One in 900

One in I

Older mothers are more likely to give birth to a child with Down syndrome.

One in 900

30 40 50

Maternal age

9.23 The incidence of primary Down syndrome increases with maternal age.

not normally recombine, most notably near the centromere. Although aberrant recombination appears to play a role in nondisjunction, the maternal age effect is more complex. In female mammals, prophase I begins in all oogonia during fetal development, and recombination is completed prior to birth. Meisosis then arrests in diplotene, and the primary oocytes remain suspended until just before ovulation. As each primary oocyte is ovulated, meiosis resumes and the first division is completed, producing a secondary oocyte. At this point, meiosis is suspended again, and remains so until the secondary oocyte is penetrated by a sperm. The second meiotic division takes place immediately before the nuclei of egg and sperm unite to form a zygote.

An explanation of the maternal age effect must take into account the aberrant recombination that occurs prena-tally and the long suspension in prophase I. One theory is that the "best" oocytes are ovulated first, leaving those oocytes that had aberrant recombination to be used later in life. However, evidence indicates that the frequency of aberrant recombination is similar between oocytes that are ovu-lated in young women and those ovulated in older women. Another possible explanation is that aging of the cellular components needed for meiosis results in nondisjunction of chromosomes that are "at risk," because they have failed to recombine or had some recombination defect. In younger oocytes, these chromosomes can still be segregated from one another, but in older oocytes, they are sensitive to other perturbations in the meiotic machinery. In contrast, sperm are produced continually after puberty, with no long suspension of the meiotic divisions. This fundamental difference between the meiotic process in females and males may explain why most chromosome aneuploidy in humans is maternal in origin.

About 4% of people with Down syndrome have 46 chromosomes, but an extra copy of part of chromosome 21 is attached to another chromosome through a translocation (FIGURE 9.24). This condition is termed familial Down syndrome because it has a tendency to run in families. The phenotypic characteristics of familial Down syndrome are the same as those for primary Down syndrome.

Familial Down syndrome arises in offspring whose parents are carriers of chromosomes that have undergone a Robertsonian translocation, most commonly between chromosome 21 and chromosome 14: the long arm of 21 and the short arm of 14 exchange places. This exchange produces a chromosome that includes the long arms of chromosomes 14 and 21, and a very small chromosome that consists of the short arms of chromosomes 21 and 14. The small chromosome is generally lost after several cell divisions.

Persons with the translocation, called translocation carriers, do not have Down syndrome. Although they possess only 45 chromosomes, their phenotypes are normal because they have two copies of the long arms of chromosomes 14 and 21, and apparently the short arms of these chromosomes (which are lost) carry no essential genetic information. Although translocation carriers are completely healthy, they have an increased chance of producing children with Down syndrome.

When a translocation carrier produces gametes, the translocation chromosome may segregate in three different

9.24 The translocation of chromosome 21 onto another chromosome results in familial Down syndrome. (Dr. Dorothy Warburton, HICC, Columbia University).

I 9.25 Translocation carriers are at increased risk for producing children with Down syndrome.

ways. First, it may separate from the normal chromosomes 14 and 21 in anaphase I of meiosis ( FIGURE 9.25a). In this type of segregation, half of the gametes will have the translocation chromosome and no other copies of chromosomes 21 and 14; the fusion of such a gamete with a normal gamete will give rise to a translocation carrier. The other half of the gametes produced by this first type of segregation will be normal, each with a single copy of chromosomes 21 and 14, and will result in normal offspring.

Alternatively, the translocation chromosome may separate from chromosome 14 and pass into the same cell with the normal chromosome 21 ( FIGURE 9.25b). This type of segregation produces all abnormal gametes; half will have two functional copies of chromosome 21 (one normal and one attached to chromosome 14) and the other half will lack chromosome 21. The gametes with the two functional copies of chromosome 21 will produce children with familial Down syndrome; the gametes lacking chromosome 21 will result in zygotes with monosomy 21 and will be spontaneously aborted.

In the third type of segregation, the translocation chromosome and the normal copy of chromosome 14 segregate together, and the normal chromosome 21 segregates by itself (< Figure 9.25c). This pattern is presumably rare, because the two centromeres are both derived from chromosome 14 separately from each other. In any case, all the gametes produced by this process are abnormal: half result in monosomy 14 and the other half result in trisomy 14 — all are spontaneously aborted. Thus, only three of the six types of gametes that can be produced by a translocation carrier will result in the birth of a baby and, theoretically, these gametes should arise with equal frequency. One-third of the offspring of a translocation carrier should be translocation carriers like their parent, one-third should have familial Down syndrome, and one-third should be normal. In reality, however, fewer than one-third of the children born to translocation carriers have Down syndrome, which suggests that some of the embryos with Down syndrome are spontaneously aborted. Additional information on Down syndrome

Few autosomal aneuploids besides trisomy 21 result in human live births. Trisomy 18, also known as Edward syndrome, arises with a frequency of approximately 1 in 8000 live births. Babies with Edward syndrome are severely retarded and have low-set ears, a short neck, deformed feet, clenched fingers, heart problems, and other disabilities. Few live for more than a year after birth. Trisomy 13 has a frequency of about 1 in 15,000 live births and produces features that are collectively known as Patau syndrome. Characteristics of this condition include severe mental retardation, a small head, sloping forehead, small eyes, cleft lip and palate, extra fingers and toes, and numerous other problems. About half of children with trisomy 13 die within the first month of life, and 95% die by the age of 3. Rarer still is trisomy 8, which arises with a frequency of about 1 in 25,000 to 50,000 live births. This aneuploid is characterized by mental retardation, contracted fingers and toes, low-set malformed ears, and a prominent forehead. Many who have this condition have normal life expectancy. Additional information on trisomy 13 and trisomy 18

Uniparental Disomy

Normally, the two chromosomes of a homologous pair are inherited from different parents — one from the father and one from the mother. The development of molecular techniques that facilitate the identification of specific DNA sequences (see Chapter 18), has made it possible to determine the parental origins of chromosomes. Surprisingly, sometimes both chromosomes are inherited from the same parent, a condition termed uniparental disomy.

Uniparental disomy violates the rule that children affected with a recessive disorder appear only in families where both parents are carriers. For example, cystic fibrosis is an autosomal recessive disease; typically, both parents of an affected child are heterozygous for the cystic fibrosis mutation on chromosome 7. However, a small proportion of people with cystic fibrosis have only a single parent who is heterozygous for the cystic fibrosis gene. How can this be? These people must have inherited from the heterozygous parent two copies of the chromosome 7 that carries the defective cystic fibrosis allele and no copy of the normal allele from the other parent. Uniparental disomy has also been observed in Prader-Willi syndrome, a rare condition that arises when a paternal copy of a gene on chromosome 15 is missing. Although most cases of Prader-Willi syndrome result from a chromosome deletion that removes the paternal copy of the gene (see p. 000 in Chapter 4), from 20% to 30% arise when both copies of chromosome 15 are inherited from the mother and no copy is inherited from the father.

Many cases of uniparental disomy probably originate as a trisomy. Although most autosomal trisomies are lethal, a trisomic embryo can survive if one of the three chromosomes is lost early in development. If, just by chance, the two remaining chromosomes are both from the same parent, uniparental disomy results. More on uniparental disomy or links to information on Prader-Willi syndrome


Nondisjunction in a mitotic division may generate patches of cells in which every cell has a chromosome abnormality and other patches in which every cell has a normal karyotype. This type of nondisjunction leads to regions of tissue with different chromosome constitutions, a condition known as mosaicism. Growing evidence suggests that mosaicism is relatively common.

Only about 50% of those diagnosed with Turner syndrome have the 45,X karyotype (presence of a single X chromosome) in all their cells; most others are mosaics, possessing some 45,X cells and some normal 46,XX cells. A few may even be mosaics for two or more types of abnormal karyotypes. The 45,X/46,XX mosaic usually arises when an X chromosome is lost soon after fertilization in an XX embryo.

Fruit flies that are XX/XO mosaics (O designates the absence of a homologous chromosome; XO means the cell has a single X chromosome and no Y chromosome) develop a mixture of male and female traits, because the presence of two X chromosomes in fruit flies produces female traits and the presence of a single X chromosome produces male traits (I FIGURE 9.26). Sex determination in fruit flies occurs

2 phenotype (Jphenotype (XX) (XO)

2 phenotype (Jphenotype (XX) (XO)

wing wing

9.26 Mosaicism for the sex chromosomes produces a gynandromorph. This XX/XO gynandromorph fruit fly carries one wild-type X chromosome and one X chromosome with recessive alleles for white eyes and miniature wings. The left side of the fly has a normal female phenotype, because the cells are XX and the recessive alleles on one X chromosome are masked by the presence of wild-type alleles on the other. The right side of the fly has a male phenotype with white eyes and miniature wing, because the cells are missing the wild-type X chromosome (are XO), allowing the white and miniature alleles to be expressed.


In humans, sex-chromosome aneuploids are more common than are autosomal aneuploids. X-chromosome inactivation prevents problems of gene dosage for X-linked genes. Down syndrome results from three functional copies of chromosome 21, either through trisomy (primary Down syndrome) or a Robertsonian translocation (familial Down syndrome).

independently in each cell during development. Those cells that are XX express female traits; those that are XY express male traits. Such sexual mosaics are called gynandro-morphs. Normally, X-linked recessive genes are masked in heterozygous females but, in XX/XO mosaics, any X-linked recessive genes present in the cells with a single X chromosome will be expressed.

Concepts 9

In uniparental disomy, an individual has two copies of a chromosome from one parent and no copy from the other. It may arise when a trisomic embryo loses one of the triplicate chromosomes early in development. In mosaicism, different cells within the same individual have different chromosome constitutions.

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