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Microsatellite marker content mapping of 12 candidate genes for obesity: assembly of seven obesity screening panels for automated genotyping.

ABSTRACT: Twin studies, adoption studies, and studies of familial aggregation indicate that obesity has a genetic component. Whereas, the genetic factors predisposing to obesity have been elucidated for several rare syndromes, the factors responsible for obesity in the general population have remained elusive. Genetic studies of complex traits are often accelerated by the use of candidate genes. To facilitate genetic studies of human obesity, seven multiplex panels of candidate genes for obesity that are suitable for fluorescent genotyping have been assembled. The multiplex panels are composed of 66 microsatellite markers linked tightly to 16 human gene products that are of potential importance in the control of body weight or linked to syndromic forms of obesity. As part of these efforts 12 previously cloned genes have been placed on the human physical map. In addition the chromosomal location of three of these genes, ART, NYP Y6R, and PPARgamma, are reported for the first time. These resources will be of use in studies to identify the genetic factors responsible for human obesity. [Figures are available at http://www.genome.org]

SUBMITTER: Winick JD

PROVIDER: S-EPMC310777 | biostudies-literature | 1998 Sep

REPOSITORIES: biostudies-literature

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Microsatellite marker content mapping of 12 candidate genes for obesity: assembly of seven obesity screening panels for automated genotyping.

Winick J D JD Friedman J M JM

Genome research 19980901 9

Twin studies, adoption studies, and studies of familial aggregation indicate that obesity has a genetic component. Whereas, the genetic factors predisposing to obesity have been elucidated for several rare syndromes, the factors responsible for obesity in the general population have remained elusive. Genetic studies of complex traits are often accelerated by the use of candidate genes. To facilitate genetic studies of human obesity, seven multiplex panels of candidate genes for obesity that are ...[more]

PMID: 9750197

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Project description:Microsatellite (MS) markers have become an important tool for studying the population diversity, evolutionary history and multiplicity of infection (MOI) of malaria parasite infections. MS are typically selected on the basis of being highly polymorphic. However, it is known that the polymorphic potential (mutability) of each marker can vary as much as two orders of magnitude, which radically changes how diversity is represented in the genome from one marker to the next. Over the past decade, approximately 240 Plasmodium vivax MS have been published, comprising nine major panels of markers. Inconsistent usage of each panel has resulted in a surfeit of descriptive genetic diversity data that are largely incomparable between populations. The objective of this study was to statistically evaluate the quality of individual MS markers in order to validate a refined panel of markers that will provide a balanced picture of P. vivax population diversity.All previously published data, including genetic diversity indices, MS parameters, and population parameters, were assembled from 18 different global studies into a flat file to facilitate statistical analysis and modelling using JMP® Genomics 6.0 (SAS Institute Inc, Cary, NC, USA). Statistical modeling was employed to down-select markers with extreme variation among the mean number of alleles, expected heterozygosity, maximum repeat length and/or chromosomal location of the repeat. Individual MS were analysed by step-down whole model linear regression and standard least squares fit models, both stratified by annual parasite incidence to identify MS markers with values significantly different from the mean.Of the 42 MS under evaluation in this study, 18 (nine high priority) were identified as ideal candidates for measuring population diversity between global regions, while five (two high priority) additional markers were identified as candidates for MOI studies.MS diversity was found to be a function of endemicity and motif structure. Evaluation of individual MS permitted the assembly of a refined panel of markers that can be reliably utilized in the field to compare population structures between global regions.

Project description:Genomic selection increases the rate of genetic gain in breeding programs, which results in significant cumulative improvements in commercially important traits such as disease resistance. Genomic selection currently relies on collecting genome-wide genotype data accross a large number of individuals, which requires substantial economic investment. However, global aquaculture production predominantly occurs in small and medium sized enterprises for whom this technology can be prohibitively expensive. For genomic selection to benefit these aquaculture sectors, more cost-efficient genotyping is necessary. In this study the utility of low and medium density SNP panels (ranging from 100 to 9,000 SNPs) to accurately predict breeding values was tested and compared in four aquaculture datasets with different characteristics (species, genome size, genotyping platform, family number and size, total population size, and target trait). The traits show heritabilities between 0.19-0.49, and genomic prediction accuracies using the full density panel of 0.55-0.87. A consistent pattern of genomic prediction accuracy was observed across species with little or no accuracy reduction until SNP density was reduced below 1,000 SNPs (prediction accuracies of 0.44-0.75). Below this SNP density, heritability estimates and genomic prediction accuracies tended to be lower and more variable (93% of maximum accuracy achieved with 1,000 SNPs, 89% with 500 SNPs, and 70% with 100 SNPs). A notable drop in accuracy was observed between 200 SNP panels (0.44-0.75) and 100 SNP panels (0.39-0.66). Now that a multitude of studies have highlighted the benefits of genomic over pedigree-based prediction of breeding values in aquaculture species, the results of the current study highlight that these benefits can be achieved at lower SNP densities and at lower cost, raising the possibility of a broader application of genetic improvement in smaller and more fragmented aquaculture settings.

Project description:BACKGROUND & AIMS:Fifty percent of colorectal cancers show elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) and are associated with inflammation, metastasis, and poor patient outcome. EMAST results from interleukin 6-induced nuclear-to-cytosolic displacement of the DNA mismatch repair protein Mutated S Homolog 3, allowing frameshifts of dinucleotide and tetranucleotide but not mononucleotide microsatellites. Unlike mononucleotide frameshifts that universally shorten in length, we previously observed expansion and contraction frameshifts at tetranucleotide sequences. Here, we developed cell models to assess tetranucleotide frameshifts in real time. METHODS:We constructed plasmids containing native (AAAG)18 and altered-length ([AAAG]15 and [AAAG]12) human D9S242 locus that placed enhanced green fluorescent protein +1 bp/-1 bp out-of-frame for protein translation and stably transfected into DNA mismatch repair-deficient cells for clonal selection. We used flow cytometry to detect enhanced green fluorescent protein-positive cells to measure mutational behavior. RESULTS:Frameshift mutation rates were 31.6 to 71.1 × 10-4 mutations/cell/generation and correlated with microsatellite length (r2 = 0.986, P = .0375). Longer repeats showed modestly higher deletion over insertion rates, with both equivalent for shorter repeats. Accumulation of more deletion frameshifts contributed to a distinct mutational bias for each length (overall: 77.8% deletions vs 22.2% insertions), likely owing to continual deletional mutation of insertions. Approximately 78.9% of observed frameshifts were 1 AAAG repeat, 16.1% were 2 repeats, and 5.1% were 3 or more repeats, consistent with a slipped strand mispairing mutation model. CONCLUSIONS:Tetranucleotide frameshifts show a deletion bias and undergo more than 1 deletion event via intermediates, with insertions converted into deletions. Tetranucleotide markers added to traditional microsatellite instability panels will be able to determine both EMAST and classic microsatellite instability, but needs to be assessed by multiple markers to account for mutational behavior and intermediates.

Dataset Information

Microsatellite marker content mapping of 12 candidate genes for obesity: assembly of seven obesity screening panels for automated genotyping.

Publications

Microsatellite marker content mapping of 12 candidate genes for obesity: assembly of seven obesity screening panels for automated genotyping.

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