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PubMed2001

Methods for genotyping single nucleotide polymorphisms.

One of the fruits of the Human Genome Project is the discovery of millions of DNA sequence variants in the human genome. The majority of these variants are single nucleotide polymorphisms (SNPs). A dense set of SNP markers opens up the possibility of studying the genetic basis of complex diseases by population approaches. In all study designs, a large number of individuals must be genotyped with a large number of markers. In this review, the current status of SNP genotyping is discussed in terms of the mechanisms of allelic discrimination, the reaction formats, and the detection modalities. A number of genotyping methods currently in use are described to illustrate the approaches being taken. Although no single genotyping method is ideally suited for all applications, a number of good genotyping methods are available to meet the needs of many study designs. The challenges for SNP genotyping in the near future include increasing the speed of assay development, reducing the cost of the assays, and performing multiple assays in parallel. Judging from the accelerated pace of new method development, it is hopeful that an ideal SNP genotyping method will be developed soon.

Alleles↗
PubMed2026

Genomic background of gestation length and calving-related traits in Holstein cattle.

The reproductive success of cows directly influences the profitability of dairy farms. Reproductive traits, particularly calving-related traits, generally have low heritability but sufficient additive genetic variance to enable genetic progress through genomic selection. Thus, the primary objectives of this study were to estimate genetic parameters and perform single-step genome-wide association studies (ssGWAS) for calf size, calving ease, gestation length, and stillbirth in Holstein cattle. Variance components were estimated based on animal models and Bayesian inference using a data set containing 226,717 animals with phenotypic records, 15,761 animals genotyped with 45,101 SNP markers, and 461,819 animals in the pedigree. SNP effects were estimated using the single-step GBLUP method. For direct and maternal genetic effects, heritability estimates (posterior standard deviation) ranged from 0.001 (0.002) for gestation length in heifers to 0.16 (0.001) for gestation length in cows. Genetic correlations ranged from -0.57 (0.01) between calving ease and stillbirth in heifers to 0.74 (0.01) between gestation length evaluated in heifers and cows. The ssGWAS results supported a highly polygenic architecture for calving-related traits, with most genomic signals not reaching genome-wide significance. A genome-wide significant association was detected for calving ease in cows on BTA23, highlighting FARS2 as a positional candidate gene. The strongest GWAS signals for each trait harbored additional biologically important candidate genes, including NPPA, NPPB, BCHE, EPHA4, DLD, and GTF2I. Given the generally low heritability estimates and the predominantly polygenic architecture observed for these traits, genomic selection may contribute to the genetic improvement of calving-related traits in Holstein cattle, with potential benefits for cow welfare, calf survival, and overall dairy production efficiency.

dairy cattle↗
PubMed2006

Variants in the gene encoding C3 are associated with asthma and related phenotypes among African Caribbean families.

Proinflammatory and immunoregulatory products from C3 play a major role in phagocytosis, respiratory burst, and airways inflammation. C3 is critical in adaptive immunity; studies in mice deficient in C3 demonstrate that features of asthma are significantly attenuated in the absence of C3. To test the hypothesis that the C3 gene on chromosome 19p13.3-p13.2 contains variants associated with asthma and related phenotypes, we genotyped 25 single nucleotide polymorphism (SNP) markers distributed at intervals of approximately 1.9 kb within the C3 gene in 852 African Caribbean subjects from 125 nuclear and extended pedigrees. We used the multiallelic test in the family-based association test program to examine sliding windows comprised of 2-6 SNPs. A five-SNP window between markers rs10402876 and rs366510 provided strongest evidence for linkage in the presence of linkage disequilibrium for asthma, high log[total IgE], and high log[IL-13]/[log[IFN-gamma] in terms of global P-values (P = 0.00027, 0.00013, and 0.003, respectively). A three-SNP haplotype GGC for the first three of these markers showed best overall significance for the three phenotypes (P = 0.003, 0.007, 0.018, respectively) considering haplotype-specific tests. Taken together, these results implicate the C3 gene as a priority candidate controlling risk for asthma and allergic disease in this population of African descent.

Asthma↗
PubMed2002

Can long-range microsatellite data be used to predict short-range linkage disequilibrium?

The distribution of linkage disequilibrium (LD) across the genome is highly complex. Little is known about the relationship between long-range and short-range LD in a genomic region. We assessed whether a dense set of microsatellite data could be used to predict short-range LD in family samples. We analyzed intermarker LD in data derived from chromosomal regions 18q22 and 10q25-26, densely genotyped with microsatellite markers. The pattern of LD was highly heterogeneous within and between both chromosomal regions. On 10q25-26, very little LD was detected. On 18q22, where marker density was higher, many marker pairs were in LD. We modeled the decay of LD over distance in this region. A classical model accounted for most of the relationship between LD and distance (R (2)=63%). We used this model to predict the proportion of markers expected to show useful levels of LD at short distances. This prediction agreed with estimates based on single-nucleotide polymorphism (SNP) marker genotypes in the region. Both microsatellite and SNP data predict that about 80% of marker pairs would display levels of LD that are useful for association studies at distances of up to 15 kb in this region. These projections also agree with levels of LD directly measured in a 10 kb set of SNP genotypes generated in a nearby region of finished sequence. Our results suggest that existing sets of microsatellite data, if sufficiently dense, may be used to develop good initial estimates of the density of additional markers needed to screen a region for disease alleles by association analysis.

Chromosome Mapping↗
PubMed2005

Discovery of SNPs in soybean genotypes frequently used as the parents of mapping populations in the United States and Korea.

Single nucleotide polymorphisms (SNPs) including insertion/deletions (indels) serve as useful and informative genetic markers. The availability of high-throughput and inexpensive SNP typing systems has increased interest in the development of SNP markers. After fragments of genes were amplified with primers derived from 110 soybean GenBank ESTs, sequencing data of PCR products from 15 soybean genotypes from Korea and the United States were analyzed by SeqScape software to find SNPs. Among 35 gene fragments with at least one SNP among the 15 genotypes, SNPs occurred at a frequency of 1 per 2,038 bp in 16,302 bp of coding sequence and 1 per 191 bp in 16,960 bp of noncoding regions. This corresponds to a nucleotide diversity (theta) of 0.00017 and 0.00186, respectively. Of the 97 SNPs discovered, 78 or 80.4% were present in the six North American soybean mapping parents. The addition of "Hwaeomputkong," which originated from Japan, increased the number to 92, or 94.8% of the total number of SNPs present among the 15 genotypes. Thus, Hwaeomputkong and the six North American mapping parents provide a diverse set of soybean genotypes that can be successfully used for SNP discovery in coding DNA and closely associated introns and untranslated regions.

Base Sequence↗
PubMed2000

Future directions of research in statistical genetics.

From a global perspective, two external developments are having dramatic effects upon the field of statistical genetics: improved genetic data, for example, human DNA sequence, and new technologies, for example, microarray technology. Meiotic mapping techniques will have to be adapted to benefit from the improved data, for example, allelic association studies have to be extended to multiple markers to profit from the new genetic map of SNP markers. Changing technology has led to ever-increasing knowledge about gene function which has enabled novel gene mapping strategies which we refer to as functional mapping. Functional mapping has great potential for mapping complex disease genes since it uses pathway fractions to intermediate between genotype and phenotype information. Methods used in whole-genome gene expression studies are used to illustrate concepts of functional mapping.

Biomedical Technology↗
PubMed2006

Genetic structural differences between responders and non-responders to interferon therapy for chronic hepatitis-B patients.

Interferon-alpha therapy has become a main stay of treatment for hepatitis-B patients. The sustained remission rates are around 30%, and the factors determining response are poorly defined. Our study aimed to search for the genetic differences between responder and non-responder patients. We have found 13 short tandem repeat markers (STR) that display different allele and/or genotype frequency between the two patient groups. Eleven out of 13 STR markers were selected to perform principal component analysis and hierarchical clustering. The study subjects could be further divided into six groups based on their genetic similarity, which correlated with the drug response rate. In conclusion, this pilot study has developed a new approach to identify genetic markers that allows us to predict the drug response in hepatitis B patients. Our study utilizing STR markers may provide an alternative approach to the utilized SNP markers in pharmacogenetic study.

Alleles↗
PubMed2004

Tag SNP selection for association studies.

This report describes current methods for selection of informative single nucleotide polymorphisms (SNPs) using data from a dense network of SNPs that have been genotyped in a relatively small panel of subjects. We discuss the following issues: (1) Optimal selection of SNPs based upon maximizing either the predictability of unmeasured SNPs or the predictability of SNP haplotypes as selection criteria. (2) The dependence of the performance of tag SNP selection methods upon the density of SNP markers genotyped for the purpose of haplotype discovery and tag SNP selection. (3) The likely power of case-control studies to detect the influence upon disease risk of common disease-causing variants in candidate genes in a haplotype-based analysis. We propose a quasi-empirical approach towards evaluating the power of large studies with this calculation based upon the SNP genotype and haplotype frequencies estimated in a haplotype discovery panel. In this calculation, each common SNP in turn is treated as a potential unmeasured causal variant and subjected to a correlation analysis using the remaining SNPs. We use a small portion of the HapMap ENCODE data (488 common SNPs genotyped over approximately a 500 kb region of chromosome 2) as an illustrative example of this approach towards power evaluation.

Chromosome Mapping↗
PubMed2004

Detection and characterization of SNPs useful for identity control and parentage testing in major European dairy breeds.

We propose the use of single nucleotide polymorphisms (SNPs) instead of polymorphic microsatellite markers for individual identification and parentage control in cattle. To this end, we present an initial set of 37 SNP markers together with a gender-specific SNP for identity control and parentage testing in the Holstein, Fleckvieh and Braunvieh breeds. To obtain suitable SNPs, a total of 91.13 kb of random genomic DNA was screened yielding 531 SNPs. These, and 43 previously identified SNPs, were subjected to the following selection criteria: (1) the frequency of the minor allele must be larger than 0.1 in at least two of the three examined breeds, and (2) markers should not be linked closely. Allele frequencies were estimated by analysing sequencing traces of pooled DNA or by genotyping individual DNA samples. The selected SNP loci were physically mapped by radiation hybrid mapping or by fluorescence in situ hybridization, and tested against the neutral mutation hypothesis. The presented marker set theoretically allows probabilities of identity less than 10(-13) for individual verification and exclusion powers exceeding 99.99% for parentage testing.

Agriculture↗
PubMed2004

CHOISS for selection of single nucleotide polymorphism markers on interval regularity.

We developed algorithms that find a set of single nucleotide polymorphism (SNP) markers based on interval regularity, given either the number of SNPs to choose (m) or the desired interval (I), subject to minimum variance or minimum sum of squared deviations from I. In both cases, the number of all possible sets increases exponentially with respect to the number of input SNPs (n), but our algorithms find the minima only with O(n(2)) calculations and comparisons by elimination of redundancy.

Algorithms↗
PubMed2003

Selection of genetic markers for association analyses, using linkage disequilibrium and haplotypes.

The genotyping of closely spaced single-nucleotide polymorphism (SNP) markers frequently yields highly correlated data, owing to extensive linkage disequilibrium (LD) between markers. The extent of LD varies widely across the genome and drives the number of frequent haplotypes observed in small regions. Several studies have illustrated the possibility that LD or haplotype data could be used to select a subset of SNPs that optimize the information retained in a genomic region while reducing the genotyping effort and simplifying the analysis. We propose a method based on the spectral decomposition of the matrices of pairwise LD between markers, and we select markers on the basis of their contributions to the total genetic variation. We also modify Clayton's "haplotype tagging SNP" selection method, which utilizes haplotype information. For both methods, we propose sliding window-based algorithms that allow the methods to be applied to large chromosomal regions. Our procedures require genotype information about a small number of individuals for an initial set of SNPs and selection of an optimum subset of SNPs that could be efficiently genotyped on larger numbers of samples while retaining most of the genetic variation in samples. We identify suitable parameter combinations for the procedures, and we show that a sample size of 50-100 individuals achieves consistent results in studies of simulated data sets in linkage equilibrium and LD. When applied to experimental data sets, both procedures were similarly effective at reducing the genotyping requirement while maintaining the genetic information content throughout the regions. We also show that haplotype-association results that Hosking et al. obtained near CYP2D6 were almost identical before and after marker selection.

Alleles↗
PubMed2003

SNPs by AFLP (SBA): a rapid SNP isolation strategy for non-model organisms.

Despite the great potential of single nucleotide polymorphism (SNP) markers in evolutionary studies, in particular for inferring population genetic parameters, SNP analysis has almost exclusively been limited to humans and 'genomic model' organisms, due to the lack of available sequence data in non-model organisms. Here, we describe a rapid and cost effective method to isolate candidate SNPs in non-model organisms. This SNP isolation strategy consists basically in the direct sequencing of amplified fragment length polymorphism bands. In a first application of this method, 10 unique DNA fragments that contained 24 SNPs were discovered in 11.11 kb of sequenced genomic DNA of a non-model species, the brown trout (Salmo trutta).

Animals↗
PubMed2001

Molecular characterization and chromosome assignment of the porcine gene for leukemia inhibitory factor LIF.

Leukemia inhibitory factor (LIF) is a pleiotropic cytokine involved in early conceptus development in pig. We isolated a PAC clone containing the porcine LIF gene and determined the complete DNA sequence of the gene, which spans about 6.3 kb and consists of five exons including three alternative first exons (1D, 1M, 1T) spliced onto common second and third exons. The LIF-D transcript encodes a protein of 202 amino acids sharing 87, 84, and 78% identity with respectively human, ovine, and murine leukemia inhibitory factors. The LIF-M and LIF-T transcripts both encode a truncated protein of 158 amino acids. Two SNP markers within untranslated regions of the LIF cDNA were identified. One SNP is located in the 5'-UTR of the alternative exon 1T while the other SNP is located in the 3'-UTR of exon 3. Based on fluorescence in situ hybridization and radiation hybrid mapping, the porcine LIF gene was assigned to chromosome 14q2.1-->q2.2.

Alleles↗
PubMed2006

Stepwise haplotype analysis: are LD patterns repeatable?

A variety of techniques exist to describe and depict patterns of pairwise linkage disequilibrium (LD). In the current paper, a new log-linear framework is proposed for the summarisation of local interactions among single nucleotide polymorphisms (SNPs). Our approach provides a straightforward means of capturing the diversity of higher-order LD relationships for small numbers of loci by investigating inter-marker interactions. Our method was applied to a dataset of 76 SNP markers spanning a genomic interval of length 2.8 megabases. The analysis of three short sub-regions is described in detail here. Model and graphical representations of contiguous markers in medium to high LD are presented. In the regions studied, evidence for sub-structure was detected, supporting the view that the genomic reality is complex. Interestingly, a critical evaluation of the method by bootstrapping showed that while some LD relationships were captured in a highly repeatable fashion, the majority were not. Large numbers of small interactions, both direct and indirect, mean that many models can adequately summarise the data at hand. Our results suggest that repeatability should be further investigated in the application of LD-based approaches.

Haplotypes↗
PubMed2005

Specific detection of bacillus anthracis using a TaqMan mismatch amplification mutation assay.

Single nucleotide polymorphisms (SNPs) are increasingly recognized as important diagnostic markers for the detection and differentiation of Bacillus anthracis. The use of SNP markers for identifying B. anthracis DNA in environmental samples containing genetically similar bacteria requires the ability to amplify and detect DNA with single nucleotide specificity. We designed a TaqMan mismatch amplification mutation assay (TaqMAMA) around a SNP in the plcR gene of B. anthracis. The assay permits specific, low-level detection (25 fg DNA) of this B. anthracis-specific SNP, even in the presence of environmental DNA extracts containing a 20,000-fold excess of the alternate allele. We anticipate that the ability to selectively amplify and detect low copy number DNAs with single nucleotide specificity will represent a valuable tool in the arena of biodefense and microbial forensics.

Bacillus anthracis↗
PubMed2003

Methods for analysis and visualization of SNP genotype data for complex diseases.

SNP markers are becoming central for studying genetic determinants of complex diseases. Large SNP data collected in such studies call for the development of specialized analysis tools. We present methods for selecting sets of SNPs that can be associated to sample properties in case/control studies. We also describe how scoring and selection can be statistically tested. This is done at the single locus as well as at the set level.

Bayes Theorem↗
PubMed2003

Modeling bacterial evolution with comparative-genome-based marker systems: application to Mycobacterium tuberculosis evolution and pathogenesis.

The comparative-genomic sequencing of two Mycobacterium tuberculosis strains enabled us to identify single nucleotide polymorphism (SNP) markers for studies of evolution, pathogenesis, and epidemiology in clinical M. tuberculosis. Phylogenetic analysis using these "comparative-genome markers" (CGMs) produced a highly unusual phylogeny with a complete absence of secondary branches. To investigate CGM-based phylogenies, we devised computer models to simulate sequence evolution and calculate new phylogenies based on an SNP format. We found that CGMs represent a distinct class of phylogenetic markers that depend critically on the genetic distances between compared "reference strains." Properly distanced reference strains generate CGMs that accurately depict evolutionary relationships, distorted only by branch collapse. Improperly distanced reference strains generate CGMs that distort and reroot outgroups. Applying this understanding to the CGM-based phylogeny of M. tuberculosis, we found evidence to suggest that this species is highly clonal without detectable lateral gene exchange. We noted indications of evolutionary bottlenecks, including one at the level of the PHRI "C" strain previously associated with particular virulence characteristics. Our evidence also suggests that loss of IS6110 to fewer than seven elements per genome is uncommon. Finally, we present population-based evidence that KasA, an important component of mycolic acid biosynthesis, develops G312S polymorphisms under selective pressure.

Bacterial Proteins↗
PubMed2005

Genome scan linkage analysis comparing microsatellites and single-nucleotide polymorphisms markers for two measures of alcoholism in chromosomes 1, 4, and 7.

BACKGROUND: We analyzed 143 pedigrees (364 nuclear families) in the Collaborative Study on the Genetics of Alcoholism (COGA) data provided to the participants in the Genetic Analysis Workshop 14 (GAW14) with the goal of comparing results obtained from genome linkage analysis using microsatellite and with results obtained using SNP markers for two measures of alcoholism (maximum number of drinks -MAXDRINK and an electrophysiological measure from EEG -TTTH1). First, we constructed haplotype blocks by using the entire set of single-nucleotide polymorphisms (SNP) in chromosomes 1, 4, and 7. These chromosomes have shown linkage signals for MAXDRINK or EEG-TTTH1 in previous reports. Second, we randomly selected one, two, three, four, and five SNPs from each block (referred to as Rep1 - Rep5, respectively) to conduct linkage analysis using variance component approach. Finally, results of all SNP analyses were compared with those obtained using microsatellite markers. RESULTS: The LOD scores obtained from SNPs were slightly higher but the curves were not radically different from those obtained from microsatellite analyses. The peaks of linkage regions from SNP sets were slightly shifted to the left when compared to those from microsatellite markers. The reduced sets of SNPs provide signals in the same linkage regions but with a smaller LOD score suggesting a significant impact of the decrease in information content on linkage results. The widths of 1 LOD support interval of linkage regions from SNP sets were smaller when compared to those of microsatellite markers. However, two linkage regions obtained from the microsatellite linkage analysis on chromosome 7 for LOG of TTTH1 were not detected in the SNP based analyses. CONCLUSION: The linkage results from SNPs showed narrower linkage regions and slightly higher LOD scores when compared to those of microsatellite markers. The different builds of the genetic maps used in microsatellite and SNPs markers or/and errors in genotyping may account for the microsatellite linkage signals on chromosome 7 that were not identified using SNPs. Also, unresolved map issues between SNPs and microsatellite markers may be partly responsible for the shifted linkage peaks when comparing the two types of markers.

Alcoholism↗