Chromosomal Mutations

DNA carries the genetic information that organisms need to live and reproduce; it is integral to life. In the human body, DNA is organized into chromosomes. The chromosomes are composed of condensed chromatin, which are units made up of DNA wrapped around proteins called histones. The chromatin is loosely (euchromatin) or densely (heterochromatin) packed depending on whether the chromosome or region of the chromosome is transcriptionally active or silent, respectively.

Chromosome count varies between organisms. In the human body, all cells, except gametes, are diploid. This means they have 23 pairs of homologous chromosomes, for a total of 46 chromosomes. Gametes are haploid, so they only have half a complete set of chromosomes, or 23 chromosomes. Two gametes join together during fertilization to produce a diploid embryo. During mitosis and meiosis, chromosomes are replicated and passed on to daughter cells.

Chromosomal mutation definition

DNA is not stagnant; it changes, helping organisms adapt to their external or internal environment, or harming organisms. DNA, and the chromosomes it is organized into, changes through mutations. Chromosomal mutations may be spontaneous or the result of occurrences such as errors in DNA replication, errors in DNA repair, exposure to mutagens, or errors during mitosis or meiosis.

The structure of chromosomes can change in various ways, whether through loss, gain, or rearrangement of a section or sections of chromosomes. Changes to chromosome structure or number can occur through various mechanisms.

Types of chromosomal mutations - structural changes

The four main types of chromosomal mutations are deletion, inversion, duplication, and translocation mutations. Figure 1 shows these mutations.

Figure 1: Deletion, duplication, inversion, and translocation mutations.

Deletion chromosomal mutation

In a deletion chromosomal mutation, there is a break in the chromosome and the segment that breaks off is lost, so it is no longer part of the chromosome. The size of the section lost varies and the section lost can come from any part of the chromosome.¹

Inversion chromosomal mutation

In an inversion chromosomal mutation, a segment of the chromosome breaks in two places and is reversed (turned 180 degrees) and then reinserted into its original place in the chromosome.² After the inversion, genes and genetic material in that affected region are in reverse order. Some genes might be interrupted, depending on where the two breaks happen.

Duplication chromosomal mutation

In a duplication chromosomal mutation, a segment of the chromosome is copied multiple times. One specific type of duplication chromosomal mutation is a repeat expansion. In the human genome, there are numerous tandem repeats, or sequences of several nucleotide base pairs that repeat one after another.³ In a repeat expansion, the number of repeated sequences is increased.

Translocation chromosomal mutation

In a translocation chromosomal mutation, a segment of one chromosome breaks off and attaches to another chromosome.¹ No genetic material is lost or gained, but the location of the genetic material changes. Translocation mutations can be reciprocal or nonreciprocal. In reciprocal translocation, there is a two-way exchange of genetic information between two chromosomes; basically, two chromosomes swap segments. In a nonreciprocal translocation, a segment moves from one chromosome to another, and there is a one-way transfer of genetic material.

Types of chromosomal mutations - changes in number

Some chromosomal mutations result in changes in the number of chromosomes in a cell, known as aneuploidy. Copies of chromosomes, or chromosome pairs or sets, can be lost or additional copies gained in a cell. When one copy of a chromosome is lost, it results in monosomy, while an extra copy of a chromosome results in trisomy. Aneuploidy occurs as the result of nondisjunction. In humans, the likelihood of nondisjunction occurring increases with age.⁴

One specific type of aneuploidy is polyploidy.

Diagnosing chromosomal abnormalities

Karyotyping is used to diagnose chromosomal abnormalities. A karyotype is a lab test used to visualize chromosomes, and provides information on the size, shape, number, and structure of chromosomes. Chromosomes are stained and arranged in pairs by length, to allow for better visualization and analysis. Karyotyping can be used to identify aneuploidy as well as structural changes in chromosomes (Figure 2).

Effects of chromosomal mutations and examples

Chromosomal mutations can be serious. The potential consequences of these mutations range from none or minimal to severe. Chromosomal mutations often have severe consequences, including death of the affected organism. Aneuploidy of autosomal chromosomes is usually lethal.⁴ Fetal chromosomal abnormalities, especially aneuploidy, are responsible for half of miscarriages.⁵ Monosomy and trisomy of larger chromosomes are lethal but trisomy of smaller chromosomes (e.g., 13, 15, 18, 21, or 22) results in offspring that can survive from weeks to years⁴, although offspring will have abnormalities.

The effects of structural changes to chromosomes, and their severity, depends on the type of change, the impacted genes, and the number of genes or amount of genetic material affected.

Down syndrome

Down syndrome, or trisomy 21, occurs when an individual has an extra copy of chromosome 21. The additional genetic material disrupts normal development, resulting in the physical problems and intellectual disabilities associated with Down syndrome⁷. Features of Down syndrome include intellectual disability, facial features such as slanting eyes, increased risk of dementia, and lower life expectancy⁷. More rarely, Down syndrome can also occur when a section of chromosome 21 is translocated to another chromosome. The patient then has two copies of the full 21 chromosome, but also an extra section of that chromosome present on a different chromosome. I.e. there is a triple copy of a particular section of chromsome 21.

Cri-du-chat syndrome

Cri-du-chat, French for “cry of the cat," is the result of the deletion of the end of the short arm of chromosome 5.⁸ The syndrome's name is due to the cry that infants often have, a high-pitched cry that sounds like the cry of a cat.⁸ The syndrome is characterized by intellectual disability, developmental delays, and distinctive facial features, with larger deletions associated with more severe disability and delays.⁸

Klinfelter syndrome

Klinefelter syndrome is the result of aneuploidy of the X sex chromosome in men. Klinefelter syndrome occurs when men have an extra X chromosome, for a total of 47 chromosomes. So instead of 46,XY, men are 47,XXY. The additional copies of genes affect physical and intellectual development, including sexual development.⁹ The syndrome is characterized by infertility and other features that vary in severity.⁹ These features include being tall, low muscle tone, problems with coordination, learning disabilities, and difficulty communicating.⁹

Turner syndrome

Turner syndrome occurs as a result of the monosomy of the X chromosome. Women with Turner syndrome have only one copy of the X chromosome instead of two (45,X instead of 46,XX), or have only part of the second X chromosome.¹⁰ Loss of the genes of the X chromosome results in short height, skeleton abnormalities, ovaries that function less or not at all resulting in infertility, and other features of Turner syndrome.¹⁰