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MEDICAL BIOLOGY: ON CHROMOSOME NONDISJUNCTION

The following points are made by N.E. Lamb and T.J. Hassold (New Engl. J. Med. 2004 351:1931):

1) Chromosome nondisjunction is a serious problem for the human species. The improper segregation of chromosomes during meiosis leads to chromosomally unbalanced eggs or sperm. If these gametes participate in fertilization, the outcome is an aneuploid embryo, with either trisomy (one chromosome too many) or monosomy (one chromosome too few). Since most such embryos are inviable, one might expect that these errors would be extremely rare. This is true for most organisms, but our own species is a notable exception: aneuploidy (an abnormal number of chromosomes) is identified in at least 5 percent of all clinically recognized pregnancies, making it the leading known cause of fetal loss. Furthermore, even though only a small proportion of aneuploid fetuses survive to term (primarily those with trisomy 13, 18, or 21 and those with various sex-chromosome abnormalities), aneuploidy is still the leading genetic cause of mental impairment and developmental disabilities. This "one-two" punch of pregnancy loss and developmental impairment has placed nondisjunction at the center of an intensive research effort.

2) Despite the obvious clinical importance of nondisjunction, the predisposing genetic and environmental factors remain a mystery. However, it is clear that almost all cases involve errors in meiosis, the complex process in which one round of DNA replication is followed by two cellular divisions to generate haploid gametes. The first cell division (meiosis I) separates homologous chromosomes; the second (meiosis II) segregates the sister chromatids of each homologue. Nondisjunction can occur at either of these stages and can generally be distinguished with the use of polymorphic genetic markers at or near the centromere of the nondisjoined chromosomes. If both copies of the nondisjoined chromosomes are heterozygous for alleles at these markers, it is likely that the error arose at meiosis I. In contrast, homozygosity at the centromere suggests an error at meiosis II.

3) During the past decade, more than 1000 trisomic or monosomic conceptions have been studied to determine the parental origin and meiotic stage of the nondisjunction error.[1] Since monosomy almost always results in the loss of the embryo at an early stage, most of the available data derive from cases of trisomy. The largest data set involves trisomy 21, the condition that is responsible for Down's syndrome. Taken together, these studies indicate remarkable chromosome-to-chromosome variation in nondisjunction, but there is also one unifying and inescapable fact: regardless of the chromosome involved, most cases of human trisomy originate from errors in maternal meiosis I. Given the biology of the human egg, this is not entirely unexpected: the first stage of female meiosis is initiated in the fetal ovary and is followed by a long "arrest" phase that lasts until the time of ovulation. Thus, the first meiotic division is amazingly protracted, taking at least 10 to 15 years and as many as 45 to 50 years to complete.

4) Although the association between maternal age and trisomy has long been recognized, other predisposing factors have been elusive. However, studies conducted during the past few years have identified the first molecular correlate of nondisjunction, aberrant meiotic recombination. Recombination is familiar to most of us as the process that "shuffles" genetic material during the meiotic prophase, but it plays another equally crucial role: recombinational exchanges lock the homologues together in proper register and thereby facilitate proper segregation at meiosis I. In model organisms (e.g., flies and yeast), it has long been recognized that the absence or reduced numbers of exchanges increase the likelihood of nondisjunction.[2]

References:

1. Hassold T, Hunt P. To err (meiotically) is human: the genesis of human aneuploidy. Nat Rev Genet 2001;2:280-291

2. Lamb NE, Feingold E, Savage A, et al. Characterization of susceptible chiasma configurations that increase the risk for maternal nondisjunction of chromosome 21. Hum Mol Genet 1997;6:1391-1399

New Engl. J. Med. http://www.nejm.org

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MEDICAL BIOLOGY: ON DISORDERS OF EXTRA SEX CHROMOSOMES

The following points are made by Aubrey Milunsky (citation below):

1) As one might expect, the addition of an extra female chromosome to a male has a feminizing effect. The presence of two X chromosomes (along with one Y chromosome) instead of one X in every cell of a male results in a condition called "Klinefelter syndrome". Between 1 in 500 and 1 in 1000 males are born with this disorder every year in the US (a total of at least 4000 per year). Based on the number of live male births recorded, we can estimate that there are more than 150,000 males in the country today with this condition. Most of them probably have not yet been diagnosed: This syndrome is most commonly diagnosed at or after puberty -- when it is most easily detected. The characteristics that may be observable in childhood include tall stature; speech, language, and learning disorders; a tendency to score lower on IQ tests; and personality and behavioral problems.

2) In adulthood, males with Klinefelter syndrome are often remarkably indolent about their own care and future, and are prone to alcoholism and antisocial behavior. Breast development, which normally becomes obvious at puberty, is very pronounced in about 15 percent of cases and causes extreme embarrassment. In many cases, surgical correction by mastectomy is obtained. The male hormone testosterone (by skin patch) has been used in some cases to deepen the voice, stimulate the growth of facial hair, and improve libido (sexual drive), bone density, and overall self-esteem. Generally, men affected by this syndrome tend to be reticent, passive, and low-key. Mental illnesses, both neuroses and psychoses, are more common among them, as are periods of depression and of mania. Other common disorders also appear somewhat more frequently in men with this syndrome. Sexual behavior is normal and homosexuality is not a consequence, but the libido tends to be depressed. Breast cancer is at least 20 times more common among men with this disorder (a Swedish study has indicated that it is 50 times more common), accounting for some 4 percent of breast cancers in men. Their life expectancy appears to be somewhat shorter than that of the general population. Stroke, brain hemorrhage, lung infection, disease of the aortic heart valve, and cancer of the breast account almost entirely for their increased mortality rate.

3) Characteristically, the testicles of males with Klinefelter syndrome are smaller than normal, and no sperm are found in the semen. Fertilization is almost never achieved without medical intervention. A few instances of successful pregnancy have been reported following aspiration of a single sperm through a needle introduced directly into the testis, which is subsequently used to fertilize an egg (this procedure is called intracytoplasmic sperm injection). The potential hazard in these rare cases is that the recovered sperm may have two sex chromosomes instead of one. In such a case, an offspring could be born with either three X (female) chromosomes or with Klinefelter syndrome.

4) Men born with a mixture of XXY and normal XY cells are described as "mosaic for Klinefelter syndrome". They may be extremely difficult to diagnose and their condition may not come to light until they have a child who is diagnosed with a sex chromosome disorder.

5) Men with one female and two male sex chromosomes (XYY) in every cell are usually tall, have a tendency to acne, are likely to have lower IQs than their siblings, and in many cases have speech, language, or learning disorders, although their recorded IQ scores range from a low of 70 to a high of 145. XYY males tend to be impulsive, react poorly to frustration and adverse circumstances, and exhibit wild tempers. They are not, however, more violent or aggressive than other males, and their sexual behavior is not abnormal. Antisocial behavior in XYY males with a lower IQ and emotional lability lands this group in trouble with the police at least ten times more often than males with normal chromosomes.

6) Boys with XYY chromosomes often go undetected: About 1 in 1000 males born have the XYY complement, and most are never diagnosed. Many diagnosed XYY males retrospectively describe themselves as children with extremely defiant natures, destructiveness, terrible tempers, and inclinations to climb to dangerous places -- all evident by the age of four years. However, many boys with normal chromosomes also exhibit some of these features. Later in childhood, speech, language, and learning difficulties as well as behavioral problems tended to hamper their educational achievement. Nevertheless, a majority of XYY males have perfectly normal IQs, and at least one has been reported with a genius-level IQ of 145.

7) XYY males are fertile. Their sperm, however, may contain one X, only one Y, an X and a Y, or two Y chromosomes. Consequently, when one of their sperm fertilizes a normal ovum containing one X chromosome, the product may be a normal boy, a normal girl, an XYY male, or a male with Klinefelter syndrome (XXY).

8) No diagnostic physical features characterize the triple X female. Minor variations occurring more frequently (and not affecting health) include a relatively small head in relation to height, incurved fifth fingers and toes, low-set ears, and poor coordination. About 1 in 1200 females are born with this disorder, but most have never been diagnosed. In childhood this disorder might be detected only as part of an evaluation for disorders of speech, language, and learning. Although mental retardation is not a primary feature, the average IQ is about 85 (with a range of 64-120). The majority require special education classes. In adulthood, mental illness (psychosis or schizoid personality) appears to occur more frequently. As a group, triple X females tend to be passive and immature, have difficulty in forming interpersonal relationships, and frequently have psychological problems. There also appears to be a somewhat higher frequency of epilepsy among them.

9) Menstrual difficulties are relatively common and include late onset of periods, scanty or skipped periods, infertility or sterility, and early onset of menopause. Triple X women have a normal sex life and may bear male or female offspring, who may be born with an extra X chromosome.

10) Rarely, persons are born with four or five X chromosomes or three or even four Y chromosomes. Severe or profound mental retardation can be expected when these additional X or Y chromosomes are present.

Adapted from: Aubrey Milunsky: Your Genetic Destiny. Perseus Publishing 2001, p.37.

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CELL BIOLOGY: ON THE BINDING OF CHROMOSOMES

The following points are made by Robin Allshire (Nature 2004 427:495):

1) It is estimated that approximately 20% of human eggs have an abnormal number of chromosomes, and it is well known that the incidence of fetuses with three copies of some chromosomes --rather than the usual two -- increases markedly with the age of the mother(1,2). The fact that human eggs can arrest in the early stages of their creation for up to 45 years is clearly a factor. For this entire period, to prevent abnormal chromosome numbers, the two copies of a duplicated chromosome ("sister chromatids") need to remain tethered to each other, and the chromosome needs to be connected to its opposite number, until they are told to separate.

2) There are two ways in which cells can multiply: mitosis and meiosis. Mitosis occurs in all the body's tissues, and generates more-or-less identical daughter cells; it serves the purpose of, for example, replacing cells lost through general wear and tear. Meiosis occurs only in reproductive tissue and generates reproductive cells.

3) The starting point for both mitosis and meiosis is a cell with two copies (homologues) of each chromosome, one from the mother and one from the father. These chromosomes are duplicated, producing homologous pairs of sister chromatids. During mitosis, the two sister chromatids of each pair are pulled apart to opposite poles of the cell, and the cell splits into two. So each daughter cell again has two copies of each chromosome.

4) Meiosis, by contrast, is divided into two stages. In meiosis I, the two sister chromatids of a pair are held together, and the maternal pair is separated from the paternal pair. In meiosis II, the sister chromatids are finally separated. The result is four cells, each with half the usual number of chromosomes. The cell's genetic complement is restored when it meets a complementary reproductive cell.

5) During the early stages of meiosis I, the homologous pairs of sister chromatids are held together along their arms; the two sister chromatids of a pair are also glued together at specialized regions called "centromeres". This bonding is achieved in part by cohesin, a complex of cohesive proteins. It is well established that cohesion along the arms must be different from cohesion at centromeres, because later in meiosis I (at the onset of so-called "anaphase I"), arm cohesion is released but centromere cohesion remains intact, allowing homologous pairs to travel to opposite poles(4,5). Whatever is responsible for this difference must be lost by anaphase II of meiosis II, when sister chromatids, in turn, separate(1,4)

References (abridged):

1. Hassold, T. & Hunt, P. Nature Rev. Genet. 2, 280 291 (2001)

2. Champion, M. & Hawley, R. S. Nature Cell Biol. 4 (Suppl.), s50 s60 (2002)

3. Kitajima, T. S., Kawashima, S. A. & Watanabe, Y. Nature 427, 510 517 (2004)

4. Rieder, C. L. & Cole, R. J. Cell. Sci. 112, 2607 2613 (1999)

5. Petroncki, M., Siomos, M. F. & Nasmyth, K. Cell 112, 423 440 (2003)

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