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ScienceWeek
DEVELOPMENTAL BIOLOGY: ON INACTIVATION OF THE X CHROMOSOME
The following points are made by W. Reik and A.C. Ferguson-Smith (Nature 2005 438:297):
1) In most mammals, males have the male sex-determining Y chromosome and a single X chromosome, whereas females have two X chromosomes. In females, the resulting imbalance in the "dosage" of genes on the X chromosomes needs to be compensated so that gene expression from the X chromosome is equivalent in males and females. Mammals have evolved a unique form of dosage compensation, called X-chromosome inactivation, in which one of the two X chromosomes in female cells is silenced epigenetically[1] -- that is, by factors such as chemical modification of the DNA, or of the histone proteins that package DNA into chromosomes, often involving non-coding RNAs. Many aspects of mammalian X inactivation remain mysterious. But through elegant studies in the mouse, new work[2] has unravelled some of the earliest events in the process.
2) During early development of female mouse embryos, and in extra-embryonic tissues such as the placenta, it is always the X chromosome derived from the father that is inactivated[3]. Gene expression from only one parental member of a chromosome pair is known as "imprinting", and is caused by an epigenetic memory first arising in the egg or the sperm. Later on, in the embryonic tissues, X inactivation is random with respect to the parental origin of the X chromosomes[4].
3) There is considerable interest in understanding the mechanisms that specifically silence the paternal X chromosome in early development, and the extent to which the history of that chromosome is involved. During male meiosis, in which sperm are produced, a process known as meiotic sex chromosome inactivation (MSCI) occurs. In developing male sperm, the sex chromosomes form a unique structure, the XY body; MSCI occurs here and leads to repression of the transcription of X- (as well as Y-) linked genes[5]. This meiotic inactivation uniquely affects the sex chromosomes and may be associated with the inability of the X and Y chromosomes to pair during male meiosis[5].
4) One proposal is that when an egg is fertilized the X chromosome from the father's sperm arrives in a "pre-inactivated" state, which is a continuation of MSCI, and which persists during the period before the early embryo implants in the uterus. Okamoto et al[2], however, now show that genes on the paternal X chromosome are transcriptionally active at the very earliest embryonic stages, and that subsequent inactivation of the paternal X can occur without prior MSCI. This work shows that the two processes (MSCI and de novo paternal X inactivation after fertilization) can be mechanistically separated, and it confirms that there is a period after fertilization when the paternal X chromosome is transcriptionally active.
References (abridged):
1. Lyon, M. Nature 190, 372-373 (1961)
2. Okamoto, I. et al. Nature 438, 369-373 (2005)
3. Takagi, N. & Sasaki, M. Nature 256, 640-642 (1975)
4. Lucchesi, J. , Kelly, W. & Panning, B. Annu. Rev. Genet. PMID:16120055 24 August (2005)
5. Turner, J. et al. Curr. Biol. 14, 2135-2142 (2004)
Nature http://www.nature.com/nature
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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. More information at: http://www.amazon.com/exec/obidos/ASIN/0738203777/scienceweek
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ON EVOLUTION AND SEXUAL REPRODUCTION
The following points are made by Richard E. Lenski (Science 2001 294:533):
1) Why have some organisms evolved the capacity for sexual reproduction, whereas others make do with reproducing asexually? Since the time of August F. Weismann (1834-1914), most biologists have been taught that sex produces variation and thereby promotes evolutionary adaptation. But how does sex achieve this effect, and under what circumstances is it worthwhile?
2) The traditional explanation for sex is that it accelerates adaptation by allowing two or more beneficial mutations that have appeared in different individuals to recombine within the same individual. Without sexual recombination, individual clones that possess different beneficial mutations compete with one another, slowing adaptation by clonal interference. Sex, according to the traditional explanation, allows simultaneous improvements at several genetic loci, whereas multiple adaptations must occur sequentially in clonal organisms.
3) The above explanation, however, has recently come into question. First, sex imposes a 50 percent reduction in reproductive output: If a female can produce viable offspring on her own, why dilute her genetic contribution to subsequent generations by mating with a male? Second, the circumstances under which this kind of model provides sufficient advantage to offset the cost of sex are restrictive, requiring certain forms of selection and environmental fluctuations. Third, alternative models propose that the advantage of sex lies in eliminating deleterious mutations rather than in combining beneficial mutations. Still another hypothesis, involves an interplay between deleterious and beneficial mutations. Finally, empirical tests of these hypotheses have so far failed to produce a clear winner, so the field is ripe for significant experiments.
Science http://www.sciencemag.org
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EVOLUTIONARY BIOLOGY: EVOLUTION OF PLANT SEX CHROMOSOMES
The following points are made by Deborah Charlesworth (Current Biology 2004 14:R271):
1) Plant sex chromosomes are particularly interesting because they evolved much more recently than those of mammals or Drosophila -- most plants with separate sexes seem to have evolved recently from ancestors with both sex functions [1,2]. Plant sex chromosomes may thus tell us about the initial stages of the evolutionary process that has led to the massive gene loss that has occurred in Y chromosomes.
2) The sex determination system of papaya (Carica papaya) has been studied genetically since 1938, when it was established that an apparently single locus determines the male, female or hermaphrodite state. As in many familiar animal systems, including Drosophila and mammals, female papaya are the homozygous sex, while males and hermaphrodites are heterozygotes. In most dioecious plants -- those with separate sexes, rather than hermaphroditism -- males are also the heterozygous sex [1].
3) Many animals and most dioecious plant species, such as Silene latifolia, have a visibly distinctive X/Y sex chromosome pair. The mammalian Y is smaller than the X, whereas the S. latifolia Y chromosome is larger than its X. Many dioecious plants, however, including papaya and kiwi fruit [3], have no such chromosome heteromorphism; in these species, the sex-determining genes seem to map to small regions of one normal-looking chromosome [3,4].
4) To understand the papaya sex determining region, a detailed map has now been made of the papaya chromosome (chromosome LG1) carrying the sex-determining genes [5]. At present, most of the markers used are "anonymous" DNA sequence variants, not in coding sequences, and detected by the "amplified fragment length polymorphism" (AFLP) approach. As expected for a chromosome carrying the sex-determining genes, LG1 includes markers that co-segregate perfectly with sex. The finding of many such markers --225 out of 342 LG1 markers -- indicates that the sex-determining genes are spread over an extensive region that could include many genes. Physical mapping of the non-recombining genome region (obtained by sequencing bacterial artificial chromosome (BAC) clones carrying sequences corresponding to some of the markers) allowed Liu et al.[5] to estimate that the region involved in sex determination in papaya extends over roughly 4.4 Mb, only about 10% of chromosome LG1.
References (abridged):
1. Westergaard, M. (1958). The mechanism of sex determination in dioecious plants. Adv. Genet. 9, 217-281
2. Charlesworth, B. and Charlesworth, D. (1978). A model for the evolution of dioecy and gynodioecy. Am. Nat. 112, 975-997
3. Harvey, C.F., Gill, C.P., Fraser, L.G., and McNeilage, M.A. (1997). Sex determination in Actinidia. 1. Sex-linked markers and progeny sex ratio in diploid A. chinensis. Sex. Plant Repro. 10, 149-154
4. Semerikov, V., Lagercrantz, U., Tsarouhas, V., Ronnberg-Wastljung, A., Alstrom-Rapaport, C., and Lascoux, M. (2002). Genetic mapping of sex-linked markers in Salix viminalis L. Heredity 91, 293-299
5. Liu, Z., Moore, P.H., Ma, H., Ackerman, C.M., Ragiba, M., Pearl, H.M., Kim, M.S., Charlton, J.W., Yu, Q., and Stiles, J.I. et al. (2004). A primitive Y chromosome in Papaya marks the beginning of sex chromosome evolution. Nature 427, 348-352
Current Biology http://www.current-biology.com
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