Chromosome mutation

SIGNIFICANCE: Unlike gene mutations, which alter individual genes, chromosome mutations delete, duplicate, or rearrange chromosome segments. Chromosome mutations may create gene mutations if they delete genes or if the breakpoints of rearranged segments disrupt gene structure or alter gene expression. Even when they do not create gene mutations, chromosome mutations may reduce fertility and are an important cause of inherited infertility in humans. They also play important roles in the evolution of species.

Discovery

As the fruit fly Drosophila melanogaster became a premier organism for genetic research in the early years of the twentieth century, geneticists who worked with it were the first to discover chromosome mutations. Calvin Bridges proposed deletions in 1917, duplications in 1919, and translocations in 1923 as explanations of phenomena he had observed in genetic experiments. Alfred Sturtevant proposed inversions in 1926 to explain experimental genetic data. Their proposals were directly confirmed as chromosome mutations when methods for microscopic examination of chromosomes were developed in the 1920s and 1930s.

Deletions

A deletion results when a chromosomal segment is lost. A deletion creates an imbalance in the genetic material because a relatively large segment of it is missing. Most deletions are lethal, even when heterozygous. Some small deletions persist in the state but are usually lethal when homozygous. These small deletions are usually characterized by deleted portions of only one or two genes and behave genetically as recessive alleles when paired with a typical recessive allele of the affected gene.

Duplications

A duplication arises when a chromosomal segment is duplicated and inserted either into the same chromosome, as its parent segment, or into another chromosome. Duplications are present in most genomes. Genome projects (including the Human Genome Project) have revealed large duplicated segments containing multiple genes dispersed throughout the chromosomes in most species. Some duplications are repeated in tandem in the same chromosome and are subject to unequal crossing over, a process in which duplicated segments mispair with one another and a crossover takes place within the mispaired segment. Unequal increases the number of tandem duplications in one chromosome and decreases that number in the other.

Inversions

Two breaks within the same chromosome may liberate a chromosome segment. If the segment is reinserted into the same chromosome, but in reverse orientation, an results. Also, rare crossing over between duplicated segments in the same chromosome may produce an inversion. If a breakpoint of the inversion lies within a gene, it disrupts the gene, causing a gene mutation. Additionally, an inversion may place a gene in another location in the chromosome, removing the gene from its regulatory elements and altering its expression, a phenomenon known as the position effect.

When one chromosome carries an inversion and its partner does not, the individual carrying these two chromosomes is said to be an inversion heterozygote. The two homologous chromosomes in an inversion cannot pair properly in meiosis; one of them must form a loop in the inverted region. A crossover within the inversion loop results in chromosomes that carry large deletions and duplications. Because of the imbalance of chromosomal material created by the deletions and duplications, progeny resulting from such crossovers usually do not survive. In genetic experiments, crossing over appears to be suppressed within an inversion, whereas, in reality, crossing over does take place within the inversion but crossover-type progeny fail to survive. For this reason, inversion heterozygotes may suffer a reduction in fertility that is proportional to the size of the inversion. An individual who is for an inversion, however, suffers no loss of fertility, because the chromosomes pair normally.

Translocations

A break in a chromosome may liberate a chromosome fragment, which if reattached to a different chromosome is called a translocation. Most translocations are reciprocal: Two chromosome breaks, each in a different chromosome, liberate two fragments, and each fragment reattaches to the site where the other fragment was originally attached; in other words, the two fragments exchange places. If the breakpoint of a is within a gene, a gene mutation may result. Also, a gene at or near the breakpoint may undergo a change in its expression because of position effect.

Translocations alter chromosome pairing in meiosis. During in a heterozygote, the two chromosomes with translocated segments pair with two other chromosomes without translocations. The pairing of these four chromosomes forms an X-shaped structure called a quadrivalent, so named because it contains four chromosomes paired with one another, instead of the usual two. Depending on the orientation of the quadrivalent during meiosis, some gametes may receive a balanced complement of chromosomes and others an unbalanced complement with large duplications and deletions. Typically, about half of all gametes in a reciprocal translocation heterozygote carry an unbalanced chromosome complement, a situation that significantly reduces the individual’s fertility. However, translocation homozygotes suffer no loss of fertility, because the chromosomes pair normally with no quadrivalent.

Fusions

Very rarely, two chromosomes may fuse with one another to form a single chromosome. Chromosomes with centromeres at or very near the ends of the chromosomes may undergo breakage at the centromeres and fuse with each other in the centromeric region, resulting in a single chromosome with the long arms of the original chromosomes on either side of the fused centromere. Such a chromosome fusion is called a Robertsonian translocation. In other cases, two chromosomes may fuse with one another producing a (a chromosome with two centromeres). For the fused chromosome to persist, one of the centromeres ceases to function, leaving the other as a single, functional centromere for the fused chromosome.

Fissions

A chromosome break produces two fragments, which may function as individual chromosomes if each has telomeres on both ends and a functional centromere. Typically, chromosome breakage produces one fragment with a on one end and a centromere, and another fragment with a telomere on one end and no centromere. For both fragments to function as chromosomes, one must acquire a telomere and the other a centromere and a telomere. These events are highly unlikely, so fissions are rarer than fusions. However, complex translocations with other chromosomes may rarely produce functional chromosomes from a fission event, and cases of functional chromosomes arising from fissions have been documented.

Impact on Human Genetics and Medicine

Chromosome mutations are responsible for several human genetic disorders. For example, about 20 percent of hemophilia A cases result from a gene mutation caused by an inversion with a breakpoint in the F8C gene, which encodes blood clotting factor VIII. Cri du chat syndrome, a severe disorder characterized by severe intellectual disability and distinctive physical features, is usually caused by deletion of a small chromosomal region near the end of chromosome 5. A few cases of this syndrome are associated with deletions that result from a translocation with a breakpoint near the end of chromosome 5 or crossovers within a small inversion in that chromosome region. Robertsonian translocations that fuse the long arm of chromosome 21 with the long arm of another chromosome (usually chromosome 14) are responsible for some inherited cases of Down syndrome. A reciprocal translocation between chromosomes 9 and 22, called the Philadelphia chromosome, causes increased susceptibility to certain types of cancer by altering the expression of a gene located at the breakpoint of the translocation. Other translocations are likewise associated with certain cancers. Chromosome mutations may also cause infertility in humans. Reciprocal translocations are especially notorious, although certain inversions are also associated with infertility.

In 2024, researchers developed a new single-molecule, long-read sequencing technique called HiDEF-seq. It could detect single-strand DNA mutations, the earliest stage of genetic mutation. Rsearchers hoped to use this technology to learn how mutations emerge, particularly in cancer and aging.

Implications for Evolution

Heterozygous carriers of inversions, translocations, fusions, and fissions often suffer losses of fertility, but homozogotes do not. Thus, natural selection may disfavor heterozygotes while favoring homozygotes either for the original chromosome structure or for the mutation. Accumulation of different chromosome mutations in isolated populations of a species may eventually differentiate the chromosomes to such a degree that the isolated populations diverge into separate species. Their members can no longer produce fertile offspring when hybridized with members of another population because the chromosomes cannot properly pair with one another. Indeed, accumulated chromosome mutations are often evident when geneticists compare the chromosomes of closely related species. For example, the chromosomes of different Drosophila species are differentiated mostly by translocations and fusions. Comparison of human, chimpanzee, gorilla, and orangutan chromosomes reveals numerous inversions that distinguish the chromosomes of these species. One of the most striking cases of chromosome evolution is the origin of human chromosome 2. This chromosome matches two separate chromosomes in the great apes and apparently arose from a fusion of these two chromosomes after the divergence of the human and chimpanzee lineages. The presence in human chromosome 2 of DNA sequences corresponding to a nonfunctional centromere and telomere at sites corresponding to these structures in the great ape chromosomes is strong evidence of a chromosome fusion during evolution of the human lineage.

Key terms

• deletiona missing chromosome segment
• duplicationa chromosome segment repeated in the same or in a different chromosome
• fissionseparation of a single chromosome into two chromosomes
• fusionjoining of two chromosomes to become a single chromosome
• inversiona chromosome segment with reversed orientation when compared to the original chromosome structure
• translocationa chromosome segment transferred from one chromosome to a nonhomologous chromosome

Bibliography

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