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Preimplantation genetic diagnosis: Genetic disorders contribute to a wide range of genetic diseases that are present in the community at relatively low incidence, and treatment and support of patients with these conditions comes at some considerable cost. For diagnosis of serious genetic diseases that are known to be present in the family, it is likely that prospective parents will begin to choose IVF and preimplantation genetic diagnosis (PGD) of embryos in preference to other prenatal screening methods. Hence, there may be some shift from reproduction by intercourse to assisted reproductive techniques (eg, IVF). While this may be considered unnatural, IVF does not attract this stigma any more. The demand for technology will generally bring acceptance, unless there are dangers that can be identified with some certainty. IVF, including many associated procedures such as embryo cryopreservation, embryo donation and intracytoplasmic sperm injection (ICSI), are accepted. Even surrogacy is allowed in the Australian Capital Territory. While these techniques were widely condemned by particular interest groups, they are now well tolerated by the community.

The presence of genetic mutations that are correlated to human infertility can be screened in men for deletions in the Y chromosome¹ and mutations in the androgen receptor gene present on the X chromosome.^2,3 These will be inherited by the sons or daughters, resulting in the same or even more serious infertility in the case of sons, or carriers of the infertility genes in the case of daughters. Presently, science does not have the capacity to correct these genomic errors. It is very likely that some aspects of female infertility will also be transmitted to sons and daughters because of the availability of IVF.

Sex selection: It is perhaps of some concern that the more simple diagnostic techniques of fluorescent in situ hybridisation (FISH) can be used to identify sex of embryos, and in some States there is no barrier to the use of this for selection of the sex of children by IVF. The concern is that sex alone is considered a sufficient criterion for selection of embryos for transfer. Considering that 50% or more of all embryos are aneuploid,⁴ it would be scientifically sound that embryos should, at the very least, be selected for normal chromosomal numbers rather than simply sex. Since there are already good genetic screening processes for embryo genetic health,⁵ selection for sex alone⁶ is scientifically inadequate.

It will be interesting to see if the selection for sex of children for social reasons (balancing family sex ratio) will be tolerated. This appears to be a major departure from the strictly medical reasons for assisted reproduction.

Phenotype selection: Given the capacity to identify point mutations in single cells of human embryos,⁷ one might ask if there are more or less desired phenotypes, including intelligence,⁸ that might be selected for or against. It is difficult to believe that parents will seek IVF and PGD for other phenotypes, but the interest in balancing the sex of families for relatively high personal cost suggests that some parents will also seek to endow their children with phenotypic advantage. Given the emphasis for education of children and, on occasions, the specific selection of partners as parents, it is likely that genes controlling desired and undesired phenotypes might be identified and, where possible, requested for selection for or against. Since it is likely that much of the functional human genome will be identified within the next few years, issues of access to identification of genotype or germline gene alterations need to be explored seriously with the community.

Selection against genetic disease is recognised as a parental right, but enhancement of phenotype by genetic selection or genetic engineering needs to be considered. There will certainly be strong condemnation of selection against behaviour (eg, sex preference, aggression), but, if parental desire is high enough, there may be jurisdictions of sufficient flexibility to allow an assessment and community reaction to phenotypic enhancement.

It has been hypothesised that the Y chromosome evolved from the X chromosome by progressive alteration or additions,⁹ an important inversion of the biblical view of Eve's creation. During meiosis it is only the tips of the short arms of the X and Y chromosome that pair to exchange euchromatic DNA, severely limiting the ability of the Y chromosome to repair the deletions that are appearing. The inescapable hypothesis that follows is the Y chromosome has a limited evolutionary lifetime that means the male is facing eventual extinction. If there is a "sunset clause" that has been inserted into the genomic blueprint of evolution, an alternative may need to be found for sexual reproduction. Perhaps the recent observation of inheritance of Y chromosome deletions by sons born of severely infertile men after the IVF technique known as ICSI¹⁰ will prolong the inevitable demise of the Y chromosome. Indeed, some interest groups will applaud the good sense of evolution in preprograming the decay of the Y chromosome. Conservative sectors of the community, on the other hand, will be very disappointed and may call for scientists to immediately address germ cell genetic engineering to halt increasing Y chromosome deletions as a serious research project. It is notable that serious scientists of one of the major Australian medical research institutes have embarked on the recreation of the extinct thylacine (Tasmanian tiger)¹¹ and would probably tackle the resurrection of the decaying Y chromosome with relish.

Given the general disapproval of postmenopausal childbearing (although this does not apply to men, who have no age limit to their reproductive opportunities), it is unlikely that large numbers of older women will be in obstetric care in the near future. Perhaps this might eventually be challenged under discrimination against female age. It is probably more certain that posthumous conception will not be acceptable, despite the frequent requests to cryopreserve sperm of recently deceased male partners. While it may be understandable for a young wife or partner to desperately seek to retain a connection to a loved partner, the absence of consent from the deceased to have a child remains a major obstacle. It is much more difficult to cryopreserve eggs, so this has not been requested, to my knowledge, for a deceased partner. However, young women entering treatment for cancer have had some of their ovary cryopreserved in case of sterility after cancer therapy.¹⁵

1. de Kretser DM, Mallidis C, Ma K, Bhasin S. Male infertility and the androgen receptor: molecular, clinical and therapeutic aspects. Reprod Med Rev 1997; 6: 113.
2. Wang Q, Ghadessy FJ, Trounson A, et al. Azoospermia associated with mutation in the ligand-binding domain of the androgen receptor with normal ligand binding, but defective transactivation. J Clin Endocrin Metab 1998; 83: 4303-4309.
3. Dowsing AT, Yong EL, Clark M, et al. Linkage between male infertility and trinucleotide repeat expansion in the androgen receptor gene. Lancet 1999; 354: 640-643.
4. Gianaroli L, Magli MC, Ferraretti AP, et al. Preimplantation genetic diagnosis increases the implantation rate in human in vitro fertilization by avoiding the transfer of chromosomally abnormal embryos. Fertil Steril 1997; 68: 1128-1131.
5. Trounson AO, Wood C. Future developments in IVF and related technologies. In: Trounson AO, Gardner DK, editors. Handbook of in vitro fertilization. 2nd ed. Boca Raton: CRC Press, 1999; 543-550.
6. Smith D. $10,000 can buy parents 'designer babies'. The Age (Melbourne) 1999; 2 October: 1.
7. Wells D, Sherlock JK. Strategies for preimplantation genetic diagnosis of single gene disorders by DNA amplification. Prenatal Diagn 1998; 18: 1389-1401.
8. Tang YP, Shimizu E, Dube GR, et al. Genetic enhancement of learning and memory in mice. Nature 1999; 401: 63-69.
9. Graves JA. The origin and function of the mammalian Y chromosome and Y-borne genes -- an evolving understanding. Bioessays 1995; 17: 311-320.
10. Cram D, Ma K, de Kretser D, et al. Transmission of YQ deletions in men with spermatogenic disorders through the use of intracytoplasmic sperm injection. Proceedings of the 11th World Congress on IVF and Human Reproduction and Genetics. Sydney, 1999. Abstract S-008.
11. That tiger again! New bid for a resurrection. The Age (Melbourne) 1999; 8 September: 6.
12. Wilmut I, Schnieke AE, McWhir J, et al. Viable offspring derived from fetal and adult mammalian cells. Nature 1997; 385: 810-813.
13. Wakayama T, Perry ACF, Zuccotti M, et al. Full-term development of mice from enucleated oocytes injected with cumulus cell nuclei. Nature 1998; 394: 369-374.
14. Reprogramming cell fate -- transgenesis and cloning. Reprod Fertil Develop Special Issue 1999; 10(7,8).
15. Wood EC, Shaw JM, Trounson AO. Cryopreservation of ovarian tissue: potential "reproductive insurance" for women at risk of early ovarian failure. Med J Aust 1997; 166: 366-369.

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