Chromosome translocation

In genetics, a chromosome translocation is a chromosome abnormality caused by rearrangement of parts between nonhomologous chromosomes. It is detected on cytogenetics or a karyotype of affected cells. There are two main types, reciprocal (also known as non-Robertsonian) and Robertsonian. Also, translocations can be balanced (in an even exchange of material with no genetic information extra or missing, and ideally full functionality) or unbalanced (where the exchange of chromosome material is unequal resulting in extra or missing genes).

Of all the structural chromosome rearrangements, the most clinically significant is a translocation. Translocation involves two nonhomologous chromosomes (e.g., chromosome 2 and chromosome 6). Following a break in each of the chromosomes, and subsequent reunion, a segment of chromosome 2 becomes attached to chromosome 6 and vice versa.



Fig. 1.4. Translocation

In most cases, there is no loss or gain of chromosomal material during the exchange process. It is estimated that 1 in 500 individuals are normal translocation carriers.

On occasion, apparently balanced translocation carriers (on karyotype studies) are clinically abnormal. One explanation for this finding is that the break may have occurred in the middle of a gene which then results in the formation of an abnormally short, nonfunctional protein.

Individuals and families have been described with a translocation chromosome abnormality and a concurrent genetic condition; the genetic condition occurring because the chromosome breakpoint is in the midst of a gene. Research studies of these informative families have led to the localization of specific genes to specific chromosome segments (e.g., Duchenne muscular dystrophy on Xp21, neurofibromatosis on 17q, retinoblastoma on 13q14, etc.).

When an apparently balanced translocation is found on amniocentesis, chromosome studies are done on both parents. If the translocation is familial (one of the parents is a normal translocation carrier), then it is safe to assume that the fetus carrying a similar translocation is going to be normal. If the translocation is de novo (the parents are not translocation carriers), then the fetus has a 10% empiric risk of having a possible genetic abnormality. It may seem surprising that the risk is not much greater. This is because only 10% of the genome (genetic constitution of an individual) carries coding sequences for genes. The other 90% of the genome consists of noncoding sequences.

As previously noted, people who carry balanced translocations have a high risk of miscarriages and abnormal offspring because they are more likely to create unbalanced gametes. In meiosis, the normal chromosomes and the translocated chromosomes pair up by creating a cross figure (quadrivalent) (Figure 1.5). The chromosomes are distributed to the daughter cells by the centromeres which are attached to spindle fibers. The spindle fibers contract and draw the attached chromosome to each of the poles (segregation).

Fig. 1.5. Balanced reciprocal translocation. This figure shows the generation of a balanced reciprocal translocation between chromosomes 2 and 6, and formation of a quadrivalent in meiosis: t = translocated segment, c = centric segment, solid circle = chromosome 2 centromere, open circle = chromosome 6 centromere. Homologous centromeres are both solid or both open circles and nonhomologus centromeres are one solid and one open circle (see text).

There are three ways the chromosome pairs segregate. Adjacent 1 segregation occurs when adjacent chromosomes with nonhomologous centromeres move to daughter cells. Adjacent 2 segregation occurs when adjacent chromosomes with homologous centromeres move to daughter cells. Alternate segregation occurs when alternate chromosomes with nonhomologous centromeres move to daughter cells.

As shown by the six possible products in Figure 1.6, adjacent 1 and adjacent 2 segregation leads to unbalanced gametes, whereas alternate segregation leads to balanced gametes with a normal chromosome complement (in this illustration a normal 2 and a normal 6) or a balanced translocation complement (chromosome 2 with a piece of 6, and chromosome 6 with a piece of 2). Again from the illustration, two of the six possible gametes will lead to normal offspring, and four of the six gametes will result in chromosomally abnormal offspring. However, the actual risk for an abnormal offspring is highly variable, depending on the chromosomes involved and the size of the segments that are trisomic or monosomic.


Fig. 1.6. Six possible gametes following meiotic segregation of a reciprocal translocation

Noted above is the usual 2:2 segregation in meiosis where two chromosomes, of the original four chromosomes, are distributed to each of the two daughter cells. On occasion, a 3:1 segregation occurs in meiosis where three chromosomes go to one daughter cell and one chromosome goes to the other daughter cell; in effect an aneuploidy nondisjunction affecting translocation chromosomes.

The risk of abnormal offspring in translocation families depends to some extent on how the family was ascertained. If the family is being seen because they have a child with a chromosome abnormality, then obviously the unbalanced translocation karyotype is compatible with life. In such families empiric data suggests that the risk of recurrence is approximately 15%. If, on the other hand, the family comes to clinical attention because of multiple miscarriages, or as part of an infertility workup, then the unbalanced translocation karyotype is probably not compatible with life and the risk of abnormal offspring is probably low, around 1.5%.

A Robertsonian translocation is a particular type of translocation involving the reciprocal transfer of the long arms of two of the acrocentric chromosomes: 13, 14, 15, 21 or 22. On rare occasions, other non-acrocentric chromosomes undergo Robertsonian translocation, a reciprocal transfer of the whole long or short arms close to the centromere. A relatively common Robertsonian translocation is between chromosome 14 and chromosome 21. In meiosis, a trivalent is formed.

Fig. 1.7. Robertsonian translocation. This figure shows the formation of a Robertsonian translocation involving chromosomes 14 and 21, and the formation of a trivalent in meiosis. Alternate segregation results in gametes having either a normal (14 and 21) or balanced translocation (t(14;21)) chromosome complement. Adjacent segregation results in unbalanced gametes, either disomy (14 and t(14;21), or 21 and t(14;21)) or nullisomy (14 or 21).

With adjacent 1 and adjacent 2 segregation, the gametes produced result in trisomy 14, monosomy 14, trisomy 21 or monosomy 21 following fertilization. With alternate segregation, the resulting gametes have a balanced translocation 14;21 or the normal chromosome complement following fertilization. There are six possible gametes: one normal, one balanced translocation, and four unbalanced translocation complements.

Of the latter four, only trisomy 21 can come to term.

Theoretically, a person who carries a 14;21 translocation has a 1/3 chance of having a normal child, a 1/3 chance of having a child who carries a balanced translocation, and a 1/3 chance of having a child with Down syndrome. However, the actual risk for Down syndrome is much smaller because many of the trisomy 21 fetuses are spontaneously aborted. The empiric risk of having a child with Down syndrome is around 3 to 5% if the father is the carrier, and 10 to 15% if the mother is the carrier. The male translocation Down syndrome patient will have a karyotype of 46,XY,t(14;21) inferring that there are two normal chromosome 21s plus a third 21 that is attached to chromosome 14. The carrier mother of such a patient will have a karyotype of 45,XX,t(14;21) inferring a single chromosome 21, and a second 21 attached to chromosome 14.

Reciprocal Translocation: Philadelphia Chromosome

Can you identify the abnormal chromosome in this karyotype? This person has 46 chromosomes with a translocation of material between chromosome 9 and chromosome 22 (commonly known as the Philadelphia chromosome). Detailed studies of the Philadelphia chromosome show that most of chromosome 22 has been translocated onto the long arm of chromosome 9. In addition, the small distal portion of the short arm of chromosome 9 is translocated to chromosome 22. This translocation, which is found only in tumor cells, indicates that a patient has chronic myelogenous leukemia (CML). In CML, the cells that produce blood cells for the body (the hematopoietic cells) grow uncontrollably, leading to cancer.

The connection between this chromosomal abnormality and CML was clarified by studying the genes located on the chromosomes at the sites of the translocation breakpoints. In one of the translocated chromosomes, part of a gene called abl (pronounced A-ble) is moved from its normal location on chromosome 9 to a new location on chromosome 22. This breakage and reattachment leads to an altered abl gene. The protein produced from the mutant abl gene functions improperly, leading to CML.

Molecular biology

The exact chromosomal defect in Philadelphia chromosome is translocation. Parts of two chromosomes, 9 and 22, swap places. The result is that part of the BCR ("breakpoint cluster region") gene from chromosome 22 (region q11) is fused with part of the ABL gene on chromosome 9 (region q34). In agreement with the International System for Human Cytogenetic Nomenclature (ISCN), this chromosomal translocation is designated as t(9;22)(q34;q11). Abl stands for "Abelson", the name of a leukemia virus which carries a similar protein. The result of the translocation is a protein of p210 or sometimes p185(p simply stands for "protein"; the numbers represent the apparent molecular weight of the mutant proteins in kDa). The fused "bcr-abl" gene is located on the resulting, shorter chromosome 22. Because abl carries a domain that can add phosphate groups to tyrosine residues (tyrosine kinase) the bcr-abl fusion gene is also a tyrosine kinase. (Although the bcr region is also a serine/threonine kinase, the tyrosine kinase function is very relevant for therapy, as will be shown.)

The fused bcr-abl protein interacts with the interleukin 3beta(c) receptor subunit. The bcr-abl transcript is constitutively active, i.e. it does not require activation by other cellular messaging proteins. In turn, bcr-abl activates a number of cell cycle-controlling proteins and enzymes, speeding up cell division. Moreover, it inhibits DNA repair, causing genomic instability and potentially causing the feared blast crisis in CML.