Medical Genetics: Advances in Brief J Med Genet: First Published As 10.1136/Jmg.36.6.503 on 1 June 1999
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J Med Genet 1999;36:503 503 Medical genetics: advances in brief J Med Genet: first published as 10.1136/jmg.36.6.503 on 1 June 1999. Downloaded from Stable dicentric X chromosomes with therefore, propose that the mosaicism associ- word “eugenics”, when translated into Chi- two functional centromeres ated with dic(X) cases reflects chromosome nese, apparently means “well-bear and well- Sullivan BA, Willard FW. Nat Genet loss at the time of dicentric formation and not rear”. Chinese geneticists believe eugenics 1998;20:227-8. subsequent instability and ongoing clonal evo- implies processes designed to ensure that chil- It has long been speculated, from cytogenetic lution. Their inference may be somewhat of a dren who are born are, as far as possible, nor- observation of primary constrictions, that conceptual leap, but this caveat should not mal, and they strive to achieve this in the con- when the two centromeres of a dicentric chro- detract from what is otherwise an elegant and text of a strict limitation in the size of mosome are close then they may both be concisely described piece of work. population growth and a fundamental lack of active. That is, orientation of the respective ANDREW FISHER resources. They feel that their goal is “im- kinetochores on each chromatid to opposite provement in population quality, decrease in spindle poles is possible so that the dicentric Chinese geneticists’ views of ethical population quantity and the furtherance of can evade the “fusion-breakage-bridge” cycle issues in genetic testing and screening: eugenic principles”. In the accompanying edi- of Barbara McClintock and segregate eY- evidence for eugenics in China torial, Knoppers tries to understand how such ciently. Thus, for example, Robertsonian Mao X. Am J Hum Genet 1998;63:688-95. diametrically opposing views could have arisen translocation chromosomes usually have two on opposite sides of the world. Primarily, the active centromeres. Conversely, it is suggested Invited editorial. “Well-bear and argument is between the North American that widely spaced centromeres of a dicentric well-rear in China” ideal of individualism at all costs versus may misalign on the spindle, since the Knoppers BM. Am J Hum Genet communitarian values. However, it is impor- chromatin between them can twist; the dicen- 1998;63:686-7. tant to acknowledge that even though the rights of people with genetic disorders may be tric is thus forced to somehow undergo inacti- Mao reports the results of the responses of more freely acknowledged in the west, such vation of one of the centromeres for eYcient 63% (255) of 402 Chinese geneticists who people do not necessarily receive better care, segregation to be possible. Until now it has not participated in a national survey designed to particularly in countries where large numbers been possible to extrapolate from cytogenetic identify their views on the ethical issues of people have no access to free health care. observations of dicentric chromosomes to involved in genetic testing and screening. The centromere distances in terms of megabases of Chinese geneticists diVer in almost every area FRANCES FLINTER DNA. The recent letter to Nature Genetics by from their North American and west Euro- Sullivan and Willard now addresses this prob- pean counterparts, and the degree of polarisa- Mutations in the gene encoding gap lem nicely. These authors describe experi- tion may at first seem astonishing to geneticists junction protein beta-3 associated with ments with a variety of dicentric (dic)X working in developed countries who have a autosomal dominant hearing impair- chromosomes, in which the extent of the X fundamental objection to eugenics. The Chi- ment short arm chromatin between centromeres is nese respondents strongly favoured oVering Xia J-H, Liu C-Y, Tang B-S, et al. Nat Genet defined, varying from 4 to 34 Mb. Sullivan and genetic testing at work for á1-antitrypsin defi- 1998;20.4:370-3. Willard used antibodies to CENP-C and E, ciency (95%) and for genetic predisposition to specific to active centromeres. They found heart disease, cancer, and diabetes in execu- Over 40 loci for deafness have been genetically that, in the four dic(X)s with the shortest tives (94%). A total of 86% wanted genetic mapped but only in very recent years have intercentromeric distances (4-12 Mb), these testing included in pre-employment physical causative genes been identified. Two of these http://jmg.bmj.com/ et al proteins were present at both centromeres in examinations and 86% also felt that the are connexins and this promted Xia to 67-87% of cells. Excitingly, however, dic(X) government should require premarital carrier search for new human connexin genes and chromosomes with greater intercentromeric tests. Newborn screening tests for sickle cell look for mutations in families with deafness. distances, for example, the cited case of 34 disease (77%) and Duchenne muscular dys- From a database, two overlapping ESTs were Mb, showed only a single CENP positive cen- trophy (71%) were recommended and, per- identified with 83% identity to rat Gjb3 and a tromere in 100% of cells; they were thus func- haps most surprisingly, 85% felt that children homologous fragment amplified from human tionally monocentric. The authors attempted should be tested for late onset disorders such DNA. This identified human GJB3 (connexin to correlate these findings with stability of as Huntington’s disease. In the western world 31) which mapped to 1p32-p35. RT-PCR chromosome segregation at anaphase. They there is almost universal opposition to testing analysis showed it to be expressed in the inner on September 24, 2021 by guest. Protected copyright. therefore monitored movement of the respec- children for genetic susceptibility to late onset ear. Of six families with sensorineural deafness tive dicentric and control chromosomes using disorders because of a fundamental respect for linked to 1p32-p35, two were found to have a technique involving enriching for anaphase the autonomy of the child, but most Chinese mutations in the connexin 31 gene. One and telophase cells. As expected, controls and geneticists favoured such testing on the resulted in an amino acid change and the other functionally monocentric X chromosomes grounds that parents should be able to decide in a premature stop codon causing absence of showed no evidence of anaphase lag, that is, for their children and should have the power to part of the C terminus of the protein. Both of they segregated eYciently. However, in two of direct their children’s lives. This cultural these mutations were in regions highly con- three functionally dicentric X cell lines the division reflects the extent of individual served in other connexins. In both families, dic(X) was shown at the spindle midzone in autonomy in developed countries including inheritance was autosomal dominant but V anaphase, or between two newly formed the preservation of the autonomy of minors. In males were a ected with progressive bilateral daughter cells in telophase, in approximately China, the child is seen as part of the family, high frequency hearing impairment with onset 25% of cells, as illustrated in the elegantly pre- rather than as a potentially autonomous from 20 to 40 years of age, whereas females V sented figures. It is not clear why the above person. Traditionally, China is a very paternal- were either una ected or much less severely V unstable segregation was not seen in the third istic society and parents have absolute power a ected. A significant proportion of families functionally dicentric X cell line tested, or why to make family decisions. Most Chinese with AD hearing loss show linkage to 1p32-35, et al the two cell lines showing high degrees of ana- geneticists believed that partners should know so Xia may have identified a common phase lag did not eventually lose the dic(X) each other’s genetic status before marriage cause of deafness. Interestingly, in the same Nature Genetics completely. Sullivan and Willard suggest that (92%) and 91% believe that carriers of the issue of , an independent group there are other mechanisms involved in ensur- same recessive gene should not have children; describe the identification of the same gene V ing the stability of dicentric chromosomes. 91% felt that a woman at risk of having a child but found mutations in a di erent region to be Behaviour of the dic(X)s at cell division did with a genetic condition should have prenatal responsible for erythrokeratodermia variabilis not, moreover, correlate with the presence of diagnosis. Finally, more than half of the in which deafness is not a feature. These find- mosaicism in the karyotype, although it was respondents felt that there were no laws in ings are discussed in the “News and views” not made clear whether this mosaicism applied China to prevent discrimination on the section and represent an interesting example V to the original patients’ karyotypes or to those grounds of disability. The frankly eugenic of di erent mutations in the same gene being V of the cell lines derived from these patients views expressed are hard for western geneti- responsible for two completely di erent phe- (mosaicism in cell lines being subject to cists to begin to comprehend because they are notypes. distortion by clonal expansion). The authors, so diametrically opposed to our own. The DAVID O ROBINSON.