ScienceWeek

GENOME BIOLOGY: ON THE Y CHROMOSOME

The following points are made by J.A. Graves (Science 2005 307:50):

1) The Y chromosome must be the strangest element of any genome. In mammals and insects where the mode of chromosomal sex determination is an XX female and XY male, the male-specific Y chromosome is usually small and, unlike ordinary chromosomes, contains numerous repetitive DNA sequences. The Y bears only a few active genes, many of which encode proteins that determine male sex or are involved in reproduction. Comparisons between different species indicate that Y chromosomes degrade rapidly and can even disappear. What happens then?

2) Fruit flies are model insects that have proved valuable for studying evolutionary changes in sex chromosomes. The original Y chromosome of Drosophila species apparently disappeared more than 60 million years ago, and was replaced by a usurper -- a blob of repetitive DNA that learned how to pair with the X, and scrounged useful genes from other chromosomes. This "ancestral" Y is shared by species in both major Drosophila subgroups. But that is far from the end of the story. Now it appears that in one group of drosophilids, this ancestral Y has itself been retired, and has been recycled by hitching a ride on a non-sex chromosome (autosome).

3) Carvalho and Clark [1] have revealed that the Y chromosome of D. pseudoobscura -- the second of many Drosophila species to have its genome sequenced -- is unrelated to the ancestral Y. Taking advantage of the outpouring of D. pseudoobscura genome data, these investigators tracked down the genes from the ancestral Y of this drosophilid species, and found them leading a blameless existence in ordinary chromosome pairs. Meanwhile, D. pseudoobscura sports a new Y, created from an autosome that at some point became fused to the X in this group of flies.

4) Studies of the Y chromosome in many taxa have implied that Y degradation is a one-way street. X and Y chromosomes are thought to have evolved from an ordinary pair of autosomes when one member of the pair acquired a male-determining locus [2]. Other male-advantage alleles accumulated at this site on the proto-Y, and the male-specific package was preserved by preventing recombination between the X and Y during meiosis. All sorts of dreadful genetic accidents -- mutations, deletions, invasion by repetitive elements -- occurred in this region of low recombination, progressively degrading the Y into a wasteland of discarded and defunct sequences, and sparing only those genes that acquired a selectable male-specific function. In addition, the Y appropriated some handy genes from autosomes that already had, or later acquired, a male-specific function.[2-5]

References (abridged):

1. A. B. Carvalho, A. G., Clark, Science 307, 108 (2005)

2. B. Charlesworth, D. Charlesworth, Philos. Trans. R. Soc. London B Biol. Sci. 355, 1563 (2000)

3. H. Skaletsky et al., Nature 423, 825 (2003)

4. J. A. M. Graves, Trends Genet. 18, 259 (2002)

5. W. Just et al., Nature Genet. 11, 17 (1995)

Science http://www.sciencemag.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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EVOLUTIONARY BIOLOGY: ON CHROMOSOMES AND SEX DETERMINATION

The following points are made by Brian Charlesworth (Current Biology 2004 14:R745):

1) Determination of sexual identity by genes associated with highly differentiated sex chromosomes is often assumed to be the norm, given our familiarity with the X and Y chromosomes of mammals and model organisms such as Drosophila. Even within tetrapod vertebrates, however, there is a wide diversity of sex determination mechanisms, with many examples of species with genetic sex determination but microscopically similar X and Y chromosomes, and numerous cases of environmental sex determination [1]. There is an even wider range of sexual systems in teleost fishes, with examples of self-fertilizing hermaphrodites [2], sequential hermaphrodites [3], and environmental sex determination [1].

2) Even where sex is genetically determined, the mechanisms vary enormously, with clearly distinguishable sex chromosomes being very rare [1,4]. It is easiest to see the footprints of the evolutionary forces that drive the evolution of sex chromosomes in cases where the divergence of X and Y chromosomes has not reached its limit, with no genetic recombination between X and Y chromosomes over most of their length and a lack of functional genes on the Y chromosome [5]. The comparative genetics of sex determination systems in fish species may thus yield important insights into the evolution of sex chromosomes.

3) Despite pioneering classical genetic studies of sex determination in fish such as the medaka, the guppy, and the platyfish [1], it has been difficult to obtain detailed genetic information on sex chromosome organisation in these species. With modern genomic methods, however, it is now feasible, but laborious, to characterize the sex determining regions of fish genomes. Studies of chromosomal regions that determine male development in two unrelated groups of fish species show the promise of this approach.

References (abridged):

1. Bull, J.J. (1983). Evolution of Sex Determining Mechanisms. (Menlo Park, CA: Benjamin Cummings)

2. Weibel, A.C., Dowling, T.E. and Turner, B.J. (1999). Evidence that an outcrossing population is a derived lineage in a hermaphroditic fish (Rivulus marmoratus). Evolution 53, 1217-1225

3. Charnov, E.L. (1982). The Theory of Sex Allocation. (Princeton, NJ: Princeton University Press)

4. Volff, J.-N. and Schartl, M. (2001). Variability of sex determination in poeciliid fishes. Genetica 111, 101-110

5. Charlesworth, B. and Charlesworth, D. (2000). The degeneration of Y chromosomes. Phil. Trans. Roy. Soc. Lond. B. 355, 1563-1572

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