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S L Sherman

Publications and source records attributed to S L Sherman.

At least 19 recordsLinked to original sources
PubMed2006

Relationship of recombination patterns and maternal age among non-disjoined chromosomes 21.

Advancing maternal age has long been identified as the primary risk factor for human chromosome trisomy. More recently, altered patterns of meiotic recombination have been found to be associated with non-disjunction. We have used trisomy 21 as a model for human non-disjunction that occurs during the formation of oocytes to understand the role of maternal age and recombination. Patterns of recombination that increase the risk for non-disjunction of chromosome 21 include absence of any exchange, an exchange near the centromere or a single, telomeric exchange. Our recent work has shown that different susceptibility patterns are associated with the origin of the meiotic error and maternal age. For MI (meiosis I) errors, the proportion of oocytes with susceptible recombination patterns is highest among young mothers and decreases significantly in the oldest age group. In fact, the pattern of exchanges among the oldest age group mimics the pattern observed among normally disjoining chromosomes 21. These results suggest that oocytes of younger women, with functional meiotic apparatus and/or robust ovarian environment, are able to properly resolve all but the most susceptible exchange patterns. As women age, however, meiotic mechanisms erode, making it difficult to resolve even stable exchange events. Interestingly, our preliminary recombination results on MII errors reveal the opposite relationship with maternal age: susceptible pericentromeric exchanges occur most often in the older age group compared with the younger age group. If confirmed, we will have further evidence for multiple risk factors for non-disjunction that act at different times in the meiotic process.

Chromosomes, Human, Pair 21↗
PubMed2005

Effect of meiotic recombination on the production of aneuploid gametes in humans.

Within the last decade, aberrant meiotic recombination has been confirmed as a molecular risk factor for chromosome nondisjunction in humans. Recombination tethers homologous chromosomes, linking and guiding them through proper segregation at meiosis I. In model organisms, mutations that disturb the recombination pathway increase the frequency of chromosome malsegregation and alterations in both the amount and placement of meiotic recombination are associated with nondisjunction. This association has been established for humans as well. Significant alterations in recombination have been found for all meiosis I-derived trisomies studied to date and a subset of so called "meiosis II" trisomy. Often exchange levels are reduced in a subset of cases where the nondisjoining chromosome fails to undergo recombination. For other trisomies, the placement of meiotic recombination has been altered. It appears that recombination too near the centromere or too far from the centromere imparts an increased risk for nondisjunction. Recent evidence from trisomy 21 also suggests an association may exist between recombination and maternal age, the most widely identified risk factor for aneuploidy. Among cases of maternal meiosis I-derived trisomy 21, increasing maternal age is associated with a decreasing frequency of recombination in the susceptible pericentromeric and telomeric regions. It is likely that multiple risk factors lead to nondisjunction, some age dependent and others age independent, some that act globally and others that are chromosome specific. Future studies are expected to shed new light on the timing and placement of recombination, providing additional clues to the link between altered recombination and chromosome nondisjunction.

Aneuploidy↗
PubMed2005

Risk factors for nondisjunction of trisomy 21.

The leading cause of Down syndrome (DS) is nondisjunction of chromosome 21 occurring during the formation of gametes. In this review, we discuss the progress made to identify risk factors associated with this type of chromosome error occurring in oogenesis and spermatogenesis. For errors occurring in oocytes, the primary risk factors are maternal age and altered recombination. We review the current progress made with respect to these factors and briefly outline the potential environmental and genetic influences that may play a role. Although the studies of paternal nondisjunction are limited due to the relatively small proportion of errors of this type, we review the potential influence of paternal age, recombination and other environmental and genetic factors on susceptibility. Although progress has been made to understand the mechanisms and risk factors that underlie nondisjunction, considerably more research needs to be conducted to dissect this multifactorial trait, one that has a considerable impact on our species.

Adolescent↗
PubMed2004

Association of FMR1 repeat size with ovarian dysfunction.

BACKGROUND: Women who carry the FMR1 premutation allele have a significantly increased risk for ovarian dysfunction. We hypothesize that molecular characteristics of the FMR1 gene may explain this increased risk. METHODS: Thus, we examined the effect of FMR1 CGG repeat size and related factors on measures of ovarian dysfunction using data from 507 women with a wide range of repeat sizes. RESULTS AND CONCLUSIONS: We found a significant positive association of repeat size with ovarian dysfunction, but have preliminary evidence that this relationship is non-linear. We suggest that FMR1 repeat size in the lower range (<80 repeats) contributes to the variation in age at menopause; thus, FMR1 could be considered a quantitative trait locus. More importantly, when repeat size exceeds this threshold, the increase in risk for ovarian dysfunction is clinically significant. Intriguingly, this risk appears to plateau, or perhaps decrease, among women with very high repeats (> or =100 repeats).

Adolescent↗
PubMed2002

Cognitive and behavioral performance among FMR1 high-repeat allele carriers surveyed from special education classes.

The fragile X syndrome is caused by an unstable CGG repeat sequence in the 5' untranslated region of the X-linked, FMR1 gene. When the number of repeats exceeds 200, the region is hypermethylated and the gene is silenced. The lack of the protein produced by the FMR1 gene, FMRP, causes the fragile X syndrome. Recent evidence suggests that FMR1 alleles with unmethylated long repeat tracks (40-200 repeats) may cause a specific somatic phenotype in women, premature ovarian failure, and may cause variation in the levels of FMR1 mRNA and FMRP. Because FMR1 is known to be involved in the regulation of subset of genes expressed in the brain, we investigated the variation in cognitive and/or behavioral performance among carriers of high repeat alleles. Specifically, we administered cognitive, behavioral, and adaptive performance tests to children identified with high repeat alleles who attended special education classes in Atlanta, Georgia public schools and to those with < 40 repeats drawn from the same population. Overall, we found no significant effect of repeat size and the psychometric measures in our test battery after adjustment for multiple comparisons. All scales were found to be within 1 SD standard deviation of the mean. We did find an intriguing, albeit marginally statistically significant, association in the cognitive profile among males and not females, consistent with an X-linked effect. After adjusting for the overall cognitive abilities score, Verbal Ability scores decreased and Nonverbal Reasoning scores increased with repeat number to a greater extent in males than females. Spatial Ability scores were not associated with repeat number.

Adaptation, Psychological↗
PubMed2001

Multipoint genetic mapping with trisomy data.

Trisomy is the most common genetic abnormality in humans and is the leading cause of mental retardation. Although molecular studies that use a large number of highly polymorphic markers have been undertaken to understand the recombination patterns for chromosome abnormalities, there is a lack of multilocus approaches to incorporating crossover interference in the analysis of human trisomy data. In the present article, we develop two statistical methods that simultaneously use all genetic information in trisomy data. The first approach relies on a general relationship between multilocus trisomy probabilities and multilocus ordered-tetrad probabilities. Under the assumption that no more than one chiasma exists in each marker interval, we describe how to use the expectation-maximization algorithm to examine the probability distribution of the recombination events underlying meioses that lead to trisomy. One limitation of the first approach is that the amount of computation increases exponentially with the number of markers. The second approach models the crossover process as a chi(2) model. We describe how to use hidden Markov models to evaluate multilocus trisomy probabilities. Our methods are applicable when both parents are available or when only the nondisjoining parent is available. For both methods, genetic distances among a set of markers can be estimated and the pattern of overall chiasma distribution can be inspected for differences in recombination between meioses exhibiting trisomy and normal meioses. We illustrate the proposed approaches through their application to a set of trisomy 21 data.

Algorithms↗
PubMed2000

Factors involved in the initial mutation of the fragile X CGG repeat as determined by sperm small pool PCR.

The fragile X syndrome is one of more than a dozen genetic diseases attributed to the amplification of a trinucleotide repeat. Despite the number of these disease loci, relatively little is known about the mechanism(s) that cause a stable allele to become unstable. Population and family studies of the fragile X CGG repeat have identified a number of factors that may play a role in repeat instability including the number of AGG interruptions, purity of the 3' and 5' end of the repeat and cis-acting factors as related to haplotype background. However, studies that assess whether these factors have an impact on the rate and magnitude of change of the repeat are lacking, mainly due to the lack of an appropriate model system. Therefore, in order to dissect the factors involved in the initial mutations of the CGG repeat, small pool (SP)-PCR was performed on DNA derived from sperm and blood from seven unaffected males whose repeat sizes range from 20 to 33. Using the SP-PCR-derived data, regression analyses suggested that components of the repeat structure such as the number of interruptions and purity of the 3' end of the repeat are important determinants of germline repeat instability. In contrast, elements other than repeat structure, such as haplotype background, seemed to have an impact on somatic repeat instability. The factors identified for either cell type, however, explained only a small portion of the variance, suggesting that other factors may be involved in this process.

Adult↗
PubMed2000

Polymorphisms in genes involved in folate metabolism as maternal risk factors for Down syndrome.

Down syndrome is a complex genetic and metabolic disorder attributed to the presence of three copies of chromosome 21. The extra chromosome derives from the mother in 93% of cases and is due to abnormal chromosome segregation during meiosis (nondisjunction). Except for advanced age at conception, maternal risk factors for meiotic nondisjunction are not well established. A recent preliminary study suggested that abnormal folate metabolism and the 677C-->T polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene may be maternal risk factors for Down syndrome. The present study was undertaken with a larger sample size to determine whether the MTHFR 677C-->T polymorphism was associated with increased risk of having a child with Down syndrome. Methionine synthase reductase (MTRR) is another enzyme essential for normal folate metabolism. A common polymorphism in this gene was recently associated with increased risk of neural tube defects and might also contribute to increased risk for Down syndrome. The frequencies of the MTHFR 677C-->T and MTRR 66A-->G mutations were evaluated in DNA samples from 157 mothers of children with Down syndrome and 144 control mothers. Odds ratios were calculated for each genotype separately and for potential gene-gene interactions. The results are consistent with the preliminary observation that the MTHFR 677C-->T polymorphism is more prevalent among mothers of children with Down syndrome than among control mothers, with an odds ratio of 1.91 (95% confidence interval [CI] 1.19-3.05). In addition, the homozygous MTRR 66A-->G polymorphism was independently associated with a 2. 57-fold increase in estimated risk (95% CI 1.33-4.99). The combined presence of both polymorphisms was associated with a greater risk of Down syndrome than was the presence of either alone, with an odds ratio of 4.08 (95% CI 1.94-8.56). The two polymorphisms appear to act without a multiplicative interaction.

Adult↗
PubMed2000

Fragile X CGG repeat structures among African-Americans: identification of a novel factor responsible for repeat instability.

The cryptic CGG repeat responsible for the fragile X syndrome, located in the 5'-UTR of FMR1, is unique compared with the many other triplet repeat-causing diseases, making it ideal for identifying factors involved in repeat expansion that may be common to other triplet repeat diseases. To date, a number of factors have been identified which may influence repeat instability, including the number and position of interspersed AGGs, length of the 3' pure CGG repeat and haplotype background. However, nearly all such data were derived from studies of Caucasians. Using a large African-American population, we present the only comprehensive examination of factors associated with CGG repeat instability in a non-Caucasian population. Among Caucasians, susceptible alleles were thought to come from those in the intermediate repeat range (41-60 repeats); however, we find that susceptible alleles may come from a larger repeat pool (35-60 repeats) and are better defined by their pure CGG repeat and/or -presence of only one AGG interruption. These results demonstrate the existence of different susceptible alleles among world populations and may account for the similar prevalence of the fragile X syndrome in African-Americans compared with Caucasians despite the lower frequency of inter-mediate sized alleles in the African-American population. Finally, we show that repeat structures among unaffected African-Americans with the most frequent fragile X haplotype background are either pure or contain a single distal interruption. We propose that the lack of a proximal most interruption is a novel factor involved in CGG repeat instability.

5' Untranslated Regions↗
PubMed2000

Women with a reduced ovarian complement may have an increased risk for a child with Down syndrome.

Advanced maternal age is the only well-established risk factor for trisomy 21 Down syndrome (DS), but the basis of the maternal-age effect is not known. In a population-based, case-control study of DS, women who reported surgical removal of all or part of an ovary or congenital absence of one ovary were significantly more likely to have delivered a child with DS than were women who did not report a reduced ovarian complement (odds ratio 9.61; 95% confidence interval 1.18-446.3). Because others have observed that women who have had an ovary removed exhibit elevated levels of FSH and similar hallmarks of advanced maternal age, our finding suggests that the physiological status of the ovary is key to the maternal-age effect. In addition, it suggests that women with a reduced ovarian complement should be offered prenatal diagnosis.

Adolescent↗
PubMed2000

Genome-wide variation in recombination in female meiosis: a risk factor for non-disjunction of chromosome 21.

Altered recombination patterns along non-disjoined chromosomes is the first molecular correlate identified for non-disjunction in humans. To understand better the factors related to this correlate, we have asked to what extent is recombination altered in an egg with a disomic chromosome: are patterns limited to the non-disjoined chromosome or do they extend to the entire cell? More specifically, we asked whether there is reduced recombination in the total genome of an egg with a non-disjoined chromosome 21 and no detectable recombination. We chose this subclass of non-disjoined chromosomes to enrich potentially for extremes in recombination. We found a statistically significant cell-wide reduction in the mean recombination rate in these eggs with non-disjoined chromosomes 21; no specific chromosomes were driving this effect. Most importantly, we found that this reduction was consistent with normal variation in recombination observed among eggs. Thus, given that recombination is a multifactorial trait, these data suggest that when the number of genome-wide recombination events is less than some threshold, specific chromosomes may be at an increased risk for non-disjunction. Further studies are required to confirm these results, to determine the importance of genetic and environmental factors that regulate recombination and to determine their impact on non-disjunction.

Adult↗
PubMed2000

Premature ovarian failure in the fragile X syndrome.

The full mutation leading to the fragile X syndrome is a dynamic trinucleotide repeat located in the 5' untranslated region of the FMR1 gene. The premutation allele contains approximately 60 to 199 repeats, is unstable, and originally not considered detrimental; that is, there did not appear to be a phenotype consequence of the long repeat tract. However, in the late 1980s and early 1990s, preliminary findings suggested that nonimpaired heterozygotes were at risk of early menopause and increased rates of twinning, both indications of ovarian failure. Once premutation carriers could be distinguished from full mutation carriers, this phenotype was found to be restricted to premutation carriers only. Based on the recent studies reviewed here, approximately 21% of premutation carriers have premature ovarian failure (POF) compared to only 1% in the general population, or a relative risk of 21. Moreover, among women with idiopathic sporadic or the more rare form of familial POF, approximately 2% and 14%, respectively, carry the premutation. To date, data supporting increased twinning rates are conflicting and need to be resolved. Neither the underlying cellular pathophysiology of POF caused by the premutation allele nor molecular mechanism underlying the presence of the long repeat tract of the premutation allele is understood. Irrespective, women who carry the premutation allele should have not only genetic counseling but also fertility counseling to ensure that they reach their goals for reproduction.

Aging↗
PubMed2000

Survey of the fragile X syndrome CGG repeat and the short-tandem-repeat and single-nucleotide-polymorphism haplotypes in an African American population.

Previous studies have shown that specific short-tandem-repeat (STR) and single-nucleotide-polymorphism (SNP)-based haplotypes within and among unaffected and fragile X white populations are found to be associated with specific CGG-repeat patterns. It has been hypothesized that these associations result from different mutational mechanisms, possibly influenced by the CGG structure and/or cis-acting factors. Alternatively, haplotype associations may result from the long mutational history of increasing instability. To understand the basis of the mutational process, we examined the CGG-repeat size, three flanking STR markers (DXS548-FRAXAC1-FRAXAC2), and one SNP (ATL1) spanning 150 kb around the CGG repeat in unaffected (n=637) and fragile X (n=63) African American populations and compared them with unaffected (n=721) and fragile X (n=102) white populations. Several important differences were found between the two ethnic groups. First, in contrast to that seen in the white population, no associations were observed among the African American intermediate or "predisposed" alleles (41-60 repeats). Second, two previously undescribed haplotypes accounted for the majority of the African American fragile X population. Third, a putative "protective" haplotype was not found among African Americans, whereas it was found among whites. Fourth, in contrast to that seen in whites, the SNP ATL1 was in linkage equilibrium among African Americans, and it did not add new information to the STR haplotypes. These data indicate that the STR- and SNP-based haplotype associations identified in whites probably reflect the mutational history of the expansion, rather than a mutational mechanism or pathway.

Black or African American↗
PubMed2000

Multipoint estimation of genetic maps for human trisomies with one parent or other partial data.

Centromeric-mapping methods have been used to investigate the association between altered recombination and meiotic nondisjunction in humans. For trisomies, current methods are based on the genotypes from a trisomic offspring and both parents. Because it is sometimes difficult to obtain samples from both parents and because the ability to use sources of DNA previously not available (e.g., stored paraffin-embedded pathological samples) has increased, we have been interested in creating similar maps for trisomic populations in which one of the parents of the trisomic individual is unavailable for genotyping. In this paper, we derive multipoint likelihoods for both missing-parent data and conventional two-parent data. We find that likelihoods for two-parent data and for data generated without a sample from the correctly disjoining parent can be maximized in exactly the same way but also that missing-parent data has a high frequency of partial data of the same sort produced by intercross matings. Previously published centromeric-mapping methods use incorrect likelihoods for intercross matings and thus can perform poorly on missing-parent data. We wrote a FORTRAN program to maximize our multipoint likelihoods and used it in simulation studies to demonstrate the biases in the previous methods.

Algorithms↗
PubMed1999

Prevalence and phenotype consequence of FRAXA and FRAXE alleles in a large, ethnically diverse, special education-needs population.

We conducted a large population-based survey of fragile X (FRAXA) syndrome in ethnically diverse metropolitan Atlanta. The eligible study population consisted of public school children, aged 7-10 years, in special education-needs (SEN) classes. The purpose of the study was to estimate the prevalence among whites and, for the first time, African Americans, among a non-clinically referred population. At present, 5 males with FRAXA syndrome (4 whites and 1 African American), among 1,979 tested males, and no females, among 872 tested females, were identified. All males with FRAXA syndrome were mentally retarded and had been diagnosed previously. The prevalence for FRAXA syndrome was estimated to be 1/3,460 (confidence interval [CI] 1/7,143-1/1,742) for the general white male population and 1/4, 048 (CI 1/16,260-1/1,244) for the general African American male population. We also compared the frequency of intermediate and premutation FRAXA alleles (41-199 repeats) and fragile XE syndrome alleles (31-199 repeats) in the SEN population with that in a control population, to determine if there was a possible phenotype consequence of such high-repeat alleles, as has been reported previously. No difference was observed between our case and control populations, and no difference was observed between populations when the probands were grouped by a rough estimate of IQ based on class placement. These results suggest that there is no phenotype consequence of larger alleles that would cause carriers to be placed in an SEN class.

Alleles↗
PubMed1998

Population-based study of congenital heart defects in Down syndrome.

Mental retardation and hypotonia are found in virtually all Down syndrome (DS) individuals, whereas congenital heart defects (CHDs) are only present in a subset of cases. Although there have been numerous reports of the frequency of CHDs in DS, few of the studies have had complete ascertainment of DS in a defined geographic area. The Atlanta Down Syndrome Project, a population-based study of infants born with trisomy 21, provides such a resource. In the first 6.5 years of the study, 243 trisomy 21 livebirths were identified in the five-county Atlanta area (birth prevalence: 9.6/10,000). Cardiac diagnoses were available on 227 (93%) of the cases and 89% of these evaluations were made by echocardiography, cardiac catheterization, surgery, or autopsy. Of the 227 DS infants, 44% had CHDs including 45% atrioventricular septal defect (with or without other CHDs), 35% ventricular septal defect (with or without other CHDs), 8% isolated secundum atrial septal defect, 7%, isolated persistent patent ductus arteriosus, 4% isolated tetralogy of Fallot, and 1% other. This report is unique in that it contains the largest number of trisomy 21 infants ascertained in a population-based study where modern techniques for diagnosing cardiac abnormalities predominate.

Down Syndrome↗
PubMed1998

Testing for contributions of mitochondrial DNA mutations to complex diseases.

Several complex disorders are suspected of being associated with mitochondrial DNA (mtDNA) mutations. We studied the statistical properties of a test based on proband-relative pairs to identify potential mtDNA mutation involvement in a complex disorder. The test compares the recurrence risk of relatives of probands along the mitochondrial lineage with that of relatives along the nonmitochondrial lineage. If mtDNA mutations are involved, the recurrence risk will be higher among relatives in the mitochondrial lineage. The form of the test is independent of the assumed models of inheritance and interaction of the nuclear autosomal mutations with mtDNA mutations. The power of the test, however, differs among the different models and by the type of proband-relative pairs used in the test. We considered heterogeneity models with and without phenocopies, a three-state heteroplasmic mtDNA transmission model, and a multiplicative epistasis model. Under the heterogeneity model, the power of the test increases as the relationship between the proband and the relative becomes more distant. Under the multiplicative epistasis model, the power of the test decreases as the relationship between the proband and the relative becomes more distant.

DNA, Mitochondrial↗