Biomedical subjects

S L Sherman

Publications and source records attributed to S L Sherman.

At least 37 records · Page 2Linked to original sources

PubMed1998

Centromeric genotyping and direct analysis of nondisjunction in humans: Down syndrome.

In species with chiasmate meioses, alterations in genetic recombination are an important correlate of nondisjunction. In general, these alterations fall into one of two categories: either homologous chromosomes fail to pair and/or recombine at meiosis I, or they are united by chiasmata that are suboptimally positioned. Recent studies of human nondisjunction suggest that these relationships apply to our species as well. However, methodological limitations in human genetic mapping have made it difficult to determine whether the important determinant(s) in human nondisjunction is absent recombination, altered recombination, or both. In the present report, we describe somatic cell hybrid studies of chromosome 21 nondisjunction aimed at overcoming this limitation. By using hybrids to "capture" individual chromosomes 21 of the proband and parent of origin of trisomy, it is possible to identify complementary recombinant meiotic products, and thereby to uncover crossovers that cannot be detected by conventional mapping methods. In the present report, we summarize studies of 23 cases. Our results indicate that recombination in proximal 21q is infrequent in trisomy-generating meioses and that, in a proportion of the meioses, recombination does not occur anywhere on 21q. Thus, our observations indicate that failure to recombine is responsible for a proportion of trisomy 21 cases.

Centromere↗

PubMed1998

The relation of the dopamine transporter gene (DAT1) to symptoms of internalizing disorders in children.

The relation of the dopamine transporter gene (DAT1) to symptoms of internalizing disorders, Tourette's disorder, and obsessive-compulsive disorder was examined using both within- and between-family tests of association. The sample consisted of clinic-referred children and their siblings and controls and their siblings. Between-family association was examined via the association of DAT1 genotypes with disorder symptoms in the population. Symptoms of all eight disorders increased with a greater number of 10-repeat DAT1 alleles. Using a quantitative transmission disequilibrium test (QTDT), linkage and within-family association was indicated by increased symptoms in children who received 10 repeat alleles from heterozygous parents relative to children who received 9 repeat alleles. Four disorders were associated with DAT1 using the QTDT: generalized anxiety, social phobia, obsessive-compulsive, and Tourette's. The effects of comorbidity were investigated by repeating the same between- and within-family analyses on residual scores, with any effects of attention deficit hyperactivity disorder symptoms removed. Although the residuals were associated less strongly with DAT1 than were the original scores, three disorders continued to show association both between and within families: generalized anxiety, Tourette's, and social phobia.

Adolescent↗

PubMed1998

A branching non-linear autoregressive model for the transmission of the fragile X dynamic repeat mutation.

A non-linear time series version of a model for the transmission of fragile X previously described in Ashley & Sherman (1995) is developed. The model retains the biological features of the Ashley/Sherman model but is easier to generalize and in particular allows the inclusion of covariates such as haplotype to model different paths and random effects to model family effects. The model is fitted to data from Murray et al. (1997) and its properties are illustrated in a simulation study.

Female↗

PubMed1998

Examination of factors associated with instability of the FMR1 CGG repeat.

We examined premutation-female transmissions and premutation-male transmissions of the FMR1 CGG repeat to carrier offspring, to identify factors associated with instability of the repeat. First we investigated associations between parental and offspring repeat size. Premutation-female repeat size was positively correlated with the risk of having full-mutation offspring, confirming previous reports. Similarly, premutation-male repeat size was positively correlated with the daughter's repeat size. However, increasing paternal repeat size was associated also with both increased risk of contraction and decreased magnitude of the repeat-size change passed to the daughter. We hypothesized that the difference between the female and male transmissions was due simply to selection against full-mutation sperm. To test this hypothesis, we simulated selection against full-mutation eggs, by only examining premutation-female transmissions to their premutation offspring. Among this subset of premutation-female transmissions, associations between maternal and offspring repeat size were similar to those observed in premutation-male transmissions. This suggests that the difference between female and male transmissions may be due to selection against full-mutation sperm. Increasing maternal age was associated with increasing risk of expansion to the full mutation, possibly because of selection for smaller alleles within the offspring's soma over time; a similar effect of increasing paternal age may be due to the same selection process. Last, we have evidence that the reported association between offspring sex and risk of expansion may be due to ascertainment bias. Thus, female and male offspring are equally likely to inherit the full mutation.

Adult↗

PubMed1998

Association and linkage of the dopamine transporter gene and attention-deficit hyperactivity disorder in children: heterogeneity owing to diagnostic subtype and severity.

Attention-deficit hyperactivity disorder (ADHD) affects approximately 3%-5% of children in the United States. In the current psychiatric nomenclature, ADHD comprises three subtypes: inattentive, hyperactive-impulsive, and combined. In this study, we used four analytic strategies to examine the association and linkage of the dopamine transporter gene (DAT1) and ADHD. Our sample included 122 children referred to psychiatric clinics for behavioral and learning problems that included but were not limited to ADHD, as well as their parents and siblings. Within-family analyses of linkage disequilibrium, using the transmission disequilibrium test (TDT), confirmed the 480-bp allele as the high-risk allele. In between-family association analyses, levels of hyperactive-impulsive symptoms but not inattentive symptoms were related to the number of DAT1 high-risk alleles. Siblings discordant for the number of DAT1 high-risk alleles differed markedly in their levels of both hyperactive-impulsive and inattentive symptoms, such that the sibling with the higher number of high-risk alleles had much higher symptom levels. Within-family analyses of linkage disequilibrium, using the TDT, suggested association and linkage of ADHD with DAT1 and that this relation was especially strong with the combined but not the inattentive subtype. The relation of DAT1 to ADHD increased monotonically, from low to medium to high levels of symptom severity. Our results replicate and extend previous findings of the association between the DAT1 gene and childhood ADHD. This represents one of the first replicated relations of a candidate gene and a psychiatric disorder in children.

Alleles↗

PubMed1998

Re-examination of factors associated with expansion of CGG repeats using a single nucleotide polymorphism in FMR1.

In at least 98% of fragile X syndrome cases, the disease results from expansion of the CGG repeat in the 5' end of FMR1. The use of microsatellite markers in the FMR1 region has revealed a disparity of risk between haplotypes for CGG repeat expansion. Although instability appears to depend on both the haplotype and the AGG interspersion pattern of the repeat, these factors alone do not completely describe the molecular basis for the linkage disequilibrium between normal and fragile X chromosomes, in part due to instability of the marker loci themselves. In an effort to better understand the mechanism of dynamic mutagenesis, we have searched for and discovered a single nucleotide polymorphism in intron 1 of FMR1 and characterized this marker, called ATL1, in 564 normal and 152 fragile X chromosomes. The G allele of this marker is found in 40% of normal chromosomes, in contrast to 83% of fragile X chromosomes. Not only is the G allele exclusively linked to haplotypes over-represented in fragile X syndrome, but G allele chromosomes also appear to transition to instability at a higher rate on haplotypes negatively associated with risk of expansion. The two alleles of ATL1 also reveal a highly significant linkage disequilibrium between unstable chromosomes and the 5' end of the CGG repeat itself, specifically the position of the first AGG interruption. The data expand the number of haplotypes associated with FMR1 and specifically allow discrimination, by ATL1 alleles, of single haplotypes with differing predispositions to expansion. Such haplotypes should prove useful in further defining the mechanism of dynamic mutagenesis.

Adenine Nucleotides↗

PubMed1998

Elucidating the mechanisms of paternal non-disjunction of chromosome 21 in humans.

Paternal non-disjunction of chromosome 21 accounts for 5-10% of Down syndrome cases, therefore, relative to the maternally derived cases, little is known about paternally derived trisomy 21. We present the first analysis of recombination and non-disjunction for a large paternally derived population of free trisomy 21 conceptuses ( n = 67). Unlike maternal cases where the ratio of meiosis I (MI) to meiosis II (MII) errors is 3:1, a near 1:1 ratio exists among paternal cases, with a slight excess of MII errors. We found no paternal age effect for the overall population nor when classifying cases according to stage of non-disjunction error. Among 22 MI cases, only five had an observable recombinant event. This differs significantly from the 11 expected events ( P < 0.02, Fisher's exact), suggesting reduced recombination along the non-disjoined chromosomes 21 involved in paternal MI non-disjunction. No difference in recombination was detected among 27 paternal MII cases as compared with controls. However, cases exhibited a slight increase in the frequency of proximal and medial exchange when compared with controls (0.37 versus 0.28, respectively). Lastly, this study confirmed previous reports of excess male probands among paternally derived trisomy 21 cases. However, we report evidence suggesting an MII stage-specific sex ratio disturbance where 2.5 male probands were found for each female proband. Classification of MII cases based on the position of the exchange event suggested that the proband sex ratio disturbance was restricted to non-telomeric exchange cases. Based on these findings, we propose new models to explain the association between paternally derived trisomy 21 and excessive male probands.

Chromosomes, Human, Pair 21↗

PubMed1997

Sequential sib-pair and association studies to detect genes in quantitative traits.

We applied sib-pair and association methods to a GAW data set of nuclear families with quantitative traits. Our approaches included 1) preliminary statistical studies including correlations and linear regressions, 2) sib-pair methods, and 3) association studies. We used a single data set to screen for linkage and association and, subsequently, additional data sets to confirm the preliminary results. Using this sequential approach, sib-pair analysis provided evidence for the genes influencing Q1, Q2, and Q4. We correctly predicted MG1 for Q1, MG2 for Q2, and MG4 for Q4. We did not find any false positives using this approach. Association studies identified chromosomes 8 and 9 to be associated with Q4; however these are assumed to be false positives as no associations were modeled into the data.

Analysis of Variance↗

PubMed1997

Behavioral genetics '97: ASHG statement. Recent developments in human behavioral genetics: past accomplishments and future directions.

The field of behavioral genetics has enormous potential to uncover both genetic and environmental influences on normal and deviant behavior. Behavioral-genetic methods are based on a solid foundation of theories and methods that successfully have delineated components of complex traits in plants and animals. New resources are now available to dissect the genetic component of these complex traits. As specific genes are identified, we can begin to explore how these interact with environmental factors in development. How we interpret such findings, how we ask new questions, how we celebrate the knowledge, and how we use or misuse this knowledge are all important considerations. These issues are pervasive in all areas of human research, and they are especially salient in human behavioral genetics.

Adoption↗

PubMed1997

Estimating meiotic exchange patterns from recombination data: an application to humans.

We present analytical methods to estimate the recombinational history of chromosomes in a human population. Our analysis, similar to those utilized in Drosophila, can be used to construct meiotic maps based upon crossover frequencies observed in family data. We apply this method of exchange estimation to a population of paternally and maternally inherited chromosomes 21. The patterns of chromosomal exchange estimated by this type of analysis are comparable to those obtained by the more technically difficult method of cytologically counting chiasmata among human male meiotic events (sperm). This type of analysis can be applied to both male and female meiosis, circumventing many technical problems inherent to cytological counting. Moreover, the distribution of exchange locations along a chromosome for each exchange type (i.e., single, double, or triple exchanges) can be examined individually, an advantage compared to examination of genetic maps that only provide a summary of these distributions. We discuss how this analysis can be used to examine various assumptions concerning meiotic exchange in humans and investigate properties of the analysis that contribute to the accuracy of the results.

Female↗

PubMed1997

Characterization of susceptible chiasma configurations that increase the risk for maternal nondisjunction of chromosome 21.

Recent studies of trisomy 21 have shown that altered levels of recombination are associated with maternal non-disjunction occurring at both meiosis I (MI) and meiosis II (MII). To comprehend better the association of recombination with nondisjunction, an understanding of the pattern of meiotic exchange, i.e. the exchange of genetic material at the four-strand stage during prophase, is required. We examined this underlying exchange pattern to determine if specific meiotic configurations are associated with a higher risk of non-disjunction than others. We examined the crossover frequencies of chromosome 21 for three populations: (i) normal female meiotic events; (ii) meiotic events leading to MI non-disjunction; and (iii) those leading to MII non-disjunction. From these crossover frequencies, we estimated the array of meiotic tetrads that produced the observed crossovers. Using this approach, we found that nearly one-half of MI errors were estimated to be achiasmate. The majority of the remaining MI bivalents had exchanges that clustered at the telomere. In contrast, exchanges occurring among MII cases clustered at the pericentromeric region of the chromosome. Unlike the single exchange distributions, double exchanges from the non-disjoined populations seemed to approximate the distribution in the normal population. These data suggest that the location of certain exchanges makes a tetrad susceptible to non-disjunction. Specifically, this susceptibility is associated with the distance between the centromere and closest exchange. This result challenges the widely held concept that events occurring at MII are largely independent of events occurring at MI, and suggests that all non-disjunction events may be initiated during MI and simply resolved at either of the two meiotic stages.

Chromosomes, Human, Pair 21↗

PubMed1997

Evolving methods in genetic epidemiology. IV. Approaches to non-Mendelian inheritance.

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".

Epidemiologic Methods↗

PubMed1996

Examination of factors that influence the expansion of the fragile X mutation in a sample of conceptuses from known carrier females.

The Collaborative Prospective Fragile X Study was established to collect information on the pregnancy outcome of women known to be carriers of the fragile X syndrome. The prospective design of this study allows collection of ascertainment-free data and, thereby, avoids biases caused by sampling problems encountered in retrospective family studies. The results of 337 submitted cases are summarized. These data show that the segregation of the fragile X mutation is normal and the sex ratio of conceptuses is as expected for a prenatal sample. There is no excess of dizygotic twinning among the pre- or full mutation carrier females. Data are limited at this time but provide a suggestion that the risk of expansion to the full mutation may be correlated with maternal age and to the parental origin of premutation of carrier women. More data are needed to confirm these suggested trends. The prospective data base provides a valuable resource to continue to examine factors in an unbiased fashion.

Adult↗

PubMed1996

Survey of the fragile X syndrome and the fragile X E syndrome in a special education needs population.

To begin to understand the population dynamics of the fragile X (FRAXA) mutation and to learn more about the fragile X E (FRAXE) syndrome, we have initiated a surve of children in special needs education programs in the public school system. With respect to the FRAXA syndrome, we found approximately 1/1,000 full mutations among males. No large alleles at the FRAXE locus were observed among 462 individuals. The allele distributions at the two loci among Caucasians and among African Americans were examined as well as the level of heterozygosity. We found a significant difference in the FRAXA allele distribution among the two ethnic groups; the major difference was due to the lack of smaller alleles among the African Americans. No difference was found for the FRAXE allele distribution among the two groups. The level of heterozygosity was less than predicted by the allele distribution at both loci. This is probably due to unidentified large alleles among females with a test result of a single band. Alternatively, this excess may indicate that the population is not at equilibrium.

Black or African American↗

PubMed1996

Genetic epidemiologic methods to screen for matrilineal inheritance in mitochondrial disorders.

We propose a method to screen for the matrilineal inheritance in mitochondrial disorders by comparing the risk of disease in a person whose mother is affected or whose maternal grandmother or aunt or uncle is affected to the risk of disease in a person whose father is affected or whose paternal grandmother or aunt or uncle is affected using a modification of the reconstructed cohort design. Sampling of pedigrees is accomplished via probands and must not be influenced by family history. The cohort of the proband's offspring, and offspring of the proband's siblings, can be analyzed using survival analysis. Cox proportional hazards model, Bonney's [(1986) Biometrics 42:611-625] model, and Liang's [(1991) Genet Epidemiol 8:329-338] model. Mitochondrial transmission can be distinguished from X-linked transmission by examining sex-specific patterns of disease expression in matrilineally transmitted diseases. To illustrate our epidemiologic method, we apply our screening method to pedigrees of two disorders which have been proposed to have a mitochondrial DNA component to their inheritance.

Bipolar Disorder↗

PubMed1996

Susceptible chiasmate configurations of chromosome 21 predispose to non-disjunction in both maternal meiosis I and meiosis II.

The cause of non-disjunction of chromosome 21 remains largely unknown. Advanced maternal age is associated with both maternal meiosis I (MI) and meiosis II (MII) non-disjunction events. While reduced genetic recombination has been demonstrated in maternal MI errors, the basis for MII errors remains uncertain. We studied 133 trisomy 21 cases with maternal MII errors to test the hypothesis that segregation at MII may also be influenced by genetic recombination. Our data support a highly significant association: MII non-disjunction involves increased recombination that is largely restricted to proximal 21q. Thus, while absence of a proximal recombination appears to predispose to non-disjunction in MI, the presence of a proximal exchange predisposes to non-disjunction in MII. These findings profoundly affect our understanding of trisomy 21 as they suggest that virtually all maternal non-disjunction results from events occurring in meiosis I.

Adult↗

PubMed1996

Statistical models for trisomic phenotypes.

Certain genetic disorders are rare in the general population but more common in individuals with specific trisomies, which suggests that the genes involved in the etiology of these disorders may be located on the trisomic chromosome. As with all aneuploid syndromes, however, a considerable degree of variation exists within each phenotype so that any given trait is present only among a subset of the trisomic population. We have previously presented a simple gene-dosage model to explain this phenotypic variation and developed a strategy to map genes for such traits. The mapping strategy does not depend on the simple model but works in theory under any model that predicts that affected individuals have an increased likelihood of disomic homozygosity at the trait locus. This paper explores the robustness of our mapping method by investigating what kinds of models give an expected increase in disomic homozygosity. We describe a number of basic statistical models for trisomic phenotypes. Some of these are logical extensions of standard models for disomic phenotypes, and some are more specific to trisomy. Where possible, we discuss genetic mechanisms applicable to each model. We investigate which models and which parameter values give an expected increase in disomic homozygosity in individuals with the trait. Finally, we determine the sample sizes required to identify the increased disomic homozygosity under each model. Most of the models we explore yield detectable increases in disomic homozygosity for some reasonable range of parameter values, usually corresponding to smaller trait frequencies. It therefore appears that our mapping method should be effective for a wide variety of moderately infrequent traits, even though the exact mode of inheritance is unlikely to be known.

Abortion, Spontaneous↗

PubMed1996

Advanced maternal age and the risk of Down syndrome characterized by the meiotic stage of chromosomal error: a population-based study.

The identification of DNA polymorphisms makes it possible to classify trisomy 21 according to the parental origin and stage (meiosis I [MI], meiosis II [MII], or postzygotic mitotic) of the chromosomal error. Studying the effect of parental age on these subgroups could shed light on parental exposures and their timing. From 1989 through 1993, 170 infants with trisomy 21 and 267 randomly selected control infants were ascertained in a population-based, case-control study in metropolitan Atlanta. Blood samples for genetic studies were obtained from case infants and their parents. Using logistic regression, we independently examined the association between maternal and paternal age and subgroups of trisomy 21 defined by parental origin and meiotic stage. The distribution of trisomy 21 by origin was 86% maternal (75% MI and 25% MII), 9% paternal (50% MI and 50% MII), and 5% mitotic. Compared with women <25 years of age, women > or = 40 years old had an odds ratio of 5.2 (95% confidence interval, 1.0-27.4) for maternal MI (MMI) errors and 51.4 (95% confidence interval, 2.3-999.0) for maternal MII (MMII) errors. Birth-prevalence rates for women > or = 40 years old were 4.2/1000 births for MMI errors and 1.9/1000 for MMII errors. These results support an association between advanced maternal age and both MMI and MMII errors. The association with MI does not pinpoint the timing of the error; however, the association with MII implies that there is at least one maternal-age related mechanism acting around the time of conception.

Adult↗