That the sporadic and inherited forms of a particular cancer could both result from mutations in the same gene was first proposed by Knudson. He further proposed that these mutations act recessively at the cellular level, and that both copies of the gene must be lost for the cancer to develop. In sporadic cases both events occur somatically whereas in dominant familial cases susceptibility is inherited through a germline mutation and the cancer develops after a somatic change in the homologous allele. This model has since been substantiated in the case of retinoblastoma, Wilms tumour, acoustic neuroma and several other tumours, in which loss of heterozygosity was shown in tumour material compared to normal tissue from the same patient. The dominantly inherited disorder, familial adenomatous polyposis (FAP, also called familial polyposis coli), which gives rise to multiple adenomatous polyps in the colon that have a relatively high probability of progressing to a malignant adenocarcinoma, provides a basis for studying recessive genes in the far more common colorectal carcinomas using this approach. Following a clue as to the location of the FAP gene given by a case report of an individual with an interstitial deletion of chromosome 5q, who had FAP and multiple developmental abnormalities, we have examined sporadic colorectal adenocarcinomas for loss of alleles on chromosome 5. Using a highly polymorphic 'minisatellite' probe which maps to chromosome 5q we have shown that at least 20% of this highly heterogeneous set of tumours lose one of the alleles present in matched normal tissue. This parallels the assignment of the FAP gene to chromosome 5 (see accompanying paper) and suggests that becoming recessive for this gene may be a critical step in the progression of a relatively high proportion of colorectal cancers.
Intimate association between autosomal translocation trivalents and XY bivalents at pachytene was observed in a majority of cells of two men ascertained through primary sterility and found to be heterozygous for a 14;21 Robertsonian translocation. The association, studied by light and electron microscopy of spread first spermatocytes, was between the unpaired short arms of the normal chromosomes of the translocation trivalent and the differential axes of the XY chromosomes. In a minority of cells, this contact was not established, or not maintained, as alternative combinations between the elements available for non-homologous pairing were realized. Following a suggestion of Lifschytz and Lindsley (1972), sterility in these patients was attributed to spermatogenic arrest caused by physical contact of sex chromosomes with autosomal material and consequent interference with the normal metabolism of the sex chromosomes. Autosomal aberrations and polymorphisms, which lead to the presence of unpaired segments at meiosis, may thus play a critical role in a general mechanism of chromosomally-derived male sterility. It is proposed that such a mechanism may also be instrumental in the initiation of reproductive barriers in nature.
The mammalian sex chromosomes are thought to be related to each other by sharing a common origin. That is, the X and Y chromosomes originally evolved from a pair of chromosomes that only differed at the locus determining sexual differentiation. For example, this evolutionary relationship is reflected during meiosis in chromosomal pairing between the tip of the human X chromosome short arm and the Y chromosome which presumably implies sequence homology. However, compelling genetic evidence for functional homology between the mammalian X and Y chromosome is lacking. We describe here the localization of a gene to the tip of the short arm of the human X chromosome and evidence for a related gene on the Y chromosome.
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