Heteroploidy

Numerical changes (heteroploidy) are of two types, polyploidy and aneuploidy. Polyploidy is a change in the number of chromosome sets. Triploidy (3n), for example, occurs in about 1% of human pregnancies, but it is almost always an embryonic lethal condition. See Meiosis, Mitosis, Polyploidy

Aneuploidy is a change in the number of chromosomes from the diploid (2n) number (usually found in the somatic cells of sexually reproducing organisms) or the haploid (n) number (usually found in germ cells and the haplophase of some unicellular organisms.) It usually involves a single chromosome, and any chromosome in the complement can be involved. Aneuploidy is the result of aberrant segregation of one or more chromosomes during meiosis or mitosis. If malsegregation or nondisjunction occurs during meiosis, one daughter cell receives two copies of the chromosome and the other daughter cell receives none. Fertilization of such an aneuploid germ cell by a euploid gamete will produce a zygote that has either three copies (trisomy) or one copy (monosomy) of the chromosome. Malsegregation of a chromosome can also take place during a mitotic division in a somatic cell, producing trisomic or monosomic cells in an otherwise euploid individual. This outcome is important primarily in the origin and progression of some forms of cancer.

The most common trisomy of autosomes (non-sex chromosomes) in human liveborns is trisomy 21, or Down syndrome, which is a major cause of mental retardation and congenital heart disease. Individuals with trisomy 18 and trisomy 13 also occur but are much less common. Most autosomal trisomies are lethal to embryos, leading to spontaneous abortion. The incidence of trisomy for any autosome increases exponentially with maternal age. See Chromosome, Down syndrome

In humans, there are more types of aneuploidy involving the sex chromosomes than the autosomes. The most common is XO, occurring in about 1% of pregnancies. Although 99% of XO fetuses die early in pregnancy, the other 1% (about 1 in 10,000 liveborn females) survive. Adults who are XO tend to be short, with some webbing of the neck. They rarely develop secondary sexual characteristics or have children because the germ cells essential for ovarian development are usually absent. These features are characteristic of Turner syndrome. Trisomy for the human X chromosome, commonly called XXX, is not associated with embryonic death or congenital malformations. The reason is that in all mammals only a single X chromosome is active in each somatic cell. See Human genetics

In contrast to autosomal trisomy, sex chromosome aneuploidy increases only slightly with maternal age, and the extra X chromosome comes from the mother in only about 60% of the cases. An additional X chromosome can be present in either egg or sperm; additional Y chromosomes can be present only in sperm. The XXX and XXY individuals display minimal phenotypic manifestations of their increased number of chromosomes. Individuals who are XYY generally are indistinguishable from XY individuals. The presence of a Y chromosome leads to male sex differentiation no matter how many X chromosomes are present, because of the presence of a single, critical gene, called SRY, on the Y chromosome. A mutation of this gene has been found in some XY individuals who developed as females.

Structural abnormalities

Structural abnormalities (chromosome mutations) involve the gain, loss, or rearrangement of chromosome segments after the continuity of the deoxyribonucleic acid (DNA) strand in one or more chromosomes is disrupted. A deletion involves the loss of a chromosome segment and the genes it carries. A terminal deletion involves the loss of a segment extending from the point of disruption (breakpoint) to the end of the same arm of a chromosome, and it is relatively uncommon. An interstitial deletion involves the loss of the segment between two breakpoints in one arm of a chromosome. The effect of such a loss depends on the genes that are included in the missing segment.

When one break occurs in each arm of a chromosome, the broken ends of the internal centromeric fragment may join, resulting in the formation of a stable ring chromosome. Each of the two end segments lacks a centromere, and such acentric fragments are lost during cell division. Ring chromosomes are subject to reduction in size, as well as doubling. An individual who has a ring chromosome may thus show phenotypic effects not only of deletion but of duplication of part of the chromosome. A duplication more commonly occurs in other ways. For example, a chromosome segment can undergo tandem or inverted duplication at the usual chromosome site, or the second copy of the segment may be carried on another chromosome.

An inversion is generated by disrupting the DNA strand in a chromosome at two breakpoints and rejoining the broken ends with the interstitial segment in the opposite orientation. This process will invert the order of the genes on the segment.

A translocation involves the interchange of one or more chromosome segments between two or more chromosomes. If a translocation breakpoint disrupts a gene, the gene's function will be blocked or abnormal, and such can have deleterious effects on development or function. Sometimes a normally silent gene is activated by a chromosome rearrangement that places it next to a strong promoter of gene expression, and this change is important as a cause of cancer. If a translocation does not block the function of an essential gene or activate a normally silent gene, the individual carrying the rearrangement will be normal.

Structural aberrations can occur spontaneously or be induced by agents that break chromosomes, such as x-rays, radioactive substances, ultraviolet rays, and certain chemicals. The most frequent cause may be the presence of enormous numbers of a few types of short interspersed elements (SINES), that is, DNA sequences that occur once every few thousand base pairs throughout the genome of most metazoans, including humans. These elements predispose to the occurrence of errors during DNA replication or genetic recombination at meiosis that can lead to the deletion or duplication of the region between two nearby interspersed repeats on one chromosome. They may also play a role in the formation of inversions and, possibly, translocations. See Gene amplification, Mutagens and carcinogens, Mutation

Another cause of structural aberrations is also inherent in the genome: the great abundance of short repeats of a 2-, 3-, or 4-base-pair unit. Some trinucleotide repeats, such as (CGG)_n or (CAG)_n, can undergo expansion during meiotic and mitotic cell divisions. This expansion sometimes affects gene function and leads to disease. The most common type of X-linked mental retardation in humans is the result of heritable expansions, in the FMR-1 gene, of a specific trinucleotide repeat, (CGG)_n, where the number of expansions (n) is increased from the normal 8–20 or so to 50–200 or more. For unknown reasons, this expanded region tends to undergo breakage under some conditions, and this particular form of mental retardation is called the fragile X syndrome. There are dozens, if not hundreds, of similar fragile sites in the human and other genomes.