A Nonparametric Approach for Mapping Quantitative Trait Loci

Genetic mapping of quantitative trait loci (QTLs) is performed typically by using a parametric approach, based on the assumption that the phenotype follows a normal distribution. Many traits of interest, however, are not normally distributed. In this paper, we present a nonparametric approach to QTL mapping applicable to any phenotypic distribution. The method is based on a statistic Z(w), which generalizes the nonparametric Wilcoxon rank-sum test to the situation of whole-genome search by interval mapping. We determine the appropriate significance level for the statistic Z(w), by showing that its asymptotic null distribution follows an Ornstein-Uhlenbeck process. These results provide a robust, distribution-free method for mapping QTLs.     

Genomewide Scan of Multiple Sclerosis in Finnish Multiplex Families

Multiple sclerosis (MS) is a neurological, demyelinating disorder with a putative autoimmune etiology. It is thought to be a multifactorial disease with a complex mode of inheritance. Here we report the results of a two-stage genomewide scan for loci predisposing to MS. The first stage of the screen, with a low-resolution map, was performed in a selection of 16 pedigrees collected from an isolated Finnish population. Multipoint, non-parametric linkage analysis of the 328 markers did not reveal statistically significant results. However, 10 slightly interesting regions (P = .1-.15) emerged, including our previous findings of the HLA complex on 6p21 and a putative locus on 5p14-p12. Eight of these novel regions were further analyzed by use of denser marker maps, in the second stage of the scan. For the chromosomal regions 4cen, 11tel, and 17q, the statistical significance increased, but not conclusively; for 2q32 and 10q21, the statistical significance did not change. Accordingly, genotyping of the high-density markers in these regions was performed, and the data were analyzed by use of two-point, parametric linkage analysis using the complete pedigree information of the 21 Finnish multiplex families. We detected suggestive evidence for a predisposing locus on chromosomal region 17q22-q24. Several markers on 17q22-q24 yielded positive LOD scores, with the maximum LOD score (Zmax) occurring with D17S807 (Zmax = 2.8, theta = .04; dominant model). Interestingly, a suggestive linkage between MS and the markers on 17q22-q24 was also revealed by a recent genomewide scan in MS families from the United Kingdom.     

Prevalence of peripheral and extra-articular disease in ankylosing spondylitis versus non-radiographic axial spondyloarthritis: a meta-analysis

BackgroundPeripheral disease (arthritis, enthesitis and dactylitis) and extra-articular disease (uveitis, psoriasis and inflammatory bowel disease) is common in ankylosing spondylitis (AS) and non-radiographic axial spondyloarthritis (nr-axSpA). So far, however, summary data on the prevalence are lacking. The objective of this meta-analysis was to assess the prevalence of peripheral and extra-articular manifestations in ankylosing spondylitis (AS) and nr-axSpA.MethodsWe performed a systematic literature search to identify publications describing the prevalence of peripheral and extra-articular disease manifestations in patients with AS and nr-axSpA. We assessed the risk of bias and between-study heterogeneity, and extracted data. Pooled prevalence and prevalence differences were calculated.ResultsEight studies comprising 2236 patients with AS and 1242 with nr-axSpA were included: 7 of the studies were longitudinal cohort studies. There was male predominance in AS (70.4 %, 95 % CI 64.4, 76.0 %) but not in nr-axSpA (46.8 %, 95 % CI 41.7, 51.9), which was independent of the prevalence of human leukocyte antigen (HLA)-B27. The prevalence of HLA-B27 was similar in AS (78.0 % (95 % CI 73.9, 81.9 %) and nr-axSpA (77.4 %, 95 % CI 68.9, 84.9 %)). The pooled prevalence of arthritis (29.7 % (95 % CI 22.4, 37.4 %) versus 27.9 % (95 % CI 16.0, 41.6 %)), enthesitis (28.8 % (95 % CI 2.6, 64.8) versus 35.4 % (95 % CI 6.1, 71.2)). dactylitis (6.0 % (95 % CI 4.7, 7.5 %) versus 6.0 % (95 % CI 1.9, 12.0 %)), psoriasis (10.2 % (95 % CI 7.5, 13.2 %) versus 10.9 % (95 % CI 9.1, 13.0 %)) and inflammatory bowel disease (4.1 % (95 % CI 2.3, 6.5 %) versus 6.4 % (95 % CI 3.6, 9.7 %)) were similar in AS and nr-axSpA. The pooled prevalence of uveitis was higher in AS (23.0 % (95 % CI 19.2, 27.1 %)) than in nr-axSpA (15.9 % (95 % CI 11.8, 20.4 %)).ConclusionPeripheral and extra-articular manifestations are equally prevalent in AS and nr-axSpA, except for uveitis, which is slightly more prevalent in AS. These data provide evidence for the largely equal nature of disease manifestations in nr-axSpA and AS.

Electronic supplementary material

The online version of this article (doi:10.1186/s13075-016-1093-z) contains supplementary material, which is available to authorized users.     

Staphylococcus aureus Nasal Carriage among Beefpacking Workers in a Midwestern United States Slaughterhouse

Occupational contact with livestock is an established risk factor for exposure to livestock-associated methicillin-resistant Staphylococcus aureus (MRSA), particularly among industrial swine workers. While S. aureus is known to infect cattle, livestock-associated S. aureus carriage among workers in the beef production chain has received limited attention. Beefpacking workers, who slaughter, butcher and process cattle, have intensified exposure to potentially infectious animal materials and may be at risk of livestock-associated S. aureus exposure. We conducted a cross-sectional study of beefpacking workers (n = 137) at an industrial slaughterhouse in the Midwestern United States to evaluate prevalence and characteristics of S. aureus nasal colonization, specifically the absence of the scn gene to identify putative association with livestock, antibiotic susceptibility, presence of Panton-Valentin leukocidin (PVL) genes lukS-PV and lukF-PV, and spa type. Overall prevalence of S. aureus nasal carriage was 27.0%. No workers carried livestock-associated MRSA. Methicillin-sensitive S. aureus isolates (MSSA) recovered from five workers (3.6%) lacked the scn gene and were considered putative livestock-associated S. aureus (pLA-SA). Among pLA-SA isolates, spa types t338, t748, t1476 and t2379 were identified. To our knowledge, these spa types have not previously been identified as associated with livestock. Prevalence of human-adapted MRSA carriage in workers was 3.6%. MRSA isolates were identified as spa types t002, t008 and t024, and four of five MRSA isolates were PVL-positive. To date, this is the first study to indicate that industrial beefpacking workers in the United States may be exposed to livestock-associated S. aureus, notably MSSA, and to spa types not previously identified in livestock and livestock workers. Occupational exposure to livestock-associated S. aureus in the beef production chain requires further epidemiologic investigation.     

Genomes of murine leukemia viruses isolated from wild mice.

The genomes of murine leukemia viruses (MuLV) isolated from wild mice have been studied. Detailed restriction endonuclease maps of the 8.8-kilobase (kb) unintegrated linear viral DNAs were derived for five ecotropic and five amphotropic MuLV's from California field mice, for Friend MuLV, and for one ecotropic and one xenotropic MuLV from Mus musculus castaneus. In general, the California MuLV's were similar in their leftward 6 kb (corresponding to the leftward long terminal repeat [LTR], gag, and pol) and rightward 1 kb (7.8 to 8.8 kb, corresponding to p15E and the rightward LTR). For the region spanning 6.0 to 7.7 kb (which includes the sequences that encode gp70) the amphotropic MuLV's shared few enzyme sites with the ecotropic MuLV's, although the California ecotropic MuLV's were highly related to each other in this region, as were the amphotropic MuLV's. Cross-hybridization studies between amphotropic and California ecotropic MuLV DNAs indicated that they were not homologous in the region 6.3 to 7.6 kb; the California ecotropic viral DNAs cross-hybridized in this region to AKR ecotropic MuLV. When the California viral DNAs were compared with AKR ecotropic viral DNA, many differences in enzyme sites were noted throughout the genome. The U3 regions of the wild mouse LTRs showed partial homology to this region in AKR MuLV. The LTR of Moloney MuLV was highly related to that of the California MuLV's, whereas the LTR of Friend MuLV appeared to be a recombinant between the two types of LTRs. The M. musculus castaneus isolates were most closely related to ecotropic and xenotropic MuLV's isolated from inbred mice. One amphotropic MuLV DNA was cloned from supercoiled viral DNA at its unique EcoRI site in pBR322. Viral DNAs with one and two LTRs were isolated. After digestion with EcoRI, DNAs of both types were infectious. It is concluded that ecotropic and amphotropic MuLV's differ primarily in the region which encodes gp70.     

Genomic mapping by anchoring random clones: a mathematical analysis.

A complete physical map of the DNA of an organism, consisting of overlapping clones spanning the genome, is an extremely useful tool for genomic analysis. Various methods for the construction of such physical maps are available. One approach is to assemble the physical map by "fingerprinting" a large number of random clones and inferring overlap between clones with sufficiently similar fingerprints. E.S. Lander and M.S. Waterman (1988, Genomics 2:231-239) have recently provided a mathematical analysis of such physical mapping schemes, useful for planning such a project. Another approach is to assemble the physical map by "anchoring" a large number of random clones--that is, by taking random short regions called anchors and identifying the clones containing each anchor. Here, we provide a mathematical analysis of such a physical mapping scheme.     

Mendelian Factors Underlying Quantitative Traits in Tomato: Comparison across Species, Generations, and Environments

As part of ongoing studies regarding the genetic basis of quantitative variation in phenotype, we have determined the chromosomal locations of quantitative trait loci (QTLs) affecting fruit size, soluble solids concentration, and pH, in a cross between the domestic tomato (Lycopersicon esculentum Mill.) and a closely-related wild species, L. cheesmanii. Using a RFLP map of the tomato genome, we compared the inheritance patterns of polymorphisms in 350 F2 individuals with phenotypes scored in three different ways: (1) from the F2 progeny themselves, grown near Davis, California; (2) from F3 families obtained by selfing each F2 individual, grown near Gilroy, California (F3-CA); and (3) from equivalent F3 families grown near Rehovot, Israel (F3-IS). Maximum likelihood methods were used to estimate the approximate chromosomal locations, phenotypic effects (both additive effects and dominance deviations), and gene action of QTLs underlying phenotypic variation in each of these three environments. A total of 29 putative QTLs were detected in the three environments. These QTLs were distributed over 11 of the 12 chromosomes, accounted for 4.7-42.0% of the phenotypic variance in a trait, and showed different types of gene action. Among these 29 QTLs, 4 were detected in all three environments, 10 in two environments, and 15 in only a single environment. The two California environments were most similar, sharing 11/25 (44%) QTLs, while the Israel environment was quite different, sharing 7/20 (35%) and 5/26 (19%) QTLs with the respective California environments. One major goal of QTL mapping is to predict, with maximum accuracy, which individuals will produce progeny showing particular phenotypes. Traditionally, the phenotype of an individual alone has been used to predict the phenotype of its progeny. Our results suggested that, for a trait with low heritability (soluble solids), the phenotype of F3 progeny could be predicted more accurately from the genotype of the F2 parent at QTLs than from the phenotype of the F2 individual. For a trait with intermediate heritability (fruit pH), QTL genotype and observed phenotype were about equally effective at predicting progeny phenotype. For a trait with high heritability (mass per fruit), knowing the QTL genotype of an individual added little if any predictive value, to simply knowing the phenotype. The QTLs mapped in the L. esculentum X L. cheesmanii F2 appear to be at similar locations to many of those mapped in a previous cross with a different wild tomato (L. chmielewskii).(ABSTRACT TRUNCATED AT 400 WORDS)     

MAPMAKER: an interactive computer package for constructing primary genetic linkage maps of experimental and natural populations

With the advent of RFLPs, genetic linkage maps are now being assembled for a number of organisms including both inbred experimental populations such as maize and outbred natural populations such as humans. Accurate construction of such genetic maps requires multipoint linkage analysis of particular types of pedigrees. We describe here a computer package, called MAPMAKER, designed specifically for this purpose. The program uses an efficient algorithm that allows simultaneous multipoint analysis of any number of loci. MAPMAKER also includes an interactive command language that makes it easy for a geneticist to explore linkage data. MAPMAKER has been applied to the construction of linkage maps in a number of organisms, including the human and several plants, and we outline the mapping strategies that have been used.     

Genetic Analysis of the Fungus, Bremia Lactucae, Using Restriction Fragment Length Polymorphisms

Restriction fragment length polymorphisms (RFLPs) were developed as genetic markers for Bremia lactucae, the biotrophic Oomycete fungus which causes lettuce downy mildew. By using 55 genomic and cDNA probes, a total of 61 RFLP loci were identified among three heterothallic isolates of B. lactucae. Of these 61 RFLP loci, 53 were heterozygous in at least one of the three strains and thus were informative for linkage analysis in at least one of two F1 crosses that were performed. Analysis of the cosegregation of these 53 RFLPs, eight avirulence loci and the mating type locus allowed the construction of a preliminary genetic linkage map consisting of 13 small linkage groups. Based on the extent of linkage detected among probes, the genome of B. lactucae can be estimated to be approximately 2000 cM. Linkage was detected between a RFLP locus and an avirulence gene, providing a potential starting point for chromosome walking to clone an avirulence gene. The high frequency of DNA polymorphism in naturally occurring isolates and the proper Mendelian segregation of loci detected by low copy number probes indicates that it will be possible to construct a detailed genetic map of B. lactucae using RFLPs as markers. The method of analysis employed here should be applicable to many other outbreeding, heterozygous species for which defined inbred lines are not available.