ISSN:0893-6692    

DOI:10.1002/em.2850250602

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1995

数据来源: WILEY

ISSN:0893-6692    

DOI:10.1002/em.2850250603

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1995

数据来源: WILEY

摘要:

AbstractThis overview for the special issue ofEnvironmental and Molecular Mutagenesisdevoted to recent advances in human genetics relevant to mutagenesis briefly surveys the advances in the field. We present the evidence that trinucleotide repeat expansion can cause anticipation in human inherited disease. The finding that transposons are active in humans, as they are in other organisms, is reviewed. We present an example of two different diseases being caused by mutations in one gene. The role of mitochondrial mutations and parent‐specific gene origin effects (“imprinting”) are briefly reviewed; fuller reviews are provided in other articles in this special issue. Finally, the relevance of epigenetic inheritance by protein‐protein interaction is included. © 1995 Wiley

ISSN:0893-6692    

DOI:10.1002/em.2850250604

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1995

数据来源: WILEY

摘要:

AbstractThe existence of parent‐of‐origin differences in the expression of some genes, a process known as genomic imprinting, has been recognized and documented over the past several years. This epigenetic marking process results in the differential expression of normal genes depending upon whether they were inherited from the mother or the father. A number of human disorders have been identified as resulting from alterations in genomic imprinting. One process which can unmask genomic imprinting is uniparental disomy, in which both members of a chromosome pair are contributed by one sex parent. When uniparental disomy is present, genetic abnormality can result either from homozygosity of a single mutant allele which is present in two doses, or from the presence of two copies of an imprinted unexpressed gene or genes, rather than the usual one expressed and one unexpressed. Examples of human genetic disorders that are the consequence of genomic imprinting, and a discussion of current knowledge about the mechanisms of imprinting and the causes of uniparental disomy, are reviewed. © 1995 Wiley‐Lis

ISSN:0893-6692    

DOI:10.1002/em.2850250605

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1995

数据来源: WILEY

摘要:

AbstractMosaicism, the existence of “patches” of cells with a genetic constitution that differs from that of other cells of an organism, has been observed in both germinal and somatic tissues of several species, including humans. Mutational events occurring during early embryogenesis can give rise to an organism with a significant number of cells with the mutant genotype in one or more tissues. If this event occurs in a precursor of the germ cells, the mutation can be transferred to subsequent generations. In the F1generation, this event will usually be perceived as a de novo germinal mutation rather than a transmitted variant allele, unless significant effort is directed toward detecting the mosaicism. Similarly, mutations in oncogenes and tumor‐suppressor genes in proliferating somatic cells can generate populations of cells that are at increased risk of transforming into tumor cells. The number of potential preneoplastic cells is larger when the mutagenic event occurs in early development than if it occurs in the mature adult. Experimental data confirm that treatment of the developing embryo or fetus with carcinogenic and mutagenic agents increases the cancer incidence in these animals and the frequency of mutations in the offspring of the animals that were exposed in utero. The available data are conclusive that the developing organism is at risk from exposure to mutagenic and carcinogenic agents. However, the data are insufficient to estimate the level of risk associated with exposures in utero, relative to either the background (spontaneous) level of risk or risk associated with similar exposures to the adult organism. Given the dynamics of cell division, it can be expected that the potential risk from exposure of the developing embryo is increased relative to the risk from adult exposure if the sensitivity of the individual cells to damage in the adult and the embryo are equivalent. It seems apparent that the potential risks of cancer and heritable disease following in utero exposure are sufficient to warrant additional attention. It is important to obtain data for estimating the relative contribution of in utero exposure to mutagenic and carcinogenic agents to the total health burden and for the subsequent development of appropriate regulations. © 1995 Wiley‐L

ISSN:0893-6692    

DOI:10.1002/em.2850250606

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1995

数据来源: WILEY

摘要:

AbstractThe mitochondrial genome is essential for producing ATP (adenosine 5′ ‐triphosphate) via oxidative phosphorylation. The gradual decline of mitochondrial function with age has long been postulated as a factor in aging. More recently, a variety of diseases have been related to molecular defects in human mitochondrial DNA. In both the cases of aging and disease, symptoms were generally neuromuscular, reflecting the tissues most dependent upon mitochondrial function. Also, in both cases novel features of mitochondrial genetics led to complex relations between genotype and phenotype. Little information is yet available about the role of environmental agents in these interactions. © 1995 Wiley‐Lis

ISSN:0893-6692    

DOI:10.1002/em.2850250607

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1995

数据来源: WILEY

摘要:

AbstractAneuploidy is the most common class of chromosome abnormality in humans, occurring in at least 0.3% of newborns and approximately 50% of spontaneous abortions. Considered as a class, it is the most common known cause of mental retardation and the leading cause of pregnancy loss. Despite the high frequency of aneuploidy, its obvious clinical importance, its severe impact on human reproduction, and the 35 years of research since the first human chromosome abnormality was described, we still know very little about its causes, let alone the contribution of environmental exposures. Recently, however, with the advent of molecular and molecular cytogenetic techniques and advances in reproductive biology, a body of evidence has been generated that is beginning to shed light on the incidence, origin, and etiology of human aneuploid conditions. The bulk of this evidence comes from two sources: 1) studies of the incidence of aneuploidy in the cells of origin, namely oocytes and sperm; and 2) examinations of meiotic stage, parent of origin, and meiotic recombination in trisomic conceptuses, both liveborn and abortuses. Using a multicolor fluorescence in situ hybridization (FISH) approach, it is now possible to screen an extremely large number of human sperm to determine chromosome‐specific rates of disomy. Likewise, because of the introduction in the past decade of in vitro fertilization technology, a population of human oocytes suitable for aneuploidy screening became available. The examination of the cells of origin of aneuploidy, the sperm and oocytes, has provided data on the incidence of chromosome aberrations and valuable insight into possible mechanisms of non‐disjunction. Additionally, the recent identification of multiple, highly informative DNA polymorphisms on all human chromosomes has made the determination of parental origin and the analysis of recombination a straightforward matter. We now know that the vast majority of trisomic conceptuses are maternal in origin, that increased maternal age is associated with nondisjunction, and that the amount and position of recombination on nondisjoined chromosomes is altered. In this review we will restrict discussions to these recent developments and to new models of the mechanism(s) of human nondisjunction based on the molecular cytogenetic analyses. Additionally, we will discuss the direction of future epidemiological research made possible through the development of molecular and molecular cytogenetic techniques. These technological advances have now allowed for a systematic search for genetic and environmental components to human nondisjunction. © 1995 Wiley‐Lis

ISSN:0893-6692    

DOI:10.1002/em.2850250608

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1995

数据来源: WILEY

摘要:

AbstractSpontaneous mutation rates per generation are similar among the three species considered here—Drosophila, mouse, and human—and are not related to time, as is often assumed. Spontaneous germline mutation rates per generation averaged among loci are less variable among species than they are among loci and tests and between gender. Mutation rates are highly variable over time in diverse lineages. Recent estimates of the number of germ cell divisions per generation are: for humans, 401 (30‐year generation) in males and 31 in females; for mice, 62 (9–month generation) in males and 25 in females; and forDrosophila melanogaster, 35.5 (18‐day generation) in males and 36.5 (25‐day generation) in females. The relationships between germ cell division estimates of the two sexes in the three species closely reflect those between mutation rates in the sexes, although mutation rates per cell division vary among species.Whereas the overall rate per generation is constant among species, this consistency must be achieved by diverse mechanisms. Modifiers of mutation rates, on which selection might act, include germline characteristics that contribute disproportionately to the total mutation rates. The germline mutation rates between the sexes within a species are largely influenced by germ cell divisions per generation. Also, a large portion of the total mutations occur during the interval between the beginning of meiosis and differentiation of the soma from the germline. Significant genetic events contributing to mutations during this time may include meiosis, lack of DNA repair in sperm cells, methylation of CpG dinucleotides in mammalian sperm and early embryo, gonomeric fertilization, and rapid cleavage divisions. © 1995 Wil

ISSN:0893-6692    

DOI:10.1002/em.2850250609

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1995

数据来源: WILEY

摘要:

AbstractThe contribution of induced mutations to the burden of genetic disease in the context of population genetics is considered. A clear distinction is made between the effects of genetic disease and mutational events. Much of the existing burden of genetic disease is a consequence of mutations that occurred in the past. The problem of distinguishing between spontaneous and induced mutations is discussed. Molecular genetics techniques are blurring the definitions of these terms. Classical population genetics shows that the frequency of affected individuals will reach an equilibrium depending on the mutation rate and the selective pressure against affected individuals. Increasing the mutation rate or reducing the selective pressures would result in a new equilibrium with an increase in the frequency in subsequent generations of affected individuals with dominant and X‐linked mutant alleles. The increase in the number of recessive mutant alleles would be much slower and take many generations to reach the new equilibrium level. One assumption behind such equilibria is random mating. Changes in human demography with a rapid increase in population size, the breakup of small, relatively inbred subpopulations, and relaxed selective pressures will lead to a new equilibrium for recessive genes at probably higher frequencies.These factors will be the major contributors to increasing the burden of recessive genetic disease by increasing the total numbers of cases. The proportion of the population with a genetic disease will also continue to grow as a greater proportion of the population survives to late middle age and succumbs to diseases associated with old age, such as cancer, circulatory disease, dementias, and diabetes, each of which is likely to have a genetic component. One area where an increase in mutant heterozygotes may be of concern is when heterozygotes for recessive genes play a part in some of these diseases in later life when selective pressures have little effect. This suggests that the lower concern over the induction of harmful recessive mutations because of the long time span before they become prevalent should be tempered by the possibility that apparently asymptomatic heterozygotes, which will increase much more rapidly than homozygotes, may lead to an increased incidence of genetic disease later in life. The potential of molecular biology to provide a greater insight into the origins and causes of genetic mutations as well as to provide more accurate estimates of the true spontaneous and induced mutation rates is stressed. © 1995 Wiley‐Liss,

ISSN:0893-6692    

DOI:10.1002/em.2850250610

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1995

数据来源: WILEY

摘要:

AbstractThe induction of germ cell mutations with ionizing radiation and chemicals has been clearly demonstrated in experimental animal test systems. Less is known about the effects of environmental and other exposures on human germ cells. Epidemiologic studies of atomic bomb and childhood cancer survivors and their offspring have generally not indicated an excess risk for a variety of adverse reproductive outcomes and childhood diseases, including those due to germ cell mutations. Other epidemiologic studies, including the investigation of cancer among the offspring of fathers employed at the Sellafield nuclear facility in Great Britain and studies of paternal occupation and birth defects, have found associations. This paper reviews these studies and the methodologic problems inherent in the epidemiologic approach to evaluating environmentally induced germ cell mutagenesis in humans. Epidemiologic studies incorporating newly developed techniques for the detection of mutations and abnormalities in sperm may provide the sensitivity needed to determine precisely the magnitude of risk. © 1995 Wiley‐Liss, I

ISSN:0893-6692    

DOI:10.1002/em.2850250611

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1995

数据来源: WILEY