Errors of Meiosis

Meiosis is a mechanically complex process. Errors in chromosome segregation at either meiotic division are a major, well-characterised source of chromosomal abnormality in human conception. The specific mechanism of a segregation error, and the meiotic stage at which it occurs, directly explain the resulting chromosomal abnormality in the offspring.

Nondisjunction is the failure of paired chromosomes to separate correctly during cell division. Both members of a pair move together to the same daughter cell, rather than to opposite daughter cells as normally occurs.

Nondisjunction can occur at either meiotic division. The resulting genetic outcome differs depending on which division is affected.

Nondisjunction at meiosis I involves failure of a homologous chromosome pair to separate. Both the maternal and paternal homologues of that chromosome move together into the same secondary oocyte or secondary spermatocyte.

This produces gametes that are entirely abnormal in number for that chromosome: one gamete with two copies and one gamete with zero copies. The fundamental separation step for that chromosome pair failed completely.

Nondisjunction at meiosis II involves failure of sister chromatids to separate correctly. Both sister chromatids of an already-separated single chromosome move together into the same final gamete. This produces one gamete with two copies of that chromosome and one gamete with zero copies.

Two other, entirely normal gametes derive from the other secondary oocyte or spermatocyte produced at meiosis I, which was unaffected by the error. Meiosis II nondisjunction therefore affects only a subset of the final gametes produced from a given original primary germ cell. Meiosis I nondisjunction, by contrast, affects the entire subsequent lineage of gametes derived from that division.

Fertilisation of a gamete carrying an extra copy of a chromosome, produced by nondisjunction, results in a zygote with three copies of that chromosome (trisomy). Fertilisation of a gamete missing a chromosome entirely results in a zygote with only one copy (monosomy).

Anaphase lag is a distinct mechanism producing a similar downstream chromosomal outcome to nondisjunction, but via a different underlying error. The chromosome or chromatid does not fail to separate. It separates correctly from its homologue or sister chromatid, but then fails to be properly incorporated into the reforming nucleus of the daughter cell.

Typically the chromosome moves too slowly toward the spindle pole or is otherwise mechanically lost during the division. It is subsequently degraded.

Anaphase lag characteristically produces one daughter cell with the normal chromosome complement, since the lost chromosome was going to that cell's counterpart. The other daughter cell is missing that chromosome entirely (monosomy). Unlike nondisjunction, it does not produce a corresponding cell with an extra copy of the chromosome, since the chromosome was lost rather than misdirected to the other cell.

This distinction is one way anaphase lag can be distinguished mechanistically from nondisjunction when the resulting pattern of chromosomal abnormality is analysed.

Aneuploidy is the general term for a chromosome number that deviates from the normal diploid 46. It results from either nondisjunction or anaphase lag during gametogenesis, or, less commonly, from an equivalent error during an early postzygotic mitotic division.

It is an abnormal number of individual chromosomes that is not an exact multiple of the normal haploid set. This distinguishes it from polyploidy, in which an entire additional haploid chromosome set is present.

Trisomy is the presence of three copies of a specific chromosome, rather than the normal two. It arises when a gamete carrying two copies of that chromosome, produced by nondisjunction, is fertilised by a normal gamete carrying a single copy.

Much less commonly, a normal gamete is fertilised by a gamete carrying two copies of a chromosome due to an error originating on the other parental side.

Trisomy 21, Down syndrome, is the most common autosomal trisomy compatible with survival to birth. It most commonly results from meiosis I nondisjunction, occurring more frequently in the oocyte than in the spermatozoon. This pattern is consistent with the general association between advancing maternal age and increased risk of meiotic nondisjunction.

Trisomy of the sex chromosomes, for example an extra X or Y chromosome, is generally associated with a milder clinical phenotype than autosomal trisomy. This reflects the relative genetic tolerance of extra sex chromosome material compared to extra autosomal material.

Monosomy is the presence of only a single copy of a specific chromosome, rather than the normal two. It arises when a gamete missing that chromosome entirely, produced by nondisjunction or anaphase lag, is fertilised by a normal gamete.

Autosomal monosomy is, in the great majority of cases, incompatible with survival even to early stages of embryonic development. It is a major recognised cause of very early, often preclinical, pregnancy loss.

Monosomy of a sex chromosome is a notable exception to this general pattern of nonviability. Monosomy X (45,X, Turner syndrome) is compatible with live birth. It is also associated with a very high rate of early pregnancy loss. The great majority of 45,X conceptions do not survive to term, and those that do represent only a minority of all such conceptions that originally occur.