13.1: Chromosomal structure and cytogenetics

Chromosomes can be analyzed from living tissue and arranged in a karyotype (figure 13.1). Chromosomes can be sorted into the autosomal pairs (twenty-two) and sex chromosomes and classified to determine any abnormalities. A normal karyotype for a female is 46,XX, and a male is 46,XY. Deviations from this patterning can result in chromosomal abnormalities, which may or may not produce viable offspring.

Figure 13.1: Representative karyotype illustrating twenty-two pairs of autosomes and one pair of sex chromosomes.

Chromosome structure

Each chromosome is made up of a p and q arm held together by the centromere. The position of the centromere is a distinguishing characteristic and can be classified as metacentric, submetacentric, or acrocentric. The position of the centromere plays a key role in mitotic and meiotic division as chromosomes with skewed centromeres are more likely to be involved in nondisjunction events (figure 13.2).

Figure 13.2: Basics of chromosome structure.

Nondisjunction

The precise pairing and segregation during the two meiotic divisions ensures the equal division of the somatic diploid set of chromosomes into the four resulting haploid cells (figure 13.3). Nondisjunction is the term used when the two homologous chromosomes in the first division or the two sister chromatids in the second do not segregate from each other at anaphase, but instead move together into the same daughter cell. This term may also be used for the same occurrence in mitotic cell divisions when the sister chromatids fail to segregate properly.

Figure 13.3: Summary of meiotic and mitotic cell divisions.

 

	DNA synthesis	Synapsis of homologous chromosomes	Crossover	Homologous chromosomes line up at metaphase plate	Sister chromatids line up at metaphase plate
Meiosis	Occurs in S phase of interphase	During prophase I	During prophase I	During metaphase I	During metaphase II	Outcome: Four haploid cells at the end of meiosis II
Mitosis	Occurs in S phase of interphase	Does not occur in mitosis	Does not occur in mitosis	Does not occur in mitosis	During metaphase	Outcome: Two diploid cells at the end of mitosis

Table 13.1: Summary of meiotic and mitotic cell divisions.

 

These nondisjunction events can result in unequal distribution of chromosomes rendering a cell with an atypical chromosome number. A cell that is euploid would contain all twenty-three chromosomes, while polyploidy would suggest additional chromosomes within the cell. In humans, aneuploidy of autosomes are the most clinically important abnormalities to address, and the most common cause of this is a nondisjunction event.

Meiotic nondisjunction

Normally, one copy of each chromosome is inherited from each parent; however, when there is nondisjunction at either anaphase I or anaphase II, gametes will contain either two copies or no copies of the chromosome, which failed to disjoin. At fertilization, when the gamete provided by the other parent contributes one copy of each chromosome, the newly formed zygote will instead possess three copies (trisomy) or one copy (monosomy) of the chromosome, which failed to disjoin. Trisomy and monosomy are both examples of aneuploidy, a general term that denotes an abnormality in the number of copies of any given chromosome.

Chromosomal trisomies caused by nondisjunction at meiosis I can be distinguished from those occurring at meiosis II by examining the inheritance patterns of polymorphic markers near the centromere in cells obtained from the trisomic offspring (figure 13.4).

Figure 13.4: Comparison of nondisjunction in meiosis I versus meiosis II.

• Nondisjunction during the first division results in one copy of each of the two different markers being present on the two copies of the chromosome present in the abnormal gamete.
• Nondisjunction at meiosis II results in two copies of the same marker being present (figure 13.4).

Meiotic nondisjunction is the cause of the most common and clinically significant class of chromosomal abnormalities. This is true for chromosomal abnormalities found in spontaneous abortions where approximately 35 percent of miscarriages have a trisomy or monosomy, in stillbirths with approximately 4 percent being aneuploid, and also in live births with 0.3 percent being affected. Most autosomal trisomies and virtually all autosomal monosomies result in pregnancy failure or spontaneous abortion. Trisomies for chromosomes 13, 18, or 21 can result in the live birth of an infant with birth defects and intellectual disability. Extra copies of the X or Y chromosome are compatible with live birth, as is a small fraction of the conceptions with only a single X chromosome (Turner syndrome).

Increasing maternal age is considered a risk factor for increased frequency of nondisjunctional events. This maternal age effect is seen in both meiosis I and meiosis II, with the majority of these events occurring at meiosis I. Only a small proportion of chromosomal aneuploidies are due to errors in male meiosis, and these generally involve the sex chromosomes. Although there is little correlation with increasing paternal age and nondisjunctional events, there is some evidence to suggest that increased paternal age increases risk for other conditions (neurofibromatosis and achondroplasia) and should therefore not be ignored when determining risk.

Mitotic nondisjunction

Mitotic nondisjunction occurs after zygote formation and may be the result of misdivision of a cell after a normal conception with gain (or loss) of a chromosome during embryogenesis. This typically results in mosaicism (figure 13.5), the presence of multiple and genetically distinct cell populations in the same individual. The timing of mitotic nondisjunction events determines the ratio of aneuploid to normal cells and the types of tissues affected. For example, if the nondisjunction occurs early in development, the majority of cells and tissues would carry this aneuploidy, which would result in an increased clinical severity.

Figure 13.5: Mosaicism resulting in cells with differing genetics across the body.

Mosaicism is often found in sex chromosome abnormalities and some autosomal trisomies. Over half of mosaic trisomy 21 cases have been shown to be the result of loss of the extra 21 in subsequent mitotic divisions after a trisomic conception, while trisomy 8 mosaicism typically seems to be acquired during mitotic divisions after a normal conception.

Chimaerism is similar to mosaicism in that multiple, genetically distinct cell lines are present in the same individual. Here, however, the cell lines begin as different zygotes rather than arising through changes during mitosis. This can arise naturally from the fusion of closely implanted twins or migration of cells between embryos in multiple gestations, or it can be caused by the transplantation of tissues or organs from donors for medical treatment.

Chromosome structural defects

In addition to copy number defects, parts of the chromosome may be lost or altered. These rearrangements, regardless of the type, may be balanced or unbalanced (where the rearrangement does not produce a loss or gain).

Deletions and duplications

A deletion occurs when a chromosome breaks at two sites and the segment between them gets lost. Depending on the size and breakage site, varying numbers of genes can be lost. In rare cases the deletions are large enough to be visible under the light microscope. Smaller deletions have traditionally been identified by molecular cytogenetic (FISH) analyses, although they are now routinely detected with chromosome oligonucleotide arrays. These are called microdeletions, while the resulting pathologies are called microdeletion syndromes.

An example of this is Prader-Willi syndrome, a rare disorder due to the deletion or loss of expression from the paternal chromosome 15. This short region of genes is subject to maternal imprinting and typically only expressed from a single chromosomal loci. In these individuals, loss of expressivity from the paternal allele (either through a microdeletion or loss of chromosome 15) and imprinting of the maternal allele leads to this presentation. If both copies of the region are inherited from the paternal allele the result is the presentation of Angelman syndrome (figure 13.6).

Figure 13.6: Genetic basis of Prader-Willi syndrome (PWS) and Angelman syndrome (AS). UPD: Uniparental disomy; Square: imprinting on the maternal allele.

Duplications refer to a chromosome segment appearing in two (often sequentially inserted) copies on a single homolog. Most of the time, this is caused by a nonhomologous recombination in the first meiotic division.

Inversion

Inversion occurs when a chromosome segment between two breaks is rotated 180 degrees before reinsertion. The gene copy number remains the same; clinical symptoms may arise if there is an additional deletion or duplication, if the breaks occur within the coding region of a gene, or if the regulation of a gene is altered. Like other balanced chromosomal aberrations, inversions may cause infertility, recurrent miscarriages, or an unbalanced chromosome complement in a child (figure 13.7).

Figure 13.7: Example of a chromosome inversion and translocation.

Isochromosome

An isochromosome is a derivative chromosome with two homologous arms after the centromere divided transversely rather than longitudinally. An isochromosome can be thought of as a “mirror image” of either the short arm or the long arm of a given chromosome.

Ring chromosome

Ring chromosomes occur when a chromosome breaks at both ends and the ends join together. They typically become clinically relevant through the loss of chromosomal material distal to the breaks. Ring chromosome X causes 5 percent of Turner syndrome cases.

Translocations

Translocations occur most often during meiosis if unequal crossing over occurs. Additionally, translocations (interchange of genetic material between nonhomologous chromosomes) can be another source of chromosomal abnormality (figure 13.7).

Translocations can be classified as either reciprocal or Robertsonian.

• Reciprocal translocations occur when there is a break in two different chromosomes and the material is mutually exchanged. The newly formed "derivate chromosomes" have a full genetic complement, and the carrier is typically unaffected as no genetic information is lost.
• Robertsonian translocations occur when the short arms of two nonhomologous chromosomes are lost and the long arms (q) fuse to form a single chromosome. The acrocentric chromosomes (13, 14, 15, 21, and 22) are very susceptible to this type of translocation as they are acrocentric with very short arms. The short arms typically carry very little genetic material, so the loss of them does not usually result in a carrier phenotype. These individuals have forty-five chromosomes.

References and resources

Text

Clark, M. A. Biology, 2nd ed. Houston, TX: OpenStax College, Rice University, 2018, Chapter 10: Cell Reproduction, Chapter 11: Meiosis and Sexual Reproduction, Chapter 13: Modern Understandings of Inheritance, Chapter 17: Biotechnology and Genomics.

Le, T., and V. Bhushan. First Aid for the USMLE Step 1, 29th ed. New York: McGraw Hill Education, 2018, 52–55.

LeClair, R. J., and R. G. Best. "Chromosome Mechanics." eLS (2016): 1–11. https://onlinelibrary.wiley.com/doi/....a0001441.pub3.

Nussbaum, R. L., R. R. McInnes, H. F. Willard, A. Hamosh, and M. W. Thompson. Thompson & Thompson Genetics  in Medicine, 8th ed. Philadelphia: Saunders/Elsevier, 2016, Chapter 5: Principles of Clinical Cytogenetics.

Figures

Bolzer A, Kreth G, Solovei I, et al. Figure 13.1 Representative karyotype illustrating 22 pairs of autosomes and one pair of sex chromosomes. PLoSBiol3.5.Fig7ChromosomesAluFish. CC BY 2.5. From WIkimedia Commons.

Csink AK, Henikoff S. Figure 13.6 Genetic basis of Prader-Willi (PWS) and Angelman syndrome(AS). Adapted under Fair Use from Trends in Genetics. Volume 14, Issue 5, 1 May 1998, pp 194-200. Figure 2. Prader-Willi and Angelman syndromes.

Grey, Kindred, Figure 13.2 Basics of chromosome structure. 2021. https://archive.org/details/13.2_20210926. CC BY 4.0. Added Karyotype (normal) by National Cancer Institute. Public domain. From Wikimedia Commons.

Grey, Kindred, Figure 13.3 Summary of meiotic and mitotic cell divisions. 2021. https://archive.org/details/13.3_20210926. CC BY 4.0. Adapted from Figure 1. CC BY 4.0. From Open Oregon.

Grey, Kindred, Figure 13.4 Comparison on nondisjunction in meiosis I vs. meiosis II. 2021. https://archive.org/details/13.4_20210926. CC BY 4.0. Adapted from Figure 8. CC BY 4.0. From Open Oregon.

Grey, Kindred, Figure 13.5 Mosaicism resulting in cells with differing genetics across the body. 2021. CC BY SA 3.0. Added Sperm by Amit Hazra from the Noun Project and Woman surface diagram ahead-behind dark skin by Jmarchn. CC BY-SA 3.0. From Wikimedia Commons.

Grey, Kindred, Figure 13.7 Example of a chromosome inversion and translocation. 2021. https://archive.org/details/13.7_20210926. CC BY 4.0.