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SUBTELOMERIC BREAKAGE AND CHROMOSOME EXCHANGE
1449 tenderness is commonly associated with Australian snakebite envenomation. The above findings indicate that lymphopenia is commonly associated with Australia elapid snakebite by most species and is not necessarily associated with muscle necrosis. It is, however, not seen in all cases, even in the presence of severe envenomation, and therefore may not be a useful indicator of envenomation. The cause of the lymphopenia remains unexplained. It may be a stress response with acute relapse of cortisol causing a rise in total white-cell count and concomitant fall in lymphocytes, or possibly the venoms themselves may contain lymphotoxins. Neither of these possibilities seems to satisfactorily explain the prolonged lymphopenia seen in some of our patients. Alternatively, it may be that the snake venom, once inoculated, is transported via the lymphatics, and on reaching the draining lymph node its presence stimulates sequestration of circulating lymphocytes to the node and lymphatics, seeking to "match" available coded cell surface receptors to snake venom antigens and resulting in lymphopenia.
Fig 2-Spatial orientation of the chromosomes shown in fig 1 at first meiotic prophase, showing bouquet formed initially (a) and movement of paired telomeric regions to opposite sides of nuclear membrane (b). NM = nuclear membrane, C = centromeres, T = telomeres. pairing of homologous chromosome segments.
areas
Stippled
=
Haematology Department, Adelaide Medical Centre for Women and Children, North Adelaide, South Australia
JULIAN WHITE VAUGHAN WILLIAMS
Haemostasis and Thrombosis Laboratory, Institute of Medical and Veterinary Science,
BRUCE DUNCAN
Adelaide
Lymphopenia in the inflammatory response caused by Notechis II-5. Toxicon 1989; 27: 499-500. 2. Gaynor B. An unusual snake bite story. Med J Aust 1977; ii: 191-92. 3. Furtado MA, Lester IA. Myoglobinuria following snake bite Med J Aust 1968; i: 674-76. 1. Emslie-Smith AM, Harris JB.
SUBTELOMERIC BREAKAGE AND CHROMOSOME EXCHANGE
SIR,-Mr Lamb and colleagues (Oct 7, p 819) describe a family ascertained by a boy with a-thalassemia, some dysmorphic features, and mental retardation, and his sister who also proved to be mentally retarded. Their report reinforces the urgent need for molecular in situ hybridisation techniques to aid clinical cytogenetics screening by rapid and easy detection of reciprocal translocations, such as by telomeric colorimetric specificity. This technique is especially important because of Lamb and colleagues’ suggestion that subtelomeric reciprocal translocations, unresolvable by traditional cytogenetic analysis, may be a common cause for mental retardation. The frequency of translocations detectable by moderate chromosome banding in newborn babies is around 1 in 250 (ref 1 and Jacobs P, personal communication). Lamb et al point
that small unbalanced translocations with breakpoints near the ends of the chromosome may have an increased embryonic and fetal survival rate, whereas the larger ones, arising from breakage further away from the telomeres, may be more often lethal at an early stage of pregnancy. We agree with this notion, but we also advocate that subtelomeric chromosomal exchange per se may be more frequent than interstitial exchange. Thus subetelomeric exchange might be a common reason for mental retardation, perhaps even providing a background for some mental subnormality thought to be normal variation in intelligence. General meiotic recombination, requiring breakage and reunion, takes place more frequently in the subtelomeric 10% intervals of the chromosome arms than anywhere else along their length (fig 1). Most workers believe that any preferential location of general meiotic recombination results from some recombination signal such as DNA satellites2,3 or DNA configuration.4 We believe that subtelomeric translocations could be the result of specific mechanical stress at the first meiotic prophase, when homologous chromosomes are attached to the nuclear membrane. This attachment does not occur at random sites. Instead telomeres are associated with a small area of the nuclear envelope, the chromosomes forming a so-called bouquet (fig 2a). Pairing of homologous segments generally starts from the bundles of telomeres, but when fully paired the individual bivalent homologues are delineated by telomeres at opposite sides of the nuclear membrane (fig 2b). We suggest that the combination of chromosome movement and the vibration of the nuclear membrane may well predispose to selective and increased subtelomeric breakage, which may be the underlying cause of the higher meiotic recombination density and a high subtelomeric translocation tendency. Exchange following reunion of homologous non-sister chromatids will result in meiotic recombination, whereas interchange by reunion of nonhomologous chromosome breakage would lead to a reciprocal translocation. M. A. HULTÉN Regional Cytogenetics Laboratory, A. S. H. GOLDMAN East Birmingham Hospital, N. M. LAWRIE Birmingham B9 5PX out
EB, Healey NP, Willy AM. How much difference does chromosome banding Adjustments in prevalence and mutation rates of human structural cytogenetic abnormalities. Am Hum Genet 1989; 53: 237-42. 2. Jeffreys AJ, Wilson V, Them SL. Hypervanable ’minisatellite’ regions in human DNA. Nature 1985; 314: 67-73. 3. Jeffreys AJ, Wilson V, Thein SL Individual-specific fingerprints of human DNA. Nature 1985; 316: 76-79. 4. Timsit Y, Westhof E, Fuchs RPP, Moras G Unusual helical packing m crystals of DNA bearing a mutation hot-spot. Nature 1989; 341: 459-62. 1. Hook
make?
5. Hulten M Chiasma distribution
Fig I-Density graphs of male meiotic recombination along lengths of arms of chromosomes 1
Chromosome lengths given
length, each arm subdivided in centromere
(a) and
as
16
(b). respective proportion of total autosomal
10% intervals from centromere; numbers
positions =numbers of chiasmata scored. Data from refs 5-7.
at
at
diakinesis
in
the normal human male. Hereditas
1974; 76: 55-58. 6 Laune D, Hulten M, Jones GH. Chiasma frequency and distribution m a sample of human males: chromosomes 1, 2 and 9. Cytogen Cell Genet 1981; 31: 153-66 7. Saadallah N, Hulten M. Chiasma distribution, genetic lengths, and recombination fractions: a comparison between chromosomes 15 and 16 J Med Genet 1983; 20: 290-99.
Fig 2-Spatial orientation of the chromosomes shown in fig 1 at first meiotic prophase, showing bouquet formed initially (a) and movement of paired telomeric regions to opposite sides of nuclear membrane (b). NM = nuclear membrane, C = centromeres, T = telomeres. pairing of homologous chromosome segments.
areas
Stippled
=
Haematology Department, Adelaide Medical Centre for Women and Children, North Adelaide, South Australia
JULIAN WHITE VAUGHAN WILLIAMS
Haemostasis and Thrombosis Laboratory, Institute of Medical and Veterinary Science,
BRUCE DUNCAN
Adelaide
Lymphopenia in the inflammatory response caused by Notechis II-5. Toxicon 1989; 27: 499-500. 2. Gaynor B. An unusual snake bite story. Med J Aust 1977; ii: 191-92. 3. Furtado MA, Lester IA. Myoglobinuria following snake bite Med J Aust 1968; i: 674-76. 1. Emslie-Smith AM, Harris JB.
SUBTELOMERIC BREAKAGE AND CHROMOSOME EXCHANGE
SIR,-Mr Lamb and colleagues (Oct 7, p 819) describe a family ascertained by a boy with a-thalassemia, some dysmorphic features, and mental retardation, and his sister who also proved to be mentally retarded. Their report reinforces the urgent need for molecular in situ hybridisation techniques to aid clinical cytogenetics screening by rapid and easy detection of reciprocal translocations, such as by telomeric colorimetric specificity. This technique is especially important because of Lamb and colleagues’ suggestion that subtelomeric reciprocal translocations, unresolvable by traditional cytogenetic analysis, may be a common cause for mental retardation. The frequency of translocations detectable by moderate chromosome banding in newborn babies is around 1 in 250 (ref 1 and Jacobs P, personal communication). Lamb et al point
that small unbalanced translocations with breakpoints near the ends of the chromosome may have an increased embryonic and fetal survival rate, whereas the larger ones, arising from breakage further away from the telomeres, may be more often lethal at an early stage of pregnancy. We agree with this notion, but we also advocate that subtelomeric chromosomal exchange per se may be more frequent than interstitial exchange. Thus subetelomeric exchange might be a common reason for mental retardation, perhaps even providing a background for some mental subnormality thought to be normal variation in intelligence. General meiotic recombination, requiring breakage and reunion, takes place more frequently in the subtelomeric 10% intervals of the chromosome arms than anywhere else along their length (fig 1). Most workers believe that any preferential location of general meiotic recombination results from some recombination signal such as DNA satellites2,3 or DNA configuration.4 We believe that subtelomeric translocations could be the result of specific mechanical stress at the first meiotic prophase, when homologous chromosomes are attached to the nuclear membrane. This attachment does not occur at random sites. Instead telomeres are associated with a small area of the nuclear envelope, the chromosomes forming a so-called bouquet (fig 2a). Pairing of homologous segments generally starts from the bundles of telomeres, but when fully paired the individual bivalent homologues are delineated by telomeres at opposite sides of the nuclear membrane (fig 2b). We suggest that the combination of chromosome movement and the vibration of the nuclear membrane may well predispose to selective and increased subtelomeric breakage, which may be the underlying cause of the higher meiotic recombination density and a high subtelomeric translocation tendency. Exchange following reunion of homologous non-sister chromatids will result in meiotic recombination, whereas interchange by reunion of nonhomologous chromosome breakage would lead to a reciprocal translocation. M. A. HULTÉN Regional Cytogenetics Laboratory, A. S. H. GOLDMAN East Birmingham Hospital, N. M. LAWRIE Birmingham B9 5PX out
EB, Healey NP, Willy AM. How much difference does chromosome banding Adjustments in prevalence and mutation rates of human structural cytogenetic abnormalities. Am Hum Genet 1989; 53: 237-42. 2. Jeffreys AJ, Wilson V, Them SL. Hypervanable ’minisatellite’ regions in human DNA. Nature 1985; 314: 67-73. 3. Jeffreys AJ, Wilson V, Thein SL Individual-specific fingerprints of human DNA. Nature 1985; 316: 76-79. 4. Timsit Y, Westhof E, Fuchs RPP, Moras G Unusual helical packing m crystals of DNA bearing a mutation hot-spot. Nature 1989; 341: 459-62. 1. Hook
make?
5. Hulten M Chiasma distribution
Fig I-Density graphs of male meiotic recombination along lengths of arms of chromosomes 1
Chromosome lengths given
length, each arm subdivided in centromere
(a) and
as
16
(b). respective proportion of total autosomal
10% intervals from centromere; numbers
positions =numbers of chiasmata scored. Data from refs 5-7.
at
at
diakinesis
in
the normal human male. Hereditas
1974; 76: 55-58. 6 Laune D, Hulten M, Jones GH. Chiasma frequency and distribution m a sample of human males: chromosomes 1, 2 and 9. Cytogen Cell Genet 1981; 31: 153-66 7. Saadallah N, Hulten M. Chiasma distribution, genetic lengths, and recombination fractions: a comparison between chromosomes 15 and 16 J Med Genet 1983; 20: 290-99.