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17 The Identification and Role of Sex-Determining Genes Life can be resilient and vulnerable at the same time. We rejoice at stories of Olympic medalists who overcome severe injury or a childhood marked with tragedy. At the same time, nature can dish out genetic disorders resulting in births incompatible with life—severely limiting in organ function or leaving an adult with chronic illness. What makes life so vulnerable is the nature of genetic material. Something as simple as altering or removing one nucleotide pair out of some three billion present in a sperm or an egg can result in one of those debilitating or lethal genetic conditions. That doesn’t happen if one pulls a single brick out of a multistoried building. It won’t collapse no matter where that brick is removed. If the gene happens to involve the sex-determining programs in the embryo, the results can be quite dramatic. The sex-determining genes can be found on the sex chromosomes and the autosomes. This is no surprise, because many organ systems are involved in sex pathologies. They can result from abnormalities of the pituitary gland, the hypothalamus, the adrenal cortex, the gonads, or those embryonic structures that will form the internal and external genitalia. A major gene involved in male sex determination is the SRY gene. It is on the Y chromosome and located at Yp11.3, i.e., on the short or p arm of the Y chromosome at band region 11.3 (Figure 17.1). Andrew H. Sinclair found the SRY gene while he was working with Peter Goodfellow ’s laboratory at Cambridge University in 1990.1 Prior to that, in 1987, David C. Page believed that what was called the “testes determining factor” (TDF) was a zinc finger gene in a different region.2 The TDF was known to be Y-associated from cytological studies of certain partial or completesexreversals.Thus,ababywithXisoYpsexchromosomeshasa 122 duplicationoftheparm.Suchanindividualisamaleandsterile,because the q arm of the Y provides the genes associated with spermatogenesis, but otherwise functional. But a baby with X isoYq has a duplication of the q of the Y chromosome and an intact X chromosome and is missing the short arm of the Y chromosome. Because such babies are born as females with no testes, that is where the testes determining factor has to be located. The gonads of such babies are streaks, like those of babies with Turner syndrome. They also show other symptoms similar to those associated withTurner syndrome, suggestingthat some growthfactor is associated with the Yp region. In 1985, Page and his colleagues detected Y-chromosome material in an X chromosome that led to XX males.3 In these subjects, one of the X chromosomes contains material associated with the p arm of the Y chromosome. The region that is homologous between the Yp and the Yq tipsmayundergocrossingovertoproducethis(Figure17.2).Becausethe tips of the p arms of the Y and X are capable of pairing, and share many genesincommon,theyarecalledpseudoautosomal(PAR)regions.Page narrowedthesearchforthemale-determiningfactortothisPARregion. Numerous cases emerged of losses of DNA from the pseudoautosomal region of the Y chromosome. These produce a Y chromosome that superficially looks normal but the testes-determining factor, which was later identified as SRY and found to be located below the pseudoautosomal region, is missing. This results in XY females who have streak ovaries, but lack other Turner syndrome symptoms. They are females who, at 16 or so, discover that they are not entering puberty. They lack pubic hair, do not have a menarche and do not have breast enlargement. Examination would reveal a uterus and oviducts, streak ovaries, no male sexual components, and normal pudenda. Such individuals (and there are many similar losses or gene mutations of the SRY gene) have a medical condition called Swyer syndrome.4 When Gerald Isaac MacDonald Swyer first described such patients in 1955, he did not know the underlying genetic or cytological basis for their condition. Other Gonadal Sex-Determining Genes It is important to recognize that the conversion of the neutral gonad into a functioning testis or ovary is the initial sex-determining event in a human embryo. Two additional major genes are associated with the pathway of genes that lead to gonadal differentiation. Exactly how these genes work is still uncertain. Some believe the SRY and associated genes are male determining because they turn on male pathways in the neutral gonad. Others believe they turn off the default pathway, which is female, citing Jost’s experiments that indicated...


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