Biomedical subjects

A A Schäffer

Publications and source records attributed to A A Schäffer.

At least 19 recordsLinked to original sources

PubMed2005

Mutations in TNFRSF13B encoding TACI are associated with common variable immunodeficiency in humans.

The functional interaction of BAFF and APRIL with TNF receptor superfamily members BAFFR, TACI and BCMA is crucial for development and maintenance of humoral immunity in mice and humans. Using a candidate gene approach, we identified homozygous and heterozygous mutations in TNFRSF13B, encoding TACI, in 13 individuals with common variable immunodeficiency. Homozygosity with respect to mutations causing the amino acid substitutions S144X and C104R abrogated APRIL binding and resulted in loss of TACI function, as evidenced by impaired proliferative response to IgM-APRIL costimulation and defective class switch recombination induced by IL-10 and APRIL or BAFF. Family members heterozygous with respect to the C104R mutation and individuals with sporadic common variable immunodeficiency who were heterozygous with respect to the amino acid substitutions A181E, S194X and R202H had humoral immunodeficiency. Although signs of autoimmunity and lymphoproliferation are evident, the human phenotype differs from that of the Tnfrsf13b-/- mouse model.

Amino Acid Sequence↗

PubMed2003

Linkage of autosomal dominant common variable immunodeficiency to chromosome 5p and evidence for locus heterogeneity.

Common variable immunodeficiency (CVID, OMIM 240500) and selective immunoglobulin A deficiency (IgAD) are the most frequent primary immunodeficiencies in humans. Of the cases with CVID/IgAD, 20%-25% are familial, but the only previous claims of linkage or association are to the HLA region on chromosome 6p. We report the results of a genome-wide scan in three multiplex families with CVID, IgAD, and dysgammaglobulinemia, where affection is inherited in an autosomal dominant pattern. Two of the families are consistent with linkage to the telomeric region of chromosome 5p, whereas the third is consistent with linkage to the HLA region. Using a locus heterogeneity model and a conservative penetrance model, we obtained a LOD score of 3.35 for the 5p region. We sequenced the exons of one promising candidate gene within this region (PDCD6, also known as ALG-2) but found no causative mutation.

Adolescent↗

PubMed2003

Radiation hybrid mapping of 304 novel microsatellites in the domestic cat genome.

Effective utilization of the domestic cat as an animal model for hereditary and infectious disease requires the development and implementation of high quality gene maps incorporating microsatellites and conserved coding gene markers. Previous feline linkage and radiation hybrid maps have lacked sufficient microsatellite coverage on all chromosomes to make effective use of full genome scans. Here we report the isolation and genomic mapping of 304 novel polymorphic repeat loci in the feline genome. The new loci were mapped in the domestic cat radiation hybrid panel using an automated fluorescent TAQ-Man based assay. The addition of these 304 microsatellites brings the total number of microsatellites mapped in the feline genome to 580, and the total number of loci placed onto the RH map to 1,126. Microsatellites now span every autosome with an average spacing of roughly one polymorphic STR every five centimorgans, and full genome coverage of one marker every 2.7 megabases. These loci now provide a useful tool for undertaking full-genome scans to identify genes associated with phenotypes of interest, such as those relating to hereditary disease, coat color, patterning and morphology. These resources can also be extended to the remaining 36 species of the cat family for population genetic and evolutionary genomic analyses.

Animals↗

PubMed2001

Graph models of oncogenesis with an application to melanoma.

We describe several analytical techniques for use in developing genetic models of oncogenesis including: methods for the selection of important genetic events, construction of graph models (including distance-based trees, branching trees, contingency trees and directed acyclic graph models) from these events and methods for interpretation of the resulting models. The models can be used to make predictions about: which genetic events tend to occur early, which events tend to occur together and the likely order of events. Unlike simple path models of oncogenesis, our models allow dependencies to exist between specific genetic changes and allow for multiple, divergent paths in tumor progression. A variety of genetic events can be used with the graph models including chromosome breaks, losses or gains of large DNA regions, small mutations and changes in methylation. As an application of the techniques, we use a recently published cytogenetic analysis of 206 melanoma cases [Nelson et al. (2000), Cancer Genet. Cytogenet.122, 101-109] to derive graph models for chromosome breaks in melanoma. Among our predictions are: (1) breaks in 6q1 and 1q1 are early events, with 6q1 preferentially occurring first and increasing the probability of a break in 1q1 and (2) breaks in the two sets [1p1, 1p2, 9q1] and [1q1, 7p2, 9p2] tend to occur together. This study illustrates that the application of graph models to genetic data from tumor sets provide new information on the interrelationships among genetic changes during tumor progression.

Chromosome Breakage↗

PubMed2001

Heritability of life span in the Old Order Amish.

Although a familial contribution to human longevity is recognized, the nature of this contribution is largely unknown. We have examined the familial contribution to life span in the Old Order Amish (OOA) population of Lancaster County, Pennsylvania. Analyses were conducted on 1,655 individuals, representing all those born prior to 1890 and appearing in the most widely available genealogy, surviving until at least age 30 years, and with known date of death. Mean age at death (+/-SD) in this population was 70.7 +/- 15.6 years, and this did not change appreciably over time. Parental and offspring ages at death were significantly correlated, as were ages of death among siblings. Offspring longevity was correlated with longevity of both parents, and in more or less additive fashion. For example, mean offspring age at death was 69.4 +/- 15.3 years in individuals for whom both parents died before the age of 75 years (n = 280) and increased to 73.5 +/- 16.0 years in individuals for whom neither parent died before the age of 75 years (n = 311). These differences were highly significant (P = 0.006). We estimated heritability of life span to be 25% +/- 5%, suggesting that the additive effects of genes account for one quarter of the total variability in life span in the OOA. We conclude that longevity is moderately heritable in the OOA, that the genetic effects are additive, and that genetic influences on longevity are likely to be expressed across a broad range of ages. Published 2001 Wiley-Liss, Inc.

Adult↗

PubMed2001

An immune defect causing dominant chronic mucocutaneous candidiasis and thyroid disease maps to chromosome 2p in a single family.

We describe a large family in which a combination of chronic mucocutaneous candidiasis (fungal infections of the skin, nails, and mucous membranes) and thyroid disease segregate as an autosomal dominant trait with reduced penetrance. The family includes (a) four members with both candidiasis and thyroid disease, (b) five members, including one pair of phenotype-concordant MZ twins, with candidiasis only, and (c) three members with thyroid disease only. A whole-genome scan using DNA samples from 20 members of the family identified a candidate linkage region on chromosome 2p. By sampling additional individuals and genotyping supplementary markers, we established linkage to a region of approximately 15 cM bounded by D2S367 and D2S2240 and including seven adjacent markers consistent with linkage. With a penetrance estimate of.8, which was based on pedigree and affected status, the peak two-point LOD score was 3.70 with marker D2S2328, and the peak three-point LOD score was 3.82. This is the first linkage assignment of a dominant locus for mucocutaneous candidiasis.

Adult↗

PubMed2001

Improving the accuracy of PSI-BLAST protein database searches with composition-based statistics and other refinements.

PSI-BLAST is an iterative program to search a database for proteins with distant similarity to a query sequence. We investigated over a dozen modifications to the methods used in PSI-BLAST, with the goal of improving accuracy in finding true positive matches. To evaluate performance we used a set of 103 queries for which the true positives in yeast had been annotated by human experts, and a popular measure of retrieval accuracy (ROC) that can be normalized to take on values between 0 (worst) and 1 (best). The modifications we consider novel improve the ROC score from 0.758 +/- 0.005 to 0.895 +/- 0.003. This does not include the benefits from four modifications we included in the 'baseline' version, even though they were not implemented in PSI-BLAST version 2.0. The improvement in accuracy was confirmed on a small second test set. This test involved analyzing three protein families with curated lists of true positives from the non-redundant protein database. The modification that accounts for the majority of the improvement is the use, for each database sequence, of a position-specific scoring system tuned to that sequence's amino acid composition. The use of composition-based statistics is particularly beneficial for large-scale automated applications of PSI-BLAST.

Algorithms↗

PubMed2001

Genomic imbalances in the progression of endocrine pancreatic tumors.

Endocrine pancreatic tumors (EPTs) are neoplasms with malignant potential. To explore the molecular basis of metastatic progression in human EPTs, we analyzed 17 paired specimens of primary EPTs and their metastases and 28 nonmetastatic EPTs using comparative genomic hybridization (CGH). Genomic alterations were detected in all of the matched primary/metastatic tumors and 19 (58%) nonmetastatic EPTs. The mean number of genomic changes was 17.3 in metastases, 12.5 in their primary tumors, and 4.5 in nonmetastatic EPTs. Statistical analysis of shared genomic changes in matched pairs of primary tumors and metastases showed a high probability (>95%) of a clonal relationship in 15 of the 17 cases. A closely related genetic pattern was also demonstrated on the basis of concordance analysis of the two groups. The most striking genomic changes which were enriched in metastases included gains of chromosomes 4 and 7 and losses of 21q. Other common regions of frequent losses (>40%) identified in metastases and/or their primary tumors involved 2p, 2q, 3p, 3q, 6q, 10p, and 11p, whereas frequently detected gains (>40%) in the paired tumors involved 5p, 5q, 12q, 14q, 17q, 18q, and 20q. These chromosomal aberrations were found in significantly fewer nonmetastatic EPTs. Some of these chromosomal loci may harbor genes contributing to the progression of EPT.

Adenoma, Islet Cell↗

PubMed2001

Towards a complete North American Anabaptist Genealogy II: analysis of inbreeding.

We describe a large genealogy data base, which can be searched by computer, of 295,095 Amish and Mennonite individuals. The data base was constructed by merging our existing Anabaptist Genealogy Database 2.0 containing approximately 85,000 individuals with a genealogy file containing approximately 242,000 individuals, kindly provided by Mr. James Hostetler. The merging process corrected thousands of inconsistencies and eliminated hundreds of duplicate individuals. Geneticists have long been interested in Anabaptist populations because they are closed and have detailed written genealogies. The creation of an enlarged and unified data base affords the opportunity to examine inbreeding trends and correlates in these populations. We show the following results. The frequency of consanguineous marriages shows steady increase over time and reached approximately 85% for individuals born in 1940-1959. Among consanguineous marriages, the median kinship coefficient stayed stable in the 19th century, but rose from 0.0115 to 0.0151 in the 20th century. There are statistically significant associations (p < 0.0001) between inbreeding and family size and interbirth intervals in the 20th century. There is an association (p < 0.0005) between inbreeding and early death for individuals born in 1920-1959. However, this association reverses dramatically (p < 0.0005 in the opposite direction) for individuals born in 1960-1979. We tested for an association between inbreeding and being the mother of twins, but found none.

Birth Intervals↗

PubMed2001

Tree models for dependent copy number changes in bladder cancer.

We analyzed comparative genomic hybridization data on a collection of 237 bladder cancer tumors with the aim of identifying sets of copy number aberrations (CNAs) that tend to occur together. A test based on Fisher's exact test for pairs, but taking into account multiple testing, showed strong dependencies amongst several pairs of aberrations including (+1q, -11p), (+17q, +20q), (+10p, -17p), (-8p, -17p), (+5p, +10p). To determine whether co-occurrence of CNAs may characterize tumor subtypes, we used two recently proposed methods to construct tree models of tumor progression. We constructed tree models for all the tumors, the tumors of stage pT1, and the tumors of stages pT2-4. The tree models confirmed that most of the non-random events and the associations are the same for different stages. We conclude that the combination of large data sets and tree models provide a useful approach to systematically identifying tumor subgroups characterized by more than a single chromosomal aberration.

Algorithms↗

PubMed2000

Construction of evolutionary tree models for renal cell carcinoma from comparative genomic hybridization data.

Renal cell carcinoma is characterized by an accumulation of complex chromosomal alterations during tumor progression. Chromosome 3p deletions are known to occur early in the carcinogenesis, but the nature of subsequent events, their interrelationships, and their sequence is poorly understood, as one usually only obtains a single "view" of the dynamic process of tumor development in a particular cancer patient. To address this limitation, we used comparative genomic hybridization analysis in combination with a distance-based and a branching-tree method to search for tree models of the oncogenesis process of 116 conventional (clear cell) renal carcinomas. This provides a means to analyze and model cancer development processes based on a more dynamic model, including the presence of multiple pathways, as compared with the fixed linear model first proposed by Vogelstein et al. (N. Engl. J. Med., 319: 525-532, 1988) for colorectal cancer. The most common DNA losses involved 3p (61%), 4q (50%), 6q (40%), 9p (35%), 13q (37%), and Xq (21%). The most common gains were seen at chromosome 17p and 17q (20%). The tree model derived from the distance-based method is consistent with the established theory that -3p is an important early event in conventional (clear cell) renal cancer and supports the prediction made from the branching tree that -4q is another important early event. Both tree models suggest that there may be two groups of clear cell renal cancers: one characterized by -6q, +17q, and + 17p, and another by -9p, -13q, and -18q. Putative prognostic parameters were -9p and -13q. The distance-based tree clarifies that -8p (present in 12% of tumors) is a late event, largely independent of other events. In summary, tree modeling of comparative genomic hybridization data provided new information on the interrelationships of genetic changes in renal cancer and their possible order, as well as a clustering of these events. Using tree analysis, one can derive a more in-depth understanding of the renal cancer development process than is possible by simply focusing on the frequencies of genetic events in a given cancer type.

Carcinoma, Renal Cell↗

PubMed2000

A novel nemaline myopathy in the Amish caused by a mutation in troponin T1.

The nemaline myopathies are characterized by weakness and eosinophilic, rodlike (nemaline) inclusions in muscle fibers. Amish nemaline myopathy is a form of nemaline myopathy common among the Old Order Amish. In the first months of life, affected infants have tremors with hypotonia and mild contractures of the shoulders and hips. Progressive worsening of the proximal contractures, weakness, and a pectus carinatum deformity develop before the children die of respiratory insufficiency, usually in the second year. The disorder has an incidence of approximately 1 in 500 among the Amish, and it is inherited in an autosomal recessive pattern. Using a genealogy database, automated pedigree software, and linkage analysis of DNA samples from four sibships, we identified an approximately 2-cM interval on chromosome 19q13.4 that was homozygous in all affected individuals. The gene for the sarcomeric thin-filament protein, slow skeletal muscle troponin T (TNNT1), maps to this interval and was sequenced. We identified a stop codon in exon 11, predicted to truncate the protein at amino acid 179, which segregates with the disease. We conclude that Amish nemaline myopathy is a distinct, heritable, myopathic disorder caused by a mutation in TNNT1.

Amino Acid Sequence↗

PubMed2000

Distance-based reconstruction of tree models for oncogenesis.

Comparative genomic hybridization (CGH) is a laboratory method to measure gains and losses in the copy number of chromosomal regions in tumor cells. It is hypothesized that certain DNA gains and losses are related to cancer progression and that the patterns of these changes are relevant to the clinical consequences of the cancer. It is therefore of interest to develop models which predict the occurrence of these events, as well as techniques for learning such models from CGH data. We continue our study of the mathematical foundations for inferring a model of tumor progression from a CGH data set that we started in Desper et al. (1999). In that paper, we proposed a class of probabilistic tree models and showed that an algorithm based on maximum-weight branching in a graph correctly infers the topology of the tree, under plausible assumptions. In this paper, we extend that work in the direction of the so-called distance-based trees, in which events are leaves of the tree, in the style of models common in phylogenetics. Then we show how to reconstruct the distance-based trees using tree-fitting algorithms developed by researchers in phylogenetics. The main advantages of the distance-based models are that 1) they represent information about co-occurrences of all pairs of events, instead of just some pairs, 2) they allow quantitative predictions about which events occur early in tumor progression, and 3) they bring into play the extensive methodology and software developed in the context of phylogenetics. We illustrate the distance-based tree method and how it complements the branching tree method, with a CGH data set for renal cancer.

Algorithms↗

PubMed2000

A fast and scalable radiation hybrid map construction and integration strategy.

This paper describes a fast and scalable strategy for constructing a radiation hybrid (RH) map from data on different RH panels. The maps on each panel are then integrated to produce a single RH map for the genome. Recurring problems in using maps from several sources are that the maps use different markers, the maps do not place the overlapping markers in same order, and the objective functions for map quality are incomparable. We use methods from combinatorial optimization to develop a strategy that addresses these issues. We show that by the standard objective functions of obligate chromosome breaks and maximum likelihood, software for the traveling salesman problem produces RH maps with better quality much more quickly than using software specifically tailored for RH mapping. We use known algorithms for the longest common subsequence problem as part of our map integration strategy. We demonstrate our methods by reconstructing and integrating maps for markers typed on the Genebridge 4 (GB4) and the Stanford G3 panels publicly available from the RH database. We compare map quality of our integrated map with published maps for GB4 panel and G3 panel by considering whether markers occur in the same order on a map and in DNA sequence contigs submitted to GenBank. We find that all of the maps are inconsistent with the sequence data for at least 50% of the contigs, but our integrated maps are more consistent. The map integration strategy not only scales to multiple RH maps but also to any maps that have comparable criteria for measuring map quality. Our software improves on current technology for doing RH mapping in areas of computation time and algorithms for considering a large number of markers for mapping. The essential impediments to producing dense high-quality RH maps are data quality and panel size, not computation.

Algorithms↗

PubMed2000

Genetic modifiers of the insulin resistance phenotype in mice.

Insulin resistance can result from genetic interactions among susceptibility alleles. To identify genetic loci predisposing to insulin resistance, we used crosses between different strains of mice with a targeted null allele of the insulin receptor gene. On the genetic background of B6 mice, the insulin receptor gene mutation causes mild hyperinsulinemia. In contrast, on the genetic background of 129/Sv mice, the same mutation causes severe hyperinsulinemia, suggesting that the 129/Sv strain harbors alleles that interact with the insulin receptor mutation and predispose to insulin resistance. As a first step to identify these alleles, we generated an F2 intercross between insulin receptor heterozygous mutant mice on B6 and 129/Sv backgrounds (B6IR x 129IR) and performed a genome-wide scan with polymorphic markers at a 20-cM resolution. We report the identification of loci on chromosomes 2 (logarithm of odds [LOD] 5.58) and 10 (LOD 5.58) that show significant evidence for linkage to plasma insulin levels as a quantitative trait. These findings indicate that targeted mutations in knockout mice can be used to unravel the complex genetic interactions underlying insulin resistance.

Alleles↗

PubMed2000

Chromosome abnormalities in ovarian adenocarcinoma: III. Using breakpoint data to infer and test mathematical models for oncogenesis.

Cancer geneticists seek to identify genetic changes in tumor cells and to relate the genetic changes to tumor development. Because single changes can disrupt the cell cycle and promote other genetic changes, it is extremely hard to distinguish cause from effect. In this article we illustrate how 7 techniques from statistics, theoretical computer science, and phylogenetics can be used to infer and test possible models of tumor progression from single genome-wide descriptions of aberrations in a large sample of tumors. Specifically, we propose 4 tree models for tumor progression inferred from the large ovarian cancer data set described in the first 2 articles in this series. The models are derived from 2 different methods to select the non-random genetic aberrations and 2 different methods to infer the trees, given a set of events. Various aspects of the tree models are tested and extended by 5 methods: overall tests of independence, likelihood ratio tests, principal components analysis, directed acyclic graph modeling, and Bayesian survival analysis. All our methods lead to strikingly consistent conclusions about chromosomal breakpoints in ovarian adenocarcinoma, including (1) the non-random breakpoints in ovarian adenocarcinoma do not occur independently; (2) breakpoints in regions 1p3 and 11p1 are important early events and distinguish a class of tumors associated with poor prognosis; and (3) breakpoints in 1p1, 3p1, and 1q2 distinguish a class of ovarian tumors, and the breaks at 1p1 and 3p1 are associated with poor prognosis.

Adenocarcinoma↗

PubMed1999

Towards a complete North American Anabaptist genealogy: A systematic approach to merging partially overlapping genealogy resources.

Genetic studies on closed populations benefit from comprehensive, searchable genealogy resources. To support studies of Anabaptists, a computerized database has been developed that merges two large genealogy books, the "Fisher Family History" and the "Amish and Amish Mennonite Genealogies." The former is more current but the latter is more comprehensive for the 18th and 19th centuries. Therefore, the merger of the two books is significantly more useful than either book alone. We demonstrate the utility of the merged database with two results: an increase in inbreeding coefficients and the identification of parent-child relationships that do not exist in either book. Am. J. Med. Genet. 86:156-161, 1999. Published 1999 Wiley-Liss, Inc.

Consanguinity↗

PubMed1999

A genetic linkage map of microsatellites in the domestic cat (Felis catus).

Of the nonprimate mammalian species with developing comparative gene maps, the feline gene map (Felis catus, Order Carnivora, 2N = 38) displays the highest level of syntenic conservation with humans, with as few as 10 translocation exchanges discriminating the human and feline genome organization. To extend this model, a genetic linkage map of microsatellite loci in the feline genome has been constructed including 246 autosomal and 7 X-linked loci. Two hundred thirty-five dinucleotide (dC. dA)n. (dG. dT)n and 18 tetranucleotide repeat loci were identified and genotyped in a two-family, 108-member multigeneration interspecies backcross pedigree between the domestic cat (F. catus) and the Asian leopard cat (Prionailurus bengalensis). Two hundred twenty-nine loci were linked to at least one other marker with a lod score >/=3.0, identifying 34 linkage groups. Representative markers from each linkage group were assigned to specific cat chromosomes by somatic cell hybrid analysis, resulting in chromosomal assignments to 16 of the 19 feline chromosomes. Genome coverage spans approximately 2900 cM, and we estimate a genetic length for the sex-averaged map as 3300 cM. The map has an average intragroup intermarker spacing of 11 cM and provides a valuable resource for mapping phenotypic variation in the species and relating it to gene maps of other mammals, including human.

Animals↗