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Epldemlotoglc Reviews Copyright O 1997 by The Johns Hopkins University School of Hygiene and Public Health All rights reserved Vol. 19, Mo. 1 Printed In U.S.A Evolving Methods in Genetic Epidemiology. IV. Approaches to NonMendelian Inheritance Stephanie L. Sherman INTRODUCTION Over the years, genetic epidemiologists have identified traits that are due to the effect of a single gene, but one that does not follow the rules of Mendelian inheritance. Such anomalies in inheritance patterns were sometimes attributed to ascertainment biases or the interaction between environmental and/or other genetic influences. Recent advances in molecular genetics in humans and experimental animals, however, have provided evidence to show that single genes themselves can have attributes that result in a nonMendelian pattern of inheritance of the expressed trait. Three phenomena of genes that lead to such patterns will be reviewed below; two patterns result from mutations that alter a normal state (one due to a mutation that causes a stable trinucleotide repeated sequence to become unstable and the other due to some mechanism that alters the effect of genomic imprinting) and the other pattern results from a gene belonging to the mitochondrial genome, not the nuclear genome. Table 1 describes some of the resulting features of each of these attributes. So-called "complex traits" are also defined in the literature as non-Mendelian traits. These are usually attributed to complex interactions between more than one genetic and/or environmental factor, not to attributes of a single gene. For purposes of this review, the narrow definition of non-Mendelian inheritance due to properties of a single gene will be used. The analytic approaches used to identify such patterns fall into two general categories: 1) basic statistical and epidemiologic approaches used to detect differences among groups and 2) genetic model fitting. In the following section, the underlying biology of each of the attributes and resulting consequences with respect to the expression of the trait will be described. BIOLOGIC BASIS AND CONSEQUENCES Dynamic trinucleotide repeat sequence mutation "Anticipation" is the primary characteristic of a dynamic trinucleotide repeat sequence mutation, and is defined as the occurrence of an inherited trait that progressively increases in severity in successive generations. Measures of severity include recurrence risk, symptoms, or age-of-onset. Myotonic dystrophy has been the classic example of a trait which shows anticipation (for a review, see Harper et al. (1)). For this autosomal dominant disorder, an increase in the severity of symptoms and a decrease in the age-of-onset is observed over generations: Family members in the older generations may exhibit only cataracts late in life. In succeeding generations, affected members have typical neuromuscular features, myotonia and dystrophic changes, with onset usually in adolescence or early adult life. Finally, there is a congenital form with severe neuromuscular problems. Although this pattern of anticipation was recognized by Fleischer (2) (an ophthalmologist) and later quantitatively analyzed by Bell (3), it was thought to be a statistical artifact for over 40 years. Penrose (4), in 1948, attributed this pattern to selection biases resulting from preferential ascertainment of three groups: 1) parents with a late age-of-onset, as an earlier onset would limit their ability to reproduce, 2) the childhood generation with early onset because of the severity of the disorder, and 3) parent-offspring pairs with simultaneous onset, as most studies are conducted over a short time period. Penrose's overall conclusion was that "anticipation" was indeed apparent, but not due to a biologic phenomenon. Harper et al. (1) present a fascinating historical perspective of this conclusion and why it had such a strong influence. They remark that, since the time of Penrose's (4) paper until the early 1980s, geneticists have "almost unanimously dismissed anticipation as an artifact resulting from December 27,1996, and accepted for publication May 27,1997. Abbreviations: ANOVA, analysis of variance; FMR1, fragile X syndrome gene; MANCOVA, multiple analysis of covariances; mtDNA, mitochondrial DNA. From the Department of Genetics, Emory University, 1462 Clifton Road, Atlanta, GA 30322. (Reprint requests to Dr. Sherman at this address.) 44 Downloaded from http://epirev.oxfordjournals.org/ at Pennsylvania State University on April 26, 2014 Subsequently, a review of the analytic approaches that have been used or proposed to identify such traits will be presented. Non-Mendelian Inheritance 45 TABLE 1. Features of inheritance patterns caused by repeat sequence mutations, mutations In genomic imprinting, and mitochondria! mutations Feature of disorder Qenomtc ImprintfriQ, Mtochondrtal mutation Intergeneration effects Primary feature: arrttclpatton No anticipation—but differences observed among generations Possible anticipation observed over one or two generations (heteroplasmy-»nomoplasmy) Parentof-origin effects Yes—parental effects differ for each disorder Primary feature: parental effects differ for each disorder Yes—always female effect Transmission Mendelian Mendelian Primary feature: only maternal transmission, no paternal transmission Sex ratio of affected individuals (malerfemale) 1:1 (unless X-Unked) 1:1 (unless X-llnked) 1:1 Sex ratio among carrier parents (male:female) Complex 1:0 or 0:1 0:1 observational biases" (1, p. 13). They also point out that clinicians, on the other hand, have insisted that anticipation was real, not just apparent, in myotonic dystrophy, although they accepted that the "geneticist should know best about behavior of genes" (1, p. 13). In 1984, a similar pattern of anticipation was observed for the fragile X syndrome, an inherited form of nonspecific X-linked mental retardation (5, 6). However, in this case there was not an increase in severity of the trait; instead, there was an increased risk for an offspring of an obligate carrier to exhibit the syndrome. Various complex genetic models were proposed to explain this pattern (e.g., see Israel (7) and Laird (8)) as well as ascertainment biases. It was not until 1991, when the gene responsible for the syndrome (FMR1) was isolated, that a biologic explanation was identified (9-12). Individuals can be characterized as 1) noncarriers, 2) carriers with no symptoms, or 3) carriers with the fragile X syndrome based on the length of their FMR1 gene. This length difference is due to the instability of a trinucleotide repeat sequence within the FMR1 gene. Once mutated, this sequence becomes unstable and most often expands in size when passed from parent to child, especially from mothers to their offspring. An individual expresses the fragile X syndrome when the repeat sequence exceeds 200 repeats. Identification of this dynamic repeat sequence mutation led to the examination of other disorders that showed anticipation. Myotonic dystrophy was the next disorder to be identified (13-15). The repeated sequence, and its location within the gene, differ from that in the fragile X gene; thus, characteristics of the expression of the trait differ. However, the main feature of anticipation remains; with each succeeding generation, the disorder becomes more severe in members carrying the mutation, and this severity is highly correlated with the length of Epidemiol Rev Vol. 19, No. 1, 1997 the repeat. Subsequently, at least seven other singlegene dominant disorders have been found to be due to mutations in a trinucleotide repeat sequence (for a review, see Ashley and Warren (16)). Each disorder is unique due to the position of the repeat sequence in the gene, the trinucleotide sequence itself, the function of the gene, and the parent-of-origin effects on the rate and size of expansion to the next generation. Irrespective, each disorder shows the general phenomenon of anticipation. Genomic imprinting Genomic imprinting refers to an epigenetic effect (i.e., a nonheritable effect) that causes differential expression of a gene depending on the sex of the transmitting parent (for a review, see Cassidy (17) and Langlois et al. (18)). Such effects are functional changes, not permanent changes, that occur through the modification of DNA or chromatin structure, although the details of the process are unknown. The imprinting process dictates the expression of a gene from only one parent of a certain sex rather than both genes of an homologous pair. Imprinting is a normal developmental process that regulates gene expression and is thought to affect only a relatively small number of genes. Research shows that the process leading to the imprint must have the following characteristics: 1) it is reversible through generations, 2) it leads to expression or repression of a gene, 3) the epigenetic factor is erased and reestablished according to the sex of the parent during gametogenesis, and 4) the imprint is faithfully maintained after DNA replication and thereby remains fixed through development and the lifetime of the individual. The first human disorder recognized to be the consequence of the alternation of genomic imprint- Downloaded from http://epirev.oxfordjournals.org/ at Pennsylvania State University on April 26, 2014 Repeat sequence mutation 46 Sherman Mitochondrial genome As reviewed by Grossman (26), the field of mitochondrial genetics has gone through three significant advances: The first advance was the discovery that mitochondria are essential for energy production in the cell; they are the "power plant" for eukaryotic cells. The second advance was the finding that mitochondria contain their own genome; each contains multiple copies (two to 10 copies) of a 16,569 base-pair circular DNA duplex. The 13 polypeptides encoded by the mitochondrial DNA (mtDNA) are all subunits of enzyme complexes involved in energy production. The other subunits (over 60) involved in this system are coded in the nuclear genome. The third, and most recent, advance is that mutations in the mtDNA lead to a number of genetic disorders. The full range of diseases that have a mitochondrial component is unknown but clearly involve rare disorders, such as Leber's hereditary optic neuropathy, and common disorders, including types of epilepsy and cardiomyopathy (for a review, see Schoffner and Wallace (27) and Wallace (28)). Disorders resulting from mitochondrial mutations are expected to involve multiple systems due to the key function of mitochondria, energy production. Depending on the type and function of the cell, the number of mitochondria per cell ranges from hundreds to thousands. As a consequence, the relation between phenotype and genotype is complex. Many times, there is extreme variation in the phenotype of known mitochondrial mutations. This may be due to intrinsic properties of the mitochondria and/or to genegene or gene-environment interactions. It is important to describe the features of mitochondrial genetics to understand the possible phenotypic outcomes. First, mtDNA is located in the cytoplasm. Only the cytoplasm from the egg is transmitted to the zygote, sperm rarely contribute mtDNA to the zygote. Thus, mothers and all their offspring share the same mtDNA. Second, there are thousands of mtDNA molecules per cell. Unlike nuclear DNA, mtDNA is randomly distributed to daughter cells (termed replicative segregation). If mutant mtDNA is present among normal mtDNA (a mixture of mutant and normal mtDNA referred to as heteroplasmy), the proportion of mutant to normal mtDNA can change after one cell division. Any two offspring are likely to receive different proportions of mutant mtDNA from a mother who is heteroplasmic. The resulting mtDNA of an offspring can be of essentially three states: a mixture of nonnal and mutant mtDNA (heteroplasmy), purely normal mtDNA, or purely mutant mtDNA (homoplasmy). This phenomenon potentially causes the phenotype observed among offspring to be variable. Epidemiol Rev Vol. 19, No. 1, 1997 Downloaded from http://epirev.oxfordjournals.org/ at Pennsylvania State University on April 26, 2014 ing was the Prader-Willi syndrome (19, 20). This is a complex multisystem disorder, including infantile hypotonia, hypogonadism, developmental delay/ mild mental retardation, hyperphagia leading to obesity, short stature, and dysmorphic features (21). It is now known that the Prader-Willi syndrome is caused by any mechanism that leads to the loss of the paternal contribution of a gene(s) in the chromosome region of 15ql 1—13. A completely different syndrome, the Angelman syndrome, occurs when the maternal genetic contribution is lost in this chromosome region (22). The Angelman syndrome is characterized by severe mental retardation, ataxia, seizures, unprovoked bursts of laughter, and dysmorphic features unlike those of the PraderWilli syndrome (23). Thus, in this chromosomal region genes are normally expressed only in a single dose, and such expression is regulated by imprinting. When the genetic contribution from one parent is missing, the balance of expression is disrupted. Recent research has shown that the genes contributing to the Prader-Willi and Angelman syndromes are different, but probably adjacent (24). Loss of the specific genetic material from a parent can result from deletions or uniparental disomy. Uniparental disomy occurs when both members of a chromosome pair in an offspring are inherited from only one parent. This is a sporadic event that sometimes results from abnormal segregation of a chromosome pair during meiosis. Alterations in imprinting can result also from specific mutations in regulatory sequences of a gene. Deletions and mutations in the imprinting process can lead to recurrent cases in families. Genomic imprinting is critical for normal development; when disrupted, human disorders result. A clear understanding of its function in normal development is unknown, although it does seem that some imprinted genes are important in growth. Molecular studies of cancers provide such evidence. Some cancers, including Wilms' tumor and retinoblastoma/osteosarcoma, show genetic alteration of the paternally-derived chromosome (for a review, see Sapienza and Hall (25)). It may be that the paternal allele of a tumor suppressor gene is normally inactive due to genomic imprinting. Loss of a maternal active allele may lead to abnormal cell growth and eventually to cancer. The mechanisms leading to imprinting, and ways to disrupt those processes, are active areas of research. Inevitably, alterations in imprinting will be found to be important in other complex phenotypes and/or imprinted genes will be found to modify phenotypes of single- or multigene disorders. Non-Mendelian Inheritance ANALYTIC APPROACHES TO IDENTIFY NONMENDELIAN TRAITS Specific analytic methods to investigate involvement of the three attributes of single genes leading to non-Mendelian inheritance have lagged behind those to identify single-gene Mendelian traits. This is not surprising, as the biologic causes of these patterns have been only recently understood. Issues concerning possible ascertainment biases that lead to nonMendelian patterns have been well defined and must be considered when examining any trait. Furthermore, traits due to X-linked genes and due to the vertical transmission of infectious agents may also show similar inheritance patterns as the ones discussed. Thus, uncovering evidence for specific biologic causes is a difficult task. Table 1 outlines the features of each type of mutation that need to be considered when hypothesizing non-Mendelian inheritance of a trait. As there is overlap of features, it may be possible only to narrow down possible alternatives. Although methods to identify each primary feature will be discussed separately, all aspects of the family data must be examined and evidence put together as a puzzle. Epidemiol Rev Vol. 19, No. 1, 1997 There are two general types of questions that can be asked concerning the involvement of the above properties. Perhaps the simplest is "Can one of these phenomena be me primary cause of the observed inheritance pattern?". This was the question asked for myotonic dystrophy. The more difficult question to ask is "if one of the components of a complex trait involves one of the three phenomena." For example, this question has been asked for bipolar affective disorder, which shows excess, but not exclusive, maternal inheritance. Correcting for ascertainment Before any analytic approach is taken to examine inheritance patterns, the scheme used to ascertain family data must be defined and a method to correct for that scheme implemented. If left uncorrected, resulting biases can mimic some of the features of nonMendelian inheritance. Ottman et al. (29) provide an example from their study of the inheritance of epilepsy. One approach to ascertain probands and their offspring was examination of medical records. Histories of epilepsy in mothers are routinely included in obstetric records, while those of fathers are not. Thus, this approach may lead to better ascertainment of offspring of affected mothers than of affected fathers resulting in a sample that looked like excess maternal inheritance. There are various ways to correct for ascertainment if there is a clear understanding of all potential biases. This is a feat in itself. A typical way to identify possible problems of ascertainment in family data is to test for homogeneity among sibships, ascertained in different ways but predicted to provide similar estimates of segregation parameters. An outline of methods to correct for ascertainment is beyond the scope of this review and, therefore, will be mentioned here only to warn the reader that correction must be done prior to any of the applied methods described below. Identifying group differences Intergenerational effects: anticipation. Anticipation leads to intergenerational effects of a particular pattern: the older generation shows less severe expression of a disorder than the subsequent generation. Many dynamic repeat sequence mutation disorders, and some disorders with mitochondrial mutations, show such effects. For mitochondrial mutations, anticipation usually is observed in the early generations after the initial mutation; the original mutation is present in a heteroplasmic state and quickly becomes fixed to a homoplastic state. Downloaded from http://epirev.oxfordjournals.org/ at Pennsylvania State University on April 26, 2014 There are also tissue-specific effects. These result from different proportions of mutant mtDNA in each cell lineage and also from different energy needs of each tissue. Thus, a specific mtDNA mutation may be expressed in different phenotypic forms in different individuals within the same pedigree. Categorizing individuals within a pedigree as "affected" may be problematic as they may have vastly different phenotypes. One feature that may reduce some of the variation relates to the threshold effect. A significant decrease in energy production per mitochondrion does not occur until the proportion of mutant mtDNA is high, suggesting a threshold effect. This effect may reduce the potential variation in the phenotype expected from the continuous distribution of the proportion of mutant mtDNA. Lastly, mutations in mtDNA occur at rates 10-20 times higher than in nuclear DNA, and those mutations quickly become fixed within a few generations. As a consequence, pedigrees showing recent mtDNA mutations may occur relatively frequently. Heteroplasmy is most often observed in individuals in the older generations where the initial mutation occurs. All the described features of mitochondrial genes inevitably lead to a complex phenotype within families when a mutation occurs. Additionally, there is known interaction between the nuclear and mitochondrial genes. Thus, it may be that many complex traits will result from an effect of the variation in mitochondrial genes. 47 48 Sherman syndrome and myotonic dystrophy, the risk to expand, and the size of that expansion, is much larger when the mutation is transmitted from the mother compared with that from the father. For Huntington disease, the opposite is true. Thus, die risk and size of expansion or contraction of die repeat sequence differs when transmitted from one parental sex versus the other. Again, this is an epigenetic effect, the mutated gene itself is transmitted in a Mendelian fashion. For mitochondrial mutations, the parent-of-origin effect results from transmission dirough ova, not through sperm. Thus, the transmission of the disorder can be examined together with parental effects to distinguish mitochondrial mutations from repeat sequence mutations and imprinting. The overall methodological approach is to compare the difference in penetrance or expression of the disorder in offspring of an affected mother versus an affected father. Ottman et al. (29) examined parental effects for epilepsy. Cumulative incidences of unprovoked seizures to age 25 years were 8.7 percent and 2.4 percent in offspring of affected mothers and affected fathers, respectively. Using Cox proportional hazards analysis to calculate rate ratios for seizures in offspring, they found mat the sex of the affected parent was significant, not the etiology of the parent's seizures. These results suggest a maternally transmitted influence on seizure susceptibility. Mili et al. (31) extended the approach used by Ottman et al. (29) to include other members in the pedigree, namely offspring of probands' sibs and offspring of probands' first cousins. McMahon et al. (32) examined parental effects on bipolar affective disorder. They compared frequencies and life-time risks of disease among offspring of transmitting mothers and fathers and among maternal versus paternal relatives of probands and found evidence for a maternal effect in transmission. Lichter et al. (33) took a similar approach to look for gender-related differences in expression of the Tourette syndrome. Univariate tests including analysis of variance (ANOVA) and Mann-Whitney statistic were used first to compare clinical profiles of subjects with maternal versus paternal inheritance of the Tourette syndrome. They also used principal component analysis to reduce the measures to summary variables, and dien used multiple analysis of covariances (MANCOVA) to compare maternal versus paternal inheritance groups on factor scores. They found that maternal transmission of the Tourette syndrome was associated with a different set of clinical variables compared with paternal transmission, consistent with genomic imprinting of the Tourette syndrome. Sun et al. (Emory University, Atlanta, Georgia, unpublished manuscript) described two statistical tests to Epidemiol Rev Vol. 19, No. 1, 1997 Downloaded from http://epirev.oxfordjournals.org/ at Pennsylvania State University on April 26, 2014 Examination of the correlation of age-of-onset or severity parameters between affected parent-offspring pairs and among affected sibs is an initial screen for anticipation. There should be a smaller correlation among parent-offspring pairs compared with sib pairs. Bell (3) clearly identified this pattern for myotonic dystrophy. Mclnnis et al. (30) examined anticipation in bipolar affective disorder. As an initial screen, they used lifetable analysis and Gehan's generalized Wilcoxon test to look at differences in parameters of severity between generations. They also used the Cox proportional hazards model to analyze relationships between generations and onset of disease while controlling for an effect of birth cohort, an obvious variable that may lead to spurious conclusions. Using these intergenerational comparisons, they found both an earlier age-ofonset and an increased disease severity in subsequent generations. Anticipation also may be observed as an increase in recurrence risk with each generation, instead of an increase in disease severity. This pattern was observed for the fragile X syndrome, and was revealed by examination of segregation ratios in each generation using both classic and complex segregation analyses (5, 6). A segregation ratio is defined as the proportion of affected offspring among the total number of offspring in a sibship. Briefly, the trait was assumed to be due to a single X-linked gene, and the penetrance (i.e., the probability of expressing the disorder given the abnormal genotype) was compared among the different sibships according to their position in the extended pedigree and according to phenotype of the mother (i.e., affected mother versus unaffected mother). Penetrance assuming an X-linked genetic model (which equals twice the segregation ratio) was estimated using maximum likelihood methods, and comparison of estimates for different types of sibships was done using tests of homogeneity. Significant heterogeneity was found; penetrance was significantly lower in sibships found in older generations compared with those in younger generations. Thus, traditional methods of segregation analysis were used to identify anticipation. Parent-of-origin and transmission effects. Parentof-origin effects result from all three phenomena; thus, this feature must be observed in concert with others to conclude one or the other phenomena. Parent-of-origin effects are the sine qua non of genomic imprinting. Imprinting is an epigenetic attribute of a gene—the imprinted gene itself is transmitted in a Mendelian fashion. The parent-of-origin effect seen among many, but not all, of the repeat sequence mutations behaves like an imprint, although die biologic cause of this effect is unknown. For example, for the fragile X Non-Mendelian Inheritance Epidemiol Rev Vol. 19, No. 1, 1997 lower risk in daughters of affected females is predicted, compared with daughters of affected males. Overall, different patterns of excess maternal inheritance based on the sex of a proband's offspring would be observed for rare X-linked traits. In contrast, for mitochondrial mutations, excess maternal inheritance is seen among all offspring of affected females compared with affected males. Other relative pairs also can be used to exclude X-linked inheritance, and results from different types of pairs should increase the power to distinguish models. The ability to distinguish maternal genomic imprinting from mitochondrial inheritance is more complicated than for X-linked mutations, and, in humans, may be possible only in the simplest case of complete penetrance and no phenocopies. As an example, assume that an imprinted nuclear mutation is inherited as an autosomal dominant and expressed only when transmitted through a female. Under this scenario, full pedigree analysis of at least three generations, or use of methods that examine relative pairs that span at least three generations, can distinguish maternal imprinting from mitochondrial models. Thus, using grandparent-grandchild pairs, the maternal imprinting model predicts that the risk to the offspring of an affected female's daughter would equal that to the offspring of an affected male's daughter. Under mitochondrial inheritance, the risks would be 1.0 and 0.0, respectively. Other methods using data that span only two generations cannot be used, as the pattern of excess maternal inheritance is the same for each model. So far, differentiation of models considering only genetic or epigenetic factors have been discussed. Other factors, such as intrauterine effects, differential reproductive fitness, and transmission of infectious agents may also exhibit patterns that look like nonMendelian inheritance. Thus, methods to distinguish features of each attribute must be applied before concluding one model or another. Fitting genetic models Another general approach to identify a specific genetic component involved in a trait is to develop a mathematical model of transmission, with all the complexities of the phenomena to be tested. Such work has been done for mitochondrial and cytoplasmic inheritance in plants (e.g., see Lichter et al. (34)) and for predominantly maternally transmitted infectious diseases (e.g., see Fine (35)). For genetic disorders in humans, Schork and Guo (36) presented a variety of likelihood-based models that account for the properties of mitochondrial genetics. As they comment, their work is only a preliminary exploration of the types of Downloaded from http://epirev.oxfordjournals.org/ at Pennsylvania State University on April 26, 2014 screen for involvement of mitochondrial mutations in a complex trait using properties of maternal transmission. They examined aspects of a one-sample and two-sample test using different types of relative pairs. The one-sample test compared the observed risk of a proband's relative with the maximum risk, assuming no involvement of mitochondrial mutations. If the observed risk is higher than expected under the null hypothesis, a mitochondrial mutation is implicated. The two-sample test compared the risk of proband relatives along the matrilineal line with those along the nonmatrilineal line. If mitochondrial mutations are involved, the risk would be higher among matrilineal relatives. The power of these tests was studied under a variety of inheritance models involving both nuclear and mitochondrial mutations. Other characteristics of disease patterns. Other characteristics of a disorder can be used to distinguish the possible attributes of single genes from other complex genetic models, including the sex ratio among affected individuals and among carrier parents (table 1). In this section, to lay the groundwork, several examples of approaches to distinguish models will be presented. A complex model to explain parent-of-origin differences is the sex-specific threshold model. It is assumed that genetic and/or environmental factors lead to sex-specific liability thresholds that cause one sex to be more susceptible to a disorder than another (e.g., model assumed for pyloric stenosis). If it is assumed that females have the higher liability or threshold, two predictions result. First, the risk among offspring of affected females will be higher than that for affected males. This observation would be identified by any test of group differences or segregation ratio differences as described above. Second, the disorder will be more frequent among males than among females in the general population and in offspring of affected parents. This observation would be inconsistent with, say, mitochondrial mutations. Thus, examination of population parameters, as well as inheritance parameters, provides support for one model over another. Inheritance patterns due to X-linked mutations may lead to excess maternal inheritance. Examination of the sex-specific parent-offspring pairs can distinguish rare X-linked mutations from mitochondrial mutations. X-linked recessive inheritance predicts a higher risk in sons of affected females compared with sons of affected males, and equal risks for daughters of affected females and of affected males. Therefore, excess maternal inheritance is restricted to sons of affected females. X-linked dominant inheritance predicts a higher risk in sons of affected females compared with those of affected males. However, a 49 50 Sherman SUMMARY From this overview it can be concluded that the understanding of the biologic properties and the development of analytic tools to identify repeat sequence mutations, genomic imprinting effects, and mitochondrial mutations are only beginning. Development of approaches to identify such phenomena as modifying effects or genetic components of complex traits is a new area of research. Not mentioned here are the ways in which locating a gene with such properties (i.e., linkage analysis) would be affected if such properties were not accounted for, or how to alter such analyses to obtain full information. Again, this is an exciting new area of research that will continue to motivate epidemiologists and geneticists. Hopefully, we have learned a lesson from the earlier conclusions of the studies on myotonic dystrophy: keep an open mind and never assume that the "geneticist should know best about behavior of genes". REFERENCES 1. Harper PS, Hartey HG, Reardon W, et al. Anticipation in myotonic dystrophy: new light on an old problem. Am J Hum Genet 1992;51:10-16. 2. Fleischer B. Ueber myotonische Dystrophie mit Katarakt; eine heriditSre, familiSre Degeneration. Arch. f. Ophth., Berl 1918; 96:91-133. 3. Bell J. Dystrophia myotonica and allied diseases. In: Penrose LS, ed. Treasury of human inheritance. Cambridge, England: Cambridge University Press, 1947:343-410. 4. Penrose LS. The problem of anticipation in pedigrees of dystrophia myotonica. Ann Eugen 1947-1949;14:125-32. 5. Sherman SL, Morton NE, Jacobs PA, et al. The marker (X) syndrome: a cytogenetic and genetic analysis. Ann Hum Genet 1984;48:21-37. 6. Sherman SL, Jacobs PA, Morton NE, et al. Further segregation analysis of the fragile X syndrome with special reference to transmitting males. Hum Genet 1985;69:289-99. 7. Israel MH. Autosomal suppressor gene for fragile-X: an hypothesis. Am J Med Genet 1987;26:19-31. 8. Laird CD. Proposed mechanism of inheritance and expression of the human fragile-X syndrome of mental retardation. Genetics 1987;117:587-99. 9. Fu YH, Kuhl DPA, Pizzuti A, et al. Variation of the CGG repeat at the fragile X site results in genetic instability: resolution of the Sherman paradox. Cell 1991;67:1047-58. 10. Oberle I, Rousseau F, Heitz D, et al. Instability of a 550-base pair DNA segment and abnormal methylation in fragile X syndrome. Science 1991;252:1097-102. 11. Verkerk AJMH, Pieretti M, Sutcliffe JS, et al. Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome. Cell 1991;65:905-14. 12. Yu S, Pritchard M, Kremer E, et al. Fragile X genotype characterized by an unstable region of DNA. Science 1991; 252:1179-81. 13. Buxton J, Shelboume P, Davies J, et al. Detection of an unstable fragment of DNA specific to individuals with myotonic dystrophy. Nature 1992;355:547-8. 14. Aslanidis C, Jansen G, Amemiya C, et al. Cloning of the essential myotonic dystrophy region and mapping of the putative defect Nature 1992,355:548-51. 15. Brook JD, McCurrach ME, Hariey HG, et al. Molecular basis of myotonic dystrophy: expansion of a trinucleotide (CTG) repeat at the 3' end of a transcript encoding a protein kinase family member. Cell 1992;68:799-808. 16. Ashley CT Jr, Warren ST. Trinucleotide repeat expansion and human disease. Annu Rev Genet 1995;29:703-28. 17. Cassidy SB. Uniparental disomy and genomic imprinting as causes of human genetic disease. Environ Mol Mutagen 1995; 25(Suppl 26): 13-20. 18. Langlois S, Lopez-Rangel E, Hall JG. New mechanisms for genetic disease and nontraditional modes of inheritance. Adv Pediatr 1995;42:91-111. 19. Knoll JHM, Nicholls RD, Magenis RE, et al. Angelman and Prader-Willi syndromes share a common chromosome 15 deletion but differ in parental origin of the deletion. Am J Med Genet 1989;32:285-90. 20. Nicholls RD, Knoll JHM, Butler MG, et al. Genetic imprinting suggested by maternal heterodisomy in nondeletion PraderWilli syndrome. Nature 1989;342:281-5. 21. Cassidy SB. Prader-Willi syndrome. Curr Probl Pediatr 1984; 14:1-55. 22. Magenis RE, Brown MG, Lacey DA, et al. Is Angelman syndrome an alternate result of del(15)(qllql3)? Am J Med Genet 1987;28:829-38. 23. Clayton-Smith J, Pembrey ME. Angelman syndrome. J Med Genet 1992;29:412-15. 24. Kuwano A, Mutirangura A, Dittrich B, et al. Molecular dissection of the Prader-Willi/Angelman syndrome region Epidemiol Rev Vol. 19, No. 1, 1997 Downloaded from http://epirev.oxfordjournals.org/ at Pennsylvania State University on April 26, 2014 possible models that could be used to identify a mitochondrial component in a complex trait. More work to examine the power of such an approach, and the ability to test the fit of various genetic models using a hierarchical likelihood approach, is needed. Another type of a model-fitting approach is that used by Boehnke et al. (37) to explain anticipation (observed as an earlier age-of-onset) and parent-oforigin effects seen in families with Huntington disease. This analysis was done prior to the identification of a repeat sequence mutation mechanism. They proposed two models in which a maternal factor acts to delay onset: a cytoplasmic model and an autosomal or X-linked modifying gene model. Based on the mathematical formulation of these models, they made predictions of the age-of-onset among different relative pairs. Subsequently, they compared the predictions of the two models to their empirical data on relative pairs. As both models fit the data rather well, they concluded that more data on specific relative pairs were needed to distinguish their proposed models. A similar framework has been presented by Risch (38) using empirical risk ratio patterns among many different relative types to obtain information about specific models. The predictions of risk ratios were based on the formulation of complex genetic models involving autosomal genes. Such methods could be extended for any of the three phenomena described above. Non-Mendelian Inheritance 25. 26. 27. 28. 29. 30. Epidemiol Rev Vol. 19, No. 1, 1997 32. McMahon FJ, Stine OC, Meyers DA, et al. Patterns of maternal transmission in bipolar affective disorder. Am J Hum Genet 1995;56:1277-86. 33. 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Hum Mol Genet 1992; 1:417-25. Sapienza C, Hall JG. Genetic imprinting in human disease. In: Scriver CR, Beaudet AL, Sly WS, et al., eds. The metabolic and molecular bases of inherited disease. 7th ed. New York, NY: McGraw-Hill, 1995:437-58. Grossman LI. Mitochondria] mutations and human disease. Environ Mol Mutagen 1995;25 (Suppl 26):30-7. Schoffner JM 4th, Wallace DC. Oxidative phosphorylation diseases: disorders in two genomes. Adv Hum Genet 1990; 19:267-330. Wallace DC. Diseases of the mitochondrial DNA. Annu Rev Biochem 1992;61:1175-212. Ottman R, Annegers JF, Hauser WA, et al. Higher risk of seizures in offspring of mothers than of fathers with epilepsy. Am J Hum Genet 1988;43:257-64. Mclnnis MG, McMahon FJ, Chase GA, et al. Anticipation in bipolar affective disorder. Am J Hum Genet 1993;53:385-90. Mili F, Flanders D, Sherman SL, et al. Genetic epidemiologic methods to screen for matrilinea] inheritance in mitochondrial disorders. Genet Epidemiol 1996;13:605-14. 51