Chromosomal Basis of Inherited Disorders

Disorders in Chromosome Number

Aneuploidy, an abnormal number of chromosomes in a cell, is caused by nondisjunction, or the failure of chromosomes to separate at meiosis.

Learning Objectives

Define aneuploidy and explain how this condition results from nondisjunction

Key Takeaways

Key Points

  • Aneuploidy is caused by nondisjunction, which occurs when pairs of homologous chromosomes or sister chromatids fail to separate during meiosis.
  • The loss of a single chromosome from a diploid genome is called monosomy (2n-1), while the gain of one chromosome is called trisomy (2n+1).
  • If homologous chromosomes fail to separate during meiosis I, the result is no gametes with the normal number (one) of chromosomes.
  • If sister chromatids fail to separate during meiosis II, the result is two normal gametes each with one copy of the chromosome, and two abnormal gametes in which one carries two copies and the other carries none.
  • Aneuploidy can be lethal or result in serious developmental disorders such as Turner Syndrome (X monosomy) or Downs Syndrome (trisomy 21).

Key Terms

  • aneuploidy: the state of possessing a chromosome number that is not an exact multiple of the haploid number
  • nondisjunction: the failure of chromosome pairs to separate properly during meiosis

Disorders in Chromosome Number

Of all of the chromosomal disorders, abnormalities in chromosome number are the most obviously identifiable from a karyotype and are referred to as aneuploidy. Aneuploidy is a condition in which one or more chromosomes are present in extra copies or are deficient in number, but not a complete set. To be more specific, the loss of a single chromosome from a diploid genome is called monosomy (2n-1). The gain of one chromosome is called trisomy (2n+1).They are caused by nondisjunction, which occurs when pairs of homologous chromosomes or sister chromatids fail to separate during meiosis. Misaligned or incomplete synapsis, or a dysfunction of the spindle apparatus that facilitates chromosome migration, can cause nondisjunction. The risk of nondisjunction occurring increases with the age of the parents.

Nondisjunction can occur during either meiosis I or II, with differing results. 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. If a gamete with two copies of the chromosome combines with a normal gamete during fertilization, the result is trisomy; if a gamete with no copies of the chromosomes combines with a normal gamete during fertilization, the result is monosomy.

image

Nondisjunction in Meiosis: 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.

Aneuploidy often results in serious problems such as Turner syndrome, a monosomy in which females may contain all or part of an X chromosome. Monosomy for autosomes is usually lethal in humans and other animals. Klinefelter syndrome is a trisomy genetic disorder in males caused by the presence of one or more X chromosomes. The effects of trisomy are similar to those of monosomy. Down syndrome is the only autosomal trisomy in humans that has a substantial number of survivors one year after birth. Trisomy in chromosome 21 is the cause of Down syndrome; it affects 1 infant in every 800 live births.

Chromosomal Structural Rearrangements

Structural rearrangements of chromosomes include both inversions and translocations, which may have detrimental effects on an organism.

Learning Objectives

Describe the various types of structural rearrangements of chromosomes and how they can impact an organism

Key Takeaways

Key Points

  • A chromosome inversion is the detachment, 180° rotation, and reinsertion of part of a chromosome; this may have no effect on the organism, but if the inversion occurs within a gene or moves a gene away from its regulatory elements it can have an adverse effect.
  • Pericentric inversions include the centromere, while paracentric inversions occur outside of the centromere; a pericentric inversion can change the length of the chromosome arms above and below the centromere.
  • A pericentric inversion on chromsome 18 appears to have been involved in the evolution of humans.
  • A translocation occurs when a segment of a chromosome dissociates and reattaches to a different, nonhomologous chromosome and can be benign or detrimental; in reciprocal translocations, there is no gain or loss of genetic information, so these are usually benign.

Key Terms

  • inversion: a segment of DNA in the context of a chromosome that is reversed in orientation relative to a reference karyotype or genome
  • translocation: a transfer of a chromosomal segment to a new position, especially on a nonhomologous chromosome

Chromosomal Structural Rearrangements

Cytologists 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 Inversions

A chromosome inversion is the detachment, 180° rotation, and reinsertion of part of a chromosome. Inversions may occur in nature as a result of mechanical shear, or from the action of transposable elements (special DNA sequences capable of facilitating the rearrangement of chromosome segments with the help of enzymes that cut and paste DNA sequences). Unless they disrupt a gene sequence, inversions only change the orientation of genes and are likely to have milder effects than aneuploid errors. However, altered gene orientation can result in functional changes because regulators of gene expression could be moved out of position with respect to their targets, causing aberrant levels of gene products.

An inversion can be pericentric and include the centromere, or paracentric and occur outside of the centromere. A pericentric inversion that is asymmetric about the centromere can change the relative lengths of the chromosome arms, making these inversions easily identifiable.

image

Inversions can be pericentric or paracentric: 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.

image

Inversion heterozygotes: 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.

Not 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.

Translocations

A translocation occurs when a segment of a chromosome dissociates and reattaches to a different, nonhomologous chromosome. Translocations can be benign or have devastating effects depending on how the positions of genes are altered with respect to regulatory sequences. Notably, specific translocations have been associated with several cancers and with schizophrenia. Reciprocal translocations result from the exchange of chromosome segments between two nonhomologous chromosomes such that there is no gain or loss of genetic information.

image

Reciprocal translocations do not involve loss of genetic information: A reciprocal translocation occurs when a segment of DNA is transferred from one chromosome to another, nonhomologous chromosome.

X-Inactivation

The presence of extra X chromosomes in a cell is compensated for by X-inactivation in which all but one X chromosome are silenced.

Learning Objectives

Explain how and why X inactivation occurs in humans

Key Takeaways

Key Points

  • Extra copies of the X chromosome are silenced by becoming Barr bodies.
  • X chromosomal abnormalities are typically associated with mild mental and physical defects, as well as sterility.
  • Conditions associated with aneuploidy of the sex chromosomes include individuals with three X chromosomes, called triplo-X; the XXY genotype, known as Klinefelter syndrome; and Turner syndrome, characterized as X monosomy.
  • X-inactivation is a form of dosage compensation, in which an organism attempts to equalize the amount of X chromosome gene products in males and females.
  • Since males only have one X chromosome, females inactivate one of theirs so that only one X chromosome is active in each gender.

Key Terms

  • dosage compensation: a genetic regulatory mechanism that equalizes the phenotypic expression of characteristics determined by genes on the X chromosome so that they are equally expressed in males and females.
  • Barr body: a sex chromosome inactivated by packing in heterochromatin
  • X inactivation: a process by which one of the two copies of the X chromosome present in female mammals is inactivated

Sex Chromosome Nondisjunction in Humans

Humans 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 X chromosomes are associated with relatively mild effects. In part, this occurs because of a molecular process called X inactivation. Early in development, when female mammalian embryos consist of just a few thousand cells (relative to trillions in the newborn), one X chromosome in each cell inactivates by tightly condensing into a quiescent (dormant) structure called a Barr body. The chance that an X chromosome (maternally or paternally derived ) is inactivated in each cell is random, but once the inactivation occurs, all cells derived from that single cell will have the same inactive X chromosome or Barr body.

By this process, a phenomenon called dosage compensation is achieved. Females possess two X chromosomes, while males have only one; therefore, if both X chromosomes remained active in the female, they would produce twice as much product from the genes on the X chromosomes as males.

image

Sex Chromosome Nondisjunction: The symptoms of Klinefelter’s syndrome (XXY) in a human male.

So how does X-inactivation help alleviate the effects of extra X chromosomes? An individual carrying an abnormal number of X chromosomes will inactivate all but one X chromosome in each of her cells. If three X chromosomes are present, the cell will inactivate two of them. If four X chromosomes are present, three will be inactivated, and so on. This results in an individual that is relatively phenotypically normal. 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 Deletions

In 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). Infants with this genotype emit a characteristic high-pitched cry on which the disorder’s name is based.

image

Cri-du-chat Syndrome: This individual with cri-du-chat syndrome is shown at two, four, nine, and 12 years of age.