Multipoint analysis of human quantitative genetic variation.

A unique method of partitioning human quantitative genetic variation into effects due to specific chromosomal regions is presented. This method is based on estimating the proportion of genetic material, R, shared identical by descent (IBD) by sibling pairs in a specified chromosomal region, on the basis of their marker genotypes at a set of marker loci spanning the region. The mean and variance of the distribution of R conditional on IBD status and recombination pattern between two marker loci are derived as a function of the distance between the two loci. The distribution of the estimates of R is exemplified using data on 22 loci on chromosome 7. A method of using the estimated R values and observed values of a quantitative trait in a set of sibships to estimate the proportion of total genetic variance explained by loci in the region of interest is presented. Monte Carlo simulation techniques are used to show that this method is more powerful than existing methods of quantitative linkage analysis based on sib pairs. It is also shown through simulation studies that the proposed method is sensitive to genetic variation arising from both a single locus of large effect as well as from several loosely linked loci of moderate phenotypic effect.     

Genetic analysis of tongue size and taste papillae number and size in recombinant inbred strains of mice

Quantitative trait loci (QTLs) analysis has been used to examine natural variation of phenotypes in the mouse somatosensory cortex, hippocampus, cerebellum, and amygdala. QTL analysis has also been utilized to map and identify genes underlying anatomical features such as muscle, organ, and body weights. However, this methodology has not been previously applied to identification of anatomical structures related to gustatory phenotypes. In this study, we used QTL analysis to map and characterize genes underlying tongue size, papillae number, and papillae area. In a set of 43 BXD recombinant inbred (RI) mice (n = 111) and 2 parental strains (C57BL/6J and DBA/2J; n = 7), we measured tongue length, width, and weight. In a subset of 23 BXD RI mice and the parental mice, we measured filiform and fungiform papillae number and fungiform papillae area. Using QTL linkage analysis (through WebQTL), we detected 2 significant and noninteracting QTLs influencing tongue length on chromosomes 5 and 7. We also found a significant QTL on chromosome 19 underlying fungiform papillae area and a suggestive QTL on chromosome 2 linked to fungiform papillae number. From these QTLs, we identified a number of candidate genes within the QTL intervals that include SRY-box containing gene, nebulin-related anchoring protein, and actin-binding LIM protein 1. This study is an important first step in identifying genetic factors underlying tongue size, papillae size, and papillae number using QTL analysis.     

The genetic variance for multiple linked quantitative trait loci conditional on marker information in a crossed population

In the prediction of genetic values and quantitative trait loci (QTLs) mapping via the mixed model method incorporating marker information in animal populations, it is important to model the genetic variance for individuals with an arbitrary pedigree structure. In this study, for a crossed population originated from different genetic groups such as breeds or outbred strains, the variance of additive genetic values for multiple linked QTLs that are contained in a chromosome segment, especially the segregation variance, is investigated assuming the use of marker data. The variance for a finite number of QTLs in one chromosomal segment is first examined for the crossed population with the general pedigree. Then, applying the concept of the expectation of identity-by-descent proportion, an approximation to the mean of the conditional probabilities for the linked QTLs over all loci is obtained, and using it an expression for the variance in the case of an infinite number of linked QTLs marked by flanking markers is derived. It appears that the approach presented can be useful in the segment mapping using, and in the genetic evaluation of, crosses with general pedigrees in the population of concern. The calculation of the segregation variance through the current approach is illustrated numerically, using a small data-set.     

Saturation of two chromosome regions conferring resistance to SCMV with SSR and AFLP markers by targeted BSA

Quantitative trait loci (QTLs) and bulked segregant analyses (BSA) identified the major genes Scmv1 on chromosome 6 and Scmv2 on chromosome 3, conferring resistance against sugarcane mosaic virus (SCMV) in maize. Both chromosome regions were further enriched for SSR and AFLP markers by targeted bulked segregant analysis (tBSA) in order to identify and map only markers closely linked to either Scmv1 or Scmv2. For identification of markers closely linked to the target genes, symptomless individuals of advanced backcross generations BC5 to BC9 were employed. All AFLP markers, identified by tBSA using 400 EcoRI/ MseI primer combinations, mapped within both targeted marker intervals. Fourteen SSR and six AFLP markers mapped to the Scmv1 region. Eleven SSR and 18 AFLP markers were located in the Scmv2 region. Whereas the linear order of SSR markers and the window size for the Scmv2 region fitted well with publicly available genetic maps, map distances and window size differed substantially for the Scmv1 region on chromosome 6. A possible explanation for the observed discrepancies is the presence of two closely linked resistance genes in the Scmv1 region.     

The sockeye salmon neo-Y chromosome is a fusion between linkage groups orthologous to the coho Y chromosome and the long arm of rainbow trout chromosome 2

Unlike other Pacific salmon, sockeye salmon (Oncorhynchus nerka) have an X(1)X(2)Y sex chromosome system, with females having a diploid chromosome number of 2n = 58 and males 2n = 57 in all populations examined. To determine the origin of the sockeye Y chromosome, we mapped microsatellite loci from the rainbow trout (O. mykiss; OMY) genetic map, including those found on the Y chromosomes of related species, in kokanee (i.e. non-anadromous sockeye) crosses. Results showed that 3 microsatellite loci from the long arm of rainbow trout chromosome 8 (OMY8q), linked to SEX (the sex-determining locus) in coho salmon (O. kisutch), are also closely linked to SEX in the kokanee crosses. We also found that 3 microsatellite loci from OMY2q are linked to those markers from OMY8q and SEX in kokanee, with both linkage groups fused to form the neo-Y. These results were confirmed by physical mapping of BAC clones containing microsatellite loci from OMY8q and OMY2q to kokanee chromosomes using fluorescence in situ hybridization. The fusion of OMY2q to the ancestral Y may have resolved sexual conflict and, in turn, may have played a large role in the divergence of sockeye from a shared ancestor with coho.     

Demarcation of informative chromosomes in tropical sweet corn inbred lines using microsatellite DNA markers

A study of genetic variation among 10 pairs of chromosomes extracted from 13 tropical sweet corn inbred lines, using 99 microsatellite markers, revealed a wide range of genetic diversity. Allelic richness and the number of effective alleles per chromosome ranged from 2.78 to 4.33 and 1.96 to 3.47, respectively, with respective mean values of 3.62 and 2.73. According to the Shannon’s information index (I) and Nei’s gene diversity coefficient (Nei), Chromosome 10 was the most informative chromosome (I = 1.311 and Nei = 0.703), while Chromosome 2 possessed the least (I = 0.762 and Nei = 0.456). Based on linkage disequilibrium (LD) measurements for loci less than 50 cM apart on the same chromosome, all loci on Chromosomes 1, 6 and 7 were in equilibrium. Even so, there was a high proportion of genetic variation in Chromosomes 4, 5, 8, 9 and 10, thereby revealing their appropriateness for use in the genetic diversity investigations among tropical sweet corn lines. Chromosome 4, with the highest number of loci in linkage disequilibrium, was considered the best for marker-phenotype association and QTL mapping, followed by Chromosomes 5, 8, 9 and 10.     

Waardenberg syndrome (WS) type I is caused by defects at multiple loci, one of which is near ALPP on chromosome 2: First report of the WS consortium

Previous studies have localized the gene for Waardenburg syndrome (WS) type I to the distal portion of chromosome 2q, near the ALPP locus. We pooled linkage data obtained from 41 WS type I and 3 WS type II families which were typed for six polymorphic loci on chromosome 2q in order to refine the location of the WS locus (WS1) and evaluate the extent of genetic heterogeneity. In the course of this work, we developed diagnostic criteria for genetic and phenotypic studies. Our findings, based on two-locus and multilocus analysis using a linkage map established from reference pedigrees, suggest that there are two or more mutations causing WS, one of which (i.e., WS1) is located on chromosome 2q, between the ALPP and FN1 loci, at distances of 7.8 cM and 11.2 cM for each marker, respectively. The results also indicate that WS1 is responsible for the illness in approximately 45% of all families in this sample. However, the odds favoring this position over a location between ALPP and SAG are only 2:1 when alternate assumptions about the proportion of linked families are considered. We conclude that a more saturated map of this region of chromosome 2q, including highly polymorphic markers, will be needed to accurately distinguish linked families and, ultimately, isolate the mutant gene.     

A Sex Chromosomal Restriction-Fragment-Length Marker Linked to Melanoma-Determining Tu Loci in Xiphophorus

In Xiphophorus, the causative genetic information for melanoma formation has been assigned by classical genetics to chromosomal loci, which are located on the sex chromosomes. In our attempts to molecularly clone these melanoma-determining loci, named Tu, we have looked for restriction-fragment-length markers (RFLMs) linked to the Tu loci. These RFLMs should be useful in obtaining a physical map of a Tu locus, which will aid in the cloning of the corresponding sequences. DNA samples from various Xiphophorus strains and hybrids including those bearing different Tu wild-type, deletion and translocation chromosomes, were screened for the presence of random RFLMs using homologous or heterologous sequences as hybridization probes. We find an EcoRI restriction fragment which shows limited crosshybridization to the v-erb B gene--but not representing the authentic c-erb B gene of Xiphophorus--to be polymorphic with respect to different sex chromosomes. Linkage analysis revealed that a 5-kb fragment is linked to the Tu-Sd locus on the X chromosome, a 7-kb fragment is linked to the Tu-Sr locus on the Y chromosome, both of Xiphophorus maculatus, and that a 12-kb fragment is linked to the Tu-Li locus on the X chromosome of Xiphophorus variatus. Using different chromosomal mutants this RFLM has been mapped to a frequent deletion/translocation breakpoint of the X chromosome, less than 0.3 cM apart from the Tu locus.     

Genomewide scan in german families reveals evidence for a novel psoriasis-susceptibility locus on chromosome 19p13

Psoriasis is a common chronic inflammatory skin disease with a strong genetic component. Few psoriasis-susceptibility loci have been reported, and only two have been confirmed in independent data sets. This article reports results of a genomewide scan that was performed, using 370 microsatellite markers, for psoriasis-susceptibility loci in 32 German extended families, comprising 162 affected and 195 unaffected individuals. Nonparametric linkage analysis of all families provided strong evidence for a novel psoriasis-susceptibility locus on chromosome 19p (Zlr=3.50; P=.0002). Parametric analysis revealed a heterogeneity LOD score of 4.06, corresponding to a genomewide significance level of.037, under the assumption of a recessive model with high disease-allele frequency and 66% as the proportion of linked families. This study confirms linkage of psoriasis to the HLA region on chromosome 6p and suggests additional regions on chromosomes 8q and 21q for further investigations.     

Genetics of actin-related sequences in tomato

Summary The genomic distribution of actin-related sequences in tomato was investigated using a cloned actin gene from soybean. Ten actin loci account for most of the hybridizing fragments observed with Southern analysis. Single loci were found on chromosomes 1, 3 and 10 and two loci on chromosome 4. One locus is linked to an unmapped isozyme marker, Sod-1. The four remaining actin loci are independent of each other and of any of the other markers tested. The number of actin loci in tomato (10) is greater than that estimated for soybean (8). As soybean is apparently a tetraploid and tomato a diploid, these results suggest that the number of actin loci has not been stable during the evolution of dicots. A number of these mapped loci lie in regions of the genome previously devoid of molecular markers and thus may be useful in basic and applied genetic research.     

Plasmacytoid dendritic cells: sensing nucleic acids in viral infection and autoimmune diseases

Plasmacytoid dendritic cells (pDCs) are important mediators of antiviral immunity through their ability to produce large amounts of type I interferons (IFNs) on viral infection. This function of pDCs is linked to their expression of Toll-like receptor 7 (TLR7) and TLR9, which sense viral nucleic acids within the early endosomes. Exclusion of self nucleic acids from TLR-containing early endosomes normally prevents pDC responses to them. However, in some autoimmune diseases, self nucleic acids can be modified by host factors and gain entrance to pDC endosomes, where they activate TLR signalling. Several pDC receptors negatively regulate type I IFN responses by pDCs during viral infection and for normal homeostasis.     

Clinical significance of circulating dendritic cells in patients with systemic lupus erythematosus

Dendritic cells are a complex group of mainly bone-marrow-derived leukocytes that play a role in autoimmune diseases. The total number of circulating dendritic cells (tDC), and their plasmacytoid dendritic cell (pDC) and myeloid dendritic cell (mDC1 and mDC2) subpopulations were assessed using flow cytometry. The number of tDC and their subsets were significantly lower in systemic lupus erythematosus patients than in the control group. The count of tDC and their subsets correlated with the number of T cells. The number of tDC and pDC subpopulation were lower in the patients with lymphopenia and leukopenia than in the patients without these symptoms. Our data suggest that fluctuations in blood dendritic cell count in systemic lupus erythematosus patients are much more significant in pDC than in mDC, what may be caused by their migration to the sites of inflammation including skin lesions. Positive correlation between dendritic cell number and TCD4+, TCD8+ and CD19+ B cells, testify of their interactions and influence on SLE pathogenesis. The association between dendritic cell number and clinical features seems to be less clear.     

Distribution,inheritance and linkage relationships of ribosomal DNA spacer length variants in pea

Summary DNA restriction endonuclease fragment analysis is used to examine the genetic organization, inheritance and linkage associations of the ribosomal DNA in pea. The substantial variation observed in the length of the intergenic spacer region is shown to segregate in Mendelian fashion involving two independent genetic loci, designated Rrn1 and Rrn2. Linkage between Rrn1 and two marker loci on chromosome 4 establishes the approximate location of this tandem array. Rrn2 shows linkage with a set of isozyme loci which assort independently of other markers on all seven chromosomes. Combining these observations with previous cytological data, we suggest that Rrn2 and the isozyme loci linked to it constitute a new linkage group on chromosome 7. The general absence of spacer length classes common to both rRNA loci in any of the lines we examined indicates that little or no genetic exchange occurs between the nonhomologous nucleolar organizer regions.     

Speciation genomics and a role for the Z chromosome in the early stages of divergence between Mexican ducks and mallards

Speciation is a continuous and dynamic process, and studying organisms during the early stages of this process can aid in identifying speciation mechanisms. The mallard (Anas platyrhynchos) and Mexican duck (A. [p.] diazi) are two recently diverged taxa with a history of hybridization and controversial taxonomy. To understand their evolutionary history, we conducted genomic scans to characterize patterns of genetic diversity and divergence across the mitochondrial DNA (mtDNA) control region, 3523 autosomal loci and 172 Z‐linked sex chromosome loci. Between the two taxa, Z‐linked loci (Φ_ST = 0.088) were 5.2 times more differentiated than autosomal DNA (Φ_ST = 0.017) but comparable to mtDNA (Φ_ST = 0.092). This elevated Z differentiation deviated from neutral expectations inferred from simulated data that incorporated demographic history and differences in effective population sizes between marker types. Furthermore, 3% of Z‐linked loci, compared to <0.1% of autosomal loci, were detected as outlier loci under divergent selection with elevated relative (Φ_ST) and absolute (d_XY) estimates of divergence. In contrast, the ratio of Z‐linked and autosomal differentiation among the seven Mexican duck sampling locations was close to 1:1 (Φ_ST = 0.018 for both markers). We conclude that between mallards and Mexican ducks, divergence at autosomal markers is largely neutral, whereas greater divergence on the Z chromosome (or some portions thereof) is likely the product of selection that has been important in speciation. Our results contribute to a growing body of literature indicating elevated divergence on the Z chromosome and its likely importance in avian speciation.     

Dendritic cells from HIV-1 infected individuals are less responsive to toll-like receptor (TLR) ligands

We compared TLR responsiveness in PBMC from HIV-1-infected and uninfected individuals using the TLR agonists: TLR7 (3M-001), TLR8 (3M-002), and TLR7/8 (3M-011). Activation and maturation of plasmacytoid dendritic cells (pDC) were measured by evaluating CD86, CD40, and CD83 expression and myeloid dendritic cell (mDC) activation was measured by evaluating CD40 expression. All agonists tested induced activation and maturation of pDC in PBMC cultures of cells from HIV+ and HIV- individuals. The TLR7 agonist induced significantly less pDC maturation in cells from HIV+ individuals. Quantitative assessment of secreted IFN-alpha and pro-inflammatory cytokines at the single cell level showed that pDC from HIV+ individuals stimulated with TLR7 and TLR7/8 induced IFN-alpha. TLR8 and TLR7/8 agonists induced IL-12 and COX-2 expression in mDC from HIV+ and HIV- individuals. Understanding pDC and mDC activation and maturation in HIV-1 infection could lead to more rational development of immunotherapeutic strategies to stimulate the adaptive immune response to HIV-1.     

Copy Number Variation Screen Identifies a Rare De Novo Deletion at Chromosome 15q13.1-13.3 in a Child with Language Impairment

A significant proportion of children (up to 7% in the UK) present with pronounced language difficulties that cannot be explained by obvious causes like other neurological and medical conditions. A substantial genetic component is predicted to underlie such language problems. Copy number variants (CNVs) have been implicated in neurodevelopmental and psychiatric conditions, such as autism and schizophrenia, but it is not fully established to what extent they might contribute to language disorders. We conducted a CNV screen in a longitudinal cohort of young children with language-related difficulties (n = 85), focusing on single events at candidate loci. We detected a de novo deletion on chromosome 15q13.1–13.3. The adjacent 15q11-13.1 locus is disrupted in Prader-Willi and Angelman syndromes, while disruptions across the breakpoints (BP1-BP6) have previously been implicated in different neurodevelopmental phenotypes including autism, intellectual disability (ID), seizures and developmental delay (DD). This is the first report of a deletion at BP3-BP5 being linked to a deficit confined to language impairment, in the absence of ID, expanding the range of phenotypes that implicate the chromosome 15q13 locus.     

A study of genetic linkage heterogeneity in 35 adult-onset polycystic kidney disease families

A genetic heterogeneity analysis of 35 kindreds with adult-onset polycystic kidney disease (ADPKD) was carried out using the D16S85, D16S84, D16S125 and D16S94 loci that are closely linked to the PKD1 locus on chromosome 16. The results show that the likelihood of two ADPKD loci is 2,514.9 times greater than for a single locus (P < 0.0001). The maximum likelihood lod score is 27.38 under heterogeneity with PKD1 lying 4.9 cM proximal to D16S85 (in males). At least 3% of kindreds are unlinked to PKD1, since the 95% confidence limits of alpha, the proportion of families linked to PKD1, are 0.54–0.97. Only 2 out of 35 kindreds (5.7%) show statistically significant evidence of non-linkage to PKD1, with conditional probabilities of 0.987 and 0.993 that the disease locus is unlinked. This confirms the existence of a small subgroup of ADPKD kindreds that are unlinked to PKD1 and provides a firm basis for genetic counselling of this population on the basis of DNA probes.     

Non-Mendelian inheritance revealed in a genetic analysis of sexual progeny of Phytophthora cinnamomi with microsatellite markers

We report the development of four microsatellite loci into genetic markers for the diploid oomycete plant pathogen Phytophthora cinnamomi and that (AC)(n) and (AG)(n) microsatellites are significantly less frequent than in plant and mammal genomes. A minisatellite motif 14 bp long was also discovered. The four microsatellite loci were used to analyze sexual progeny from four separate crosses of P. cinnamomi. A large proportion of non-Mendelian inheritance was observed across all loci in all four crosses, including inheritance of more than two alleles at a locus and noninheritance of alleles from either parent at a locus. The aberrant inheritance is best explained by nondisjunction at meiosis in both the A1 parent and the A2 trisomic parents, resulting in aneuploid progeny. Two loci on the putative trisomic chromosome showed linkage and no loci were linked to mating type. One aneuploid offspring was shown to have lost alleles at two loci following subculture over 4 years, indicating that aneuploid progeny may not be mitotically stable.     

Isocitrate dehydrogenase in Aedes aegypti: formal genetics, preliminary linkage data and study of natural populations

Two loci for isocitrate dehydrogenase (Idh-1 ad Idh-2) are described in Ae. aegypti, both polymorphic with two codominant alleles. Crosses made to test linkage relationships of Idh-1 indicate that this locus is independent from sex (chromosome 1) and from Sod-1 and Hk-1 loci (chromosome 3), while it is linked to Pgm on the second chromosome. Average percent of recombination is 11.37, but significant differences have been found among strains. Data on genetic variability of Idh-1 and Idh-2 in three domestic african field populations are presented.     

A mapped set of genetic markers for human chromosome 9

A genetic map of markers for human chromosome 9, spanning a genetic distance of 147 cM in males and 231 cM in females, has been constructed from linkage studies with 19 loci in a large panel of reference families. The markers included four classical systems previously assigned to chromosome 9, and restriction fragment length polymorphisms of two cloned genes, ABL oncogene and argininosuccinase synthetase pseudogene 3 (ASSP3). The remaining 13 marker loci, with an average heterozygosity of 42%, were defined by arbitrary DNA probes newly ascertained from genomic libraries; seven of them were variable number of tandem repeat (VNTR) loci. A subset of 7 of the 19 linked markers is proposed for a primary map that could detect linkage with a genetic defect within the covered region of chromosome 9, provided that at least 45 phase-known meioses were available for study in an affected family.