II. Variations in ploidy.

III. Autosomal aneuploidy.

IV. Sex chromosome aneuploidy

Terms

Errata Page 143, definition of polyploidy: Should be "a chromosome complement that consists of three or more haploid chromosome sets." Page 149, paragraph 4, and page 164, Item 1: Relaxed selection has been ruled out as a cause of the maternal age effect.

I. Analysis of chromosomes is an important diagnostic procedure in medicine, including prenatal diagnosis.

A. The development of fluorescent molecular probes has made it possible to stain specific chromosomes or specific regions of chromosomes. This allows recognition of chromosome variations that were difficult or impossible to detect by older methods.
1. For most purposes, probes are chosen that bind to DNA at a single position on one of the 24 chromosomes. The procedure is known as fluorescent in situ hybridization or FISH.

2. Mixtures of probes can be designed that will bind the entire length of a chromosome or a large segment of a chromosome. When used in this way, the procedure is often called chromosome painting.

B. Karyotype analysis can be applied to any cell in which metaphase figures can be observed. It is often used in prenatal diagnosis.
1. Amniocentesis is the procedure for obtaining amniotic fluid. It can be done only after about 14 weeks gestation, ideally at 16 weeks. The fluid and cells can be used for various tests, including culturing and karyotyping of the cells. The procedure has been used for this purpose a number of years and has very low risk to the fetus.

2. Chorionic villi are projections from the chorion that are present during early pregnancy. Since they are derived from the zygote, genetic testing can be done. Chorionic villus biopsy can be carried out beginning about the 8th week of gestation. There is some risk to the fetus, although it is low.

3. Cells in the amniotic fluid are derived from the embryo, whereas cells from the chorion, although derived from the same zygote, may differ from the embryo if chromosome accidents have occured post zygotically. Therefore, erroneous results may occasionally be obtained from chorionic villus biopsy.

A. Polyploidy arises by two common mechanisms:
1. Dispermy, in which an ovum is fertilized by two sperm to yield a triploid zygote. This is the most common cause of triploidy and occurs in ca. 1% of conceptions (7% of spontaneous abortions).

2. Endoreduplication, in which cell division fails to occur after chromosome replication, producing a diploid gamete and leading to triploidy, or, if it occurs in mitotic divisions, producing tetraploidy. These are examples of polyploidy.

B. Cells that have a multiple of the haploid set of chromosomes are euploid.

A. Nondisjunction is the primary cause of aneuploidy, either in meiosis or mitosis.
1. Nondisjunction at meiosis I produces 4 abnormal gametes: 2 nullisomic and 2 disomic. The two disomic gametes have chromosomes that are homologs but of different grandparental origin.

2. Nondisjunction at meiosis II produces 2 normal and 2 abnormal gametes: 1 nullisomic and 1 disomic. The disomic gamete has chromosomes from the same grandparental origin.

3. Nondisjunction in mitosis in an early embryonic cell produces two cell lines [45(n – 1) and 47(n + 1). The monosomic cell usually does not survive, leaving the trisomic cell as the survivor of the nondisjunction event. There may also be euploid descendents of the original zygote. When two or more cell types are present in an individual, that person is said to be mosaic.

B. Monosomy is the situation in which only one of a pair of homologous chromosomes is present. Monosomy of any of the autosomes is lethal before recognition of conception, as is 45,Y. The only viable monosomy is 45,X, and most of those are aborted spontaneously.

C. Trisomy is the situation in which a chromosome is present three times rather than the normal two.

1. Most trisomies arise from nondisjunction in meiosis I in the mother.

2. Only three autosomal trisomies survive to the stage of live birth: trisomies 13, 18, and 21. Both tri-13 and tri-18 are lethal in the neonatal period. Several others, including trisomy 8, can survive as mosaics.

3. Ca. 95% of children with Down syndrome have simple trisomy 21. They have good viability if they survive to birth, although a majority are aborted spontaneously. Of those who are liveborn, nondisjunction occurs as follows: 73% in maternal MI, 18% in maternal MII, 2% in paternal MI, 3% in paternal MII, and 5% in early embryonic mitosis.

4. The risk of nondisjunction increases dramatically with maternal age, most sharply for trisomy 21 but also for other trisomies. In trisomy 21, the maternal age effect is seen only when nondisjunction occurs in the mother, either MI or MII. The cause is not known with certainty. It is not relaxed maternal selection as suggested in the textbook.

A. An exception is a YO embryo, which is nullisomic for the X chromosome and which therefore cannot carry out any of the functions coded on the X chromosome. YO embryos do not implant in the uterus.

B. In Turner syndrome (45,X), most cases arise by nondisjunction or chromosome loss in early mitotic divisions of the embryo. Most who survive to birth are mosaic: e.g. 45,X/46,XX; 45,X/46,XY; 45,X/46,XX/47,XXX. There is no maternal age effect. Affected persons are sex chromatin (Barr body) negative [See pp 189-190.].

C. In Klinefelter syndrome (47,XXY), there is a weak maternal age effect. Affected persons have normal or near-normal male phenotype, although they are tall. They may have some breast development, and they are sterile. They are sex-chromatin positive.

D. XYY syndrome (47,XYY) necessarily results from paternal nondisjunction. (Why?) Some appear to have increased tendencies for criminal aggression, but most lead normal lives, managing to avoid the police (except for maybe a few traffic and parking tickets). They are tall.

E. Triplo-X females (47,XXX) are essentially normal, though some have mild learning deficit, and they have normal fertility. They do not produce XXY and XXX offspring, as might be expected.

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