenetically by pericentric inversions on several chromosomes and by the fusion of two separate chromosomes in chimpanzees that correspond to chromosome two in humans. The pericentric chromosome 18 inversion is believed to have occurred in early humans following their divergence from a common ancestor with chimpanzees approximately five million years ago. Researchers characterizing this inversion have suggested that approximately 19,000 nucleotide bases were duplicated on 18p, and the duplicated region inverted and reinserted on chromosome 18 of an ancestral human. A comparison of human and chimpanzee genes in the region of this inversion indicates that two genes—ROCK1 and USP14—that are adjacent on chimpanzee chromosome 17 (which corresponds to human chromosome 18) are more distantly positioned on human chromosome 18. This suggests that one of the inversion breakpoints occurred between these two genes. Interestingly, humans and chimpanzees express USP14 at distinct levels in specific cell types, including cortical cells and fibroblasts. Perhaps the chromosome 18 inversion in an ancestral human repositioned specific genes and reset their expression levels in a useful way. Because both ROCK1 and USP14 encode cellular enzymes, a change in their expression could alter cellular function. It is not known how this inversion contributed to hominid evolution, but it appears to be a significant factor in the divergence of humans from other primates.1 1. Violaine Goidts et al., “Segmental duplication associated with the human-specific inversion of chromosome 18: a further example of the impact of segmental duplications on karyotype and genome evolution in primates,” Human Genetics. 115 (2004):116-122 TranslocationsA 
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) Section SummaryThe number, size, shape, and banding pattern of chromosomes make them easily identifiable in a karyogram and allows for the 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, aberrations 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, for example by inversion or translocation. Both of these aberrations can result in problematic phenotypic effects. Because they force chromosomes to assume unnatural topologies during meiosis, inversions and translocations are often associated with reduced fertility because of the likelihood of nondisjunction. Art ConnectionsExercise 1Figure 2. Which of the following statements about nondisjunction is true?
Show/Hide Solution Figure 2. B. Review QuestionsExercise 2Which of the following codes describes position 12 on the long arm of chromosome 13?
Show/Hide Solution B Exercise 3In agriculture, polyploid crops (like coffee, strawberries, or bananas) tend to produce ________.
Show/Hide Solution C Exercise 4Assume a pericentric inversion occurred in one of two homologs prior to meiosis. The other homolog remains normal. During meiosis, what structure—if any—would these homologs assume in order to pair accurately along their lengths?
Show/Hide Solution C Exercise 5The genotype XXY corresponds to
Show/Hide Solution A Exercise 6Abnormalities in the number of X chromosomes tends to have milder phenotypic effects than the same abnormalities in autosomes because of ________.
Show/Hide Solution D Exercise 7By definition, a pericentric inversion includes the ________.
Show/Hide Solution A Free ResponseExercise 8Using diagrams, illustrate how nondisjunction can result in an aneuploid zygote. Show/Hide Solution Exact diagram style will vary; diagram should look like Figure 2. Glossaryaneuploid autosome chromosome inversion euploid karyogram karyotype monosomy nondisjunction paracentric pericentric polyploid translocation trisomy X inactivation
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