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Review Article on the Parental Origin of De Novo Mutation In J Med Genet: first published as 10.1136/jmg.28.4.217 on 1 April 1991. Downloaded from JMedGenet 1991; 28: 217-223 217 Review article On the parental origin of de novo mutation in man Ann C Chandley Abstract Early studies, based on the inheritance of X linked Studies tracing parental origins ofhuman mutations red-green colour blindness,' showed that maternal by means of cytogenetic polymorphisms and non-disjunction played a part in some cases of RFLPs show that most trisomics arise out of Klinefelter's syndrome (47,XXY), and indicated the maternal errors of segregation at the first meiotic maternal origin of the single X chromosome in division in oocytes. Temporal disturbance of Turner's syndrome (45,X).2 Following the discovery meiotic progression seems likely to underly aneu- of the X linked gene Xg, Race and Sanger3 showed ploidy production in the female mouse, and this that for the 47,XXY condition, the extra X was could equally be true in women, most especially as paternal (XmXPY) in 33% of cases and maternal they approach the menopause when irregular (XmXmY) in 67%, while for the 45,X condition 77% cycicity sets in. For human monosomy X, a high of cases showed retention of the maternal X chromo- proportion of cases show loss of the paternal sex some (Xmo).4 chromosome, and from experimental data giving The extra chromosome in autosomal aneuploid similar findings in the mouse, it seems likely that conditions like Down's syndrome (trisomy 21) could the error could arise at the pronuclear stage after not be investigated cytologically for some time, but, sperm entry into the egg, rather than at meiosis in nevertheless, it was assumed even in the early days http://jmg.bmj.com/ the male. For human point mutations and structural that at least some of the cases originated from rearrangements, a bias exists towards paternal malsegregation in oogenesis because of the well origins. Errors arising during spermatogonial known maternal age dependency of the condition. It proliferation in men could contribute point muta- was after the introduction ofbanding techniques5 that tions, these accumulating over a lifetime to give the breakthrough really came, with a rapid realisation paternal age effects. For structural rearrangements, that cytogenetic heteromorphisms could be used in the hypersensitive stage is likely to be the post- tracing the origins ofaneuploids and polyploids, and a meiotic differentiating spermatid, a stage not wealth of data accumulated.6 7 Studies into the on September 26, 2021 by guest. Protected copyright. subject to germinal selection, and one which in parental origins of structural rearrangements were Drosophila has been shown to combine high break- also carried out.8 Now, in the era of molecular ability with enhanced repair. Lack of a comparable investigation, with RFLPs having been identified on cell type to the condensing spermatid of the male all human chromosomes, the way has been opened up might be a reason why balanced structural re- for investigation into the origin of an infinite variety arrangements are produced rather rarely in females, ofmutations arising de novo, both in the germline and at least in the mouse. somatically, and some interesting facts are emerging. It appears that while for most aneuploids, there is a bias towards maternal origins, point mutations and Ever since the beginning of human genetic and structural rearrangements seem to arise de novo much cytogenetic investigation, studies have been made into more commonly in males. Much current debate is tracing the parental origins ofchromosome anomalies. focused on this issue and questions regarding whether 'imprinting' might play some role or whether, for example, extra environmental exposure of men could MRC Human Genetics Unit, Western General Hospital, be important, have been raised in various publications. Edinburgh EH4 2XU. No clear answers, however, have yet emerged. A C Chandley In this review, I would like to focus on data which have been obtained in other species, notablyDrosophila J Med Genet: first published as 10.1136/jmg.28.4.217 on 1 April 1991. Downloaded from 218 Chandley and the mouse, which I believe can, by extrapolation, prophase of meiosis, progressive swelling occurs, the give valuable clues to the possible times and mech- nucleus assuming the characteristic configurations of anisms of origin for some de novo mutations in man. leptotene, zygotene, pachytene, diplotene, and For aneuploid conditions, hard data exist in the diakinesis. Completion of the first meiotic division mouse which can be extrapolated to the situation of produces secondary spermatocytes which divide again human chromosome loss and non-disjunction, while to produce haploid spermatids (fig 2). Newly formed for point mutation and structural rearrangement, spermatids have a small spherical nucleus but, as an abundance of data is available relating both to the spermiogenesis proceeds, they pass through an mouse and Drosophila, from mutagenesis studies extremely complex series of morphological changes carried out in the 1950s and 1960s, which may during which the nuclear chromatin condenses into an provide clues to times of origin and to the possible elongated fusiform body covered by the acrosome reasons for the extra sensitivity of male germ cells (fig 2). Spermatozoa from the testis are not functionally over female. It is first necessary, however, to provide mature; they acquire motility and fertilising capacity a general outline of gametogenesis in the human male during passage through the epididymis. Many details and female for readers who may be less familiar with of the process of spermatogonial renewal in man the important stages in germ cell development and to remain still debatable, such as there being only one which reference can be made in later sections of this generation in each class of spermatogonia, spermato- review. gonia ofe'ach type dividing once and only once during each cycle of the seminiferous epithelium and not reverting back to the stem cell condition once Spermatogenesis embarked on their course of differentiation, and the Spermatogenesis is an intricate and involved process dark type A actually being the stem cell typeY10 requiring, from puberty onwards, a continuous production of spermatozoa by the seminiferous tubules, production which, in quantitative terms, is Oogenesis astronomical over the life span of a person. In man, it The formation, development, and maturation of the has been estimated that 64 days are required for female gamete begins in embryonic life and continues spermatogenesis to be completed in the testis,9 a to the time of ovulation. During fetal development further 10 to 11 days being required for passage of there is a period of oogonial division when numbers spermatozoa through the epididymis and vas deferens increase very rapidly; during germ cell migration into the ejaculate. there are 1700 cells; during the second month of At puberty in the male, gonocytes give rise to pregnancy 600 000, and at the fifth month 7 million." http://jmg.bmj.com/ spermatogonia which then divide mitotically several After a finite number of mitoses, the oogonia become times before becoming primary spermatocytes. transformed into oocytes which then enter the According to the morphological criteria ofClermont,,0 prophase of the first meiotic division, from this time dark type A (Ad) spermatogonia are stem cells which on oocytes being incapable of increasing their divide to produce new Ad cells and pale type A (Ap) numbers and, hence, the population of germ cells cells. Ap cells divide to form type B spermatogonia only reducing with age. This occurs by the process of which then differentiate into preleptotene primary atresia and by ovulation. This is in strong contrast to spermatocytes (fig 1). As these pass through the the situation in the male where mitotically active on September 26, 2021 by guest. Protected copyright. Ap Ad .... z B ~~~~~~Pi. Ap _ .......~~~P Figure I Model illustrating the development and renewal of * t ~~~~~~Pi spermatogonia in man. Ad, Ap, B, respectively, are dark typeA, pale typeA, and ypeB spermatogonia. Pi, preleptotene spermatocytes (frm Ad reference 10, with permission). Ap .c* - PI <4c Ad/ <*--K-cT-D<- .. I.N., Ad Ad J Med Genet: first published as 10.1136/jmg.28.4.217 on 1 April 1991. Downloaded from On theparental origin ofde novo mutation in man 219 Ad __ Pl wi Ap Figure 2 The steps of spermatogenesis in man. Ad, dark typeA spermatogonia;Ap, pale tpe A spermatogoniwn; B, type B spermatogonium; Pl, preleptotene primary spermatocyte; L, leptotene; Z, zygotene; EP, earlypachytene; (tA. MP, midpachytene; LP, late pachytene; II, secondary I/ spermatocyte. Spermatids are shown at various stages ofspermiogenesis. Spermatozoa are illustrated in lateral (left) andfrontal (right) aspects (from - Spermatids reference 10, withpermission). I' ip'4)i http://jmg.bmj.com/ spermatogonia persist basally in the spermatogenic Point mutations are generally considered not to be tubules, and spermatocytes pass through the phases of visible microscopically, while structural chromosome meiosis continuously throughout adult life. By the rearrangements usually are. Nowadays, however, the time of birth, the human ovary contains about 2 distinction can become blurred by borderline cases of million oocytes in the diplotene stage of meiotic minor deletion which may only be detectable by prophase when they embark on a prolonged resting molecular analysis and would escape detection by phase or 'dictyate' stage. During
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