In this lesson, you will learn about how changes in chromosome number and structure can affect traits and about several chromosomal disorders that affect humans. Specifically, this lesson will cover:
Sometimes a new trait or genetic disease is not caused by a mutation in a gene but by the presence of an incorrect number or structure of chromosomes. Inherited disorders can arise when chromosomes behave abnormally during meiosis. We can divide chromosome disorders into two categories: abnormalities in chromosome number and chromosomal structural rearrangements. Because even small chromosome segments can span many genes, chromosomal disorders are characteristically dramatic and often fatal. Some of these chromosomal disorders are described in this lesson.
1. Nondisjunctions, Duplications, and Deletions
Of all the chromosomal disorders, abnormalities in chromosome number are the most easily identifiable from a karyogram. Recall that a karyogram is a visual representation through a photograph or diagram of a karyotype, which you learned about in a prior lesson.
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, which occurs when pairs of homologous chromosomes or sister chromatids fail to separate during meiosis. The risk of nondisjunction increases with the age of the parents.
Nondisjunction can occur during either meiosis I or II, with different results. If homologous chromosomes fail to separate during meiosis I, the result is two gametes that lack that 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.
Nondisjunction—Following meiosis, each gamete has one copy of each chromosome. Nondisjunction occurs when homologous chromosomes (meiosis I) or sister chromatids (meiosis II) fail to separate during meiosis.
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).
Monosomic human zygotes missing any one copy of an autosome invariably fail to develop to birth because they have only one copy of essential genes. Most autosomal trisomies also fail to develop to birth; however, duplications of some of the smaller chromosomes (13, 15, 18, 21, or 22) can result in offspring that survive for several weeks to many years. Trisomic individuals suffer from a different type of genetic imbalance: an excess in gene dose. Cell functions are calibrated to the amount of gene product produced by two copies (doses) of each gene; adding a third copy (dose) disrupts this balance.
IN CONTEXT
Down Syndrome
The most common trisomy is that of chromosome 21, which leads to Down syndrome. Individuals with this inherited disorder have characteristic physical features and developmental delays in growth and cognition.
An Individual With Down Syndrome
The incidence of Down syndrome is correlated with maternal age, such that older individuals are more likely to give birth to children with Down syndrome. The frequency of nondisjunction events appears to increase with age, so the frequency of bearing a child with Down syndrome increases in females over 36. The age of the male parent matters less because nondisjunction is much less likely to occur in sperm than in an egg.
Risk of Down Syndrome Relative to Mother’s Age—The incidence of having a fetus with trisomy 21 increases dramatically with maternal age.
terms to know
Nondisjunction
The failure of synapsed homologs to completely separate and migrate to separate poles during the first cell division of meiosis.
Euploid
An individual with the appropriate number of chromosomes for their species.
Aneuploid
An individual with an error in chromosome number; includes deletions and duplications of chromosome segments.
Monosomy
An otherwise diploid genotype in which one chromosome is missing.
Trisomy
An otherwise diploid genotype in which one entire chromosome is duplicated.
1a. 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 despite carrying different numbers of the X chromosome.
In part, this occurs because of a 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 condensing into a structure called a Barr body. The genes on the inactive X chromosome are not expressed. The particular X chromosome that is inactivated in each cell is random, but once the inactivation occurs, all cells descended from that cell will have the same inactive X chromosome. By this process, females compensate for their double genetic dose of the X chromosome.
In so-called “tortoiseshell” cats, X inactivation is observed as coat color diversity. Females heterozygous 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 progenitor of that region. When you see a tortoiseshell cat, it is probably female. Although very rare, male tortoiseshell cats are possible if they have an extra X chromosome.
A Tortoiseshell Cat—In cats, the gene for coat color is located on the X chromosome. In female cats' embryonic development, one of the two X chromosomes randomly inactivates in each cell, resulting in a tortoiseshell pattern if the cat has two different alleles for coat color. Male cats with a normal number of chromosomes, having only one X chromosome, never exhibit a tortoiseshell coat color. (credit: Michael Bodega)
In an individual carrying an abnormal number of X chromosomes, cellular mechanisms will inactivate all but one X in each cell. As a result, X-chromosomal abnormalities are typically associated with mild intellectual and physical disabilities, as well as sterility. If the X chromosome is absent altogether, the individual will not develop.
Several errors in sex chromosome numbers have been characterized. Individuals with three X chromosomes, called triplo-X, are assigned female but express developmental delays and reduced fertility. The XXY chromosome complement causes Klinefelter syndrome, in which male individuals have small testes, enlarged breasts, and reduced body hair. The extra X chromosome undergoes inactivation to compensate for the excess genetic dosage.
reflect
Recall that intersex describes people whose sex traits, reproductive anatomy, hormones, or chromosomes are different from the usual two ways human bodies develop. Intersex features can be caused by having a different number of chromosomes.
Jacobs syndrome, also known as XYY or 47, XYY syndrome, is a rare genetic condition that occurs in about 1 out of 1,000 male children. Affected males have normal production of testosterone, normal sexual development, and fertility. However, affected children have the following:
Increased risk of learning disabilities
Delayed development of speech and language
Weak muscle tone
Delayed development of motor skill such as walking
Turner syndrome, characterized as an X0 chromosome complement (i.e., only a single sex chromosome), corresponds to a female individual with short stature, webbed skin in the neck region, hearing and cardiac impairments, and sterility. Women with Turner syndrome are sterile because their sexual organs do not mature.
An individual with more than the correct number of chromosome sets (two for diploid species) is called polyploid. For instance, fertilization of an abnormal diploid egg with a normal haploid sperm would yield a triploid zygote. However, in humans, this typically results in miscarriage early in the pregnancy. Known instances where the pregnancy comes to term typically result in the infant dying within a few days of birth. Infants with complete triploidy exhibit growth restriction and multiple birth defects. A small number of affected individuals are known to have survived to adulthood, but they exhibited abnormalities such as developmental delay, seizures, and hearing loss. Additionally, those survivors exhibited mosaic triploidy, in which some of their cells had a normal number of chromosomes (46) and others had an abnormal number of chromosomes per cell.
Polyploid animals are rare but do exist in nature, with examples among flatworms, crustaceans, amphibians, fishes, and lizards. Triploid animals are often sterile because meiosis cannot proceed normally with an odd number of chromosome sets. In contrast, polyploidy is very common in the plant kingdom, and polyploid plants tend to be larger and more robust than euploids of their species.
term to know
X Inactivation
The condensation of X chromosomes into Barr bodies during embryonic development in females to compensate for the double genetic dose.
2. Chromosome Structural Rearrangements
In addition to losing or gaining an entire chromosome, a chromosomal segment may duplicate or be lost. Cytologists (biologists who study cell structure and function) have characterized numerous structural rearrangements in chromosomes, including partial duplications, deletions, inversions, and translocations.
Duplications and deletions often produce offspring that survive but exhibit physical and mental abnormalities. 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 the small arm of chromosome 5. Infants with this genotype emit a characteristic high-pitched cry upon which the disorder’s name is based.
An Individual With Cri-Du-Chat Syndrome at 2, 4, 9, and 12 years of age. (credit: Paola Cerruti Mainardi)
Although numerous structural rearrangements have been characterized in chromosomes, chromosome inversions and translocations are the most common. We can identify both during meiosis by the adaptive pairing of rearranged chromosomes with their former homologs to maintain appropriate gene alignment. If the genes on two homologs are not oriented correctly, a recombination event could result in losing genes from one chromosome and gaining genes on the other. This would produce aneuploid gametes.
2a. 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 transposable elements' action (special DNA sequences capable of facilitating rearranging chromosome segments with the help of enzymes that cut and paste DNA sequences). Unless they disrupt a gene sequence, inversions only change gene orientation 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 move out of position with respect to their targets, causing aberrant levels of gene products.
Chromosome Inversion
An inversion can be pericentric and include the centromere, or paracentric and occur outside the centromere. A pericentric inversion that is asymmetric around the centromere can change the chromosome arms' relative lengths, making these inversions easily identifiable.
Pericentric and Paracentric Inversions—Pericentric inversions include the centromere, and paracentric inversions do not. A pericentric inversion can change the chromosome arms' relative lengths. A paracentric inversion cannot.
When one homologous chromosome undergoes an inversion but the other does not, the individual is 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 correctly align, it also forces the homologs to stretch and can occur with imprecise synapsis regions.
Inversion Pairing—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.
terms to know
Chromosome Inversion
The detachment, 180° rotation, and reinsertion of a chromosome arm.
Pericentric
Inversion that involves the centromere.
Paracentric
Inversion that occurs outside of the centromere.
2b. Translocations
A translocation occurs when a chromosome segment 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 occur with several cancers and with schizophrenia. Reciprocal translocations result from exchanging chromosome segments between two nonhomologous chromosomes such that there is no genetic information gain or loss.
Reciprocal Translocation—A reciprocal translocation occurs when a DNA segment transfers from one chromosome to another, nonhomologous chromosome. (credit: modification of work by National Human Genome Research/USA)
IN CONTEXT
Career Connection
Geneticists Use Karyograms to Identify Chromosomal Aberrations
The karyotype is a method by 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 is then applied to the cells to arrest mitosis during metaphase. The cells are then fixed 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, chromosomes are viewed using bright-field microscopy. An experienced cytogeneticist can identify each band. In addition to the banding patterns, chromosomes are further identified based on 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 an image called a karyogram, identifies each chromosome, and manually arranges the chromosomes into this pattern.
This karyogram shows the chromosomes of a female human immune cell during mitosis. (credit: Andreas Bolzer, et al)
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 you have learned 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 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 translocations, which occur when a segment of genetic material breaks from one chromosome and reattaches to another chromosome or to a different part of the same chromosome. Translocations are implicated in certain cancers, including chronic myelogenous leukemia.
By observing a karyogram, geneticists can actually visualize the chromosomal composition of an individual to confirm or predict genetic abnormalities in offspring even before birth.
term to know
Translocation
The process by which one segment of a chromosome dissociates and reattaches to a different, nonhomologous chromosome.
make the connection
If you're taking the Human Biology Lab course simultaneously with this lecture, it's a good time to try the Activities in Unit 7 of the Lab course. Good luck!
summary
In this lesson, you learned about chromosomal abnormalities and some of the disorders they can cause. First, you explored how nondisjunctions, duplications, and deletions can alter the number of chromosomes in an individual. You then examined how sex chromosome nondisjunction in humans can result in an abnormal number of X chromosomes. Subsequently, you explored some chromosome structural rearrangements that can result in disorders, including chromosome inversions, in which a chromosome arm detaches and reattaches in an inverse orientation, and translocations, in which part of a chromosome moves and attaches to a nonhomologous chromosome.
