LDB2000: sequence-based integrated maps of the human genome.

MOTIVATION: Integrated maps are useful for gene mapping and establishing the relationship between recombination and sequence. In this paper we describe algorithms and their implementation for constructing sequence-based integrated maps of the human chromosomes, which are presented in LDB2000, a web based resource. Gene mapping efforts are now focussing on linkage disequilibrium mapping and extension of the integrated map to represent the extent of linkage disequilibrium in different genomic regions would further increase the utility of these maps. RESULTS: Sequence-based integrated maps have been completed for chromosomes 21 and 22. These maps provide locations for genes and polymorphic markers in sequence and on genetic linkage, radiation hybrid and cytogenetic scales. Single nucleotide polymorphisms associated with genes in the maps are also included and their sequence locations indicated. Related locus information, such as aliases and expression information, can be searched on the WWW site.     

Comparative mapping of human chromosome 10 to pig chromosomes 10 and 14

Identification of predictive markers in QTL regions that impact production traits in commercial populations of swine is dependent on construction of dense comparative maps with human and mouse genomes. Chromosomal painting in swine suggests that large genomic blocks are conserved between pig and human, while mapping of individual genes reveals that gene order can be quite divergent. High-resolution comparative maps in regions affecting traits of interest are necessary for selection of positional candidate genes to evaluate nucleotide variation causing phenotypic differences. The objective of this study was to construct an ordered comparative map of human chromosome 10 and pig chromosomes 10 and 14. As a large portion of both pig chromosomes are represented by HSA10, genes at regularly spaced intervals along this chromosome were targeted for placement in the porcine genome. A total of 29 genes from human chromosome 10 were mapped to porcine chromosomes 10 (SSC10) and 14 (SSC14) averaging about 5 Mb distance of human DNA per marker. Eighteen genes were assigned by linkage in the MARC mapping population, five genes were physically assigned with the IMpRH mapping panel and seven genes were assigned on both maps. Seventeen genes from human 10p mapped to SSC10, and 12 genes from human 10q mapped to SSC14. Comparative maps of mammalian species indicate that chromosomal segments are conserved across several species and represent syntenic blocks with distinct breakpoints. Development of comparative maps containing several species should reveal conserved syntenic blocks that will allow us to better define QTL regions in livestock.     

A potato molecular-function map for carbohydrate metabolism and transport

Molecular-linkage maps based on functional gene markers (molecular-function maps) are the prerequisite for a candidate-gene approach to identify genes responsible for quantitative traits at the molecular level. Genetic linkage between a quantitative trait locus (QTL) and a candidate-gene locus is observed when there is a causal relationship between alleles of the candidate gene and the QTL effect. Functional gene markers can also be used for marker-assisted selection and as anchors for structural and functional comparisons between distantly related plant species sharing the same metabolic pathways. A first molecular-function map with 85 loci was constructed in potato based on 69 genes. Priority was given to genes operating in carbohydrate metabolism and transport. Public databases were searched for genes of interest from potato, tomato, or other plant species. DNA sequence information was used to develop PCR-based marker assays that allowed the localization of corresponding potato genes on existing RFLP linkage maps. Comparing the molecular-function map for genes operating in carbohydrate metabolism and transport with a QTL map for tuber starch content indicates a number of putative candidate genes for this important agronomic trait. Received: 19 March 2000 / Accepted: 16 May 2000     

Comparison of genetic maps for two Leptospira interrogans serovars provides evidence for two chromosomes and intraspecies heterogeneity.

Genetic maps were constructed for Leptospira interrogans serovars icterohaemorrhagiae and pomona. Previously we independently constructed physical maps of the genomes for these two serovars. The genomes of both serovars consist of a large replicon (4.4 to 4.6 Mb) and a small replicon (350 kb). Genes were localized on the physical maps by using Southern blot analysis with specific probes. Among the probes used were genes encoding a variety of essential enzymes and genes usually found near bacterial chromosomal replication origins. Most of the essential genes are on the larger replicon of each serovar. However, the smaller replicons of both serovars contain the asd gene. The asd gene encodes aspartate beta-semialdehyde dehydrogenase, an enzyme essential in amino acid and cell wall biosyntheses. The finding that both L. interrogans replicons contain essential genes suggests that both replicons are chromosomes. Comparison of the genetic maps of the larger replicons of the two serovars showed evidence of large rearrangements. These data show that there is considerable intraspecies heterogeneity in L. interrogans.     

Advanced technologies for genomic analysis in farm animals and its application for QTL mapping

Rapid progress in farm animal breeding has been made in the last few decades. Advanced technologies for genomic analysis in molecular genetics have led to the identification of genes or markers associated with genes that affect economic traits. Molecular markers, large-insert libraries and RH panels have been used to build the genetic linkage maps, physical maps and comparative maps in different farm animals. Moreover, EST sequencing, genome sequencing and SNPs maps are helping us to understand how genomes function in various organisms and further areas will be studied by DNA microarray technologies and proteomics methods. Because most economically important traits in farm animals are controlled by multiple genes and the environment, the main goal of genome research in farm animals is to map and characterize genes determining QTL. There are two main strategies to identify trait loci, candidate gene association tests and genome scan approaches. In recent years, some new concepts, such as RNAi, miRNA and eQTL, have been introduced into farm animal research, especially for QTL mapping and finding QTN. Several genes that influence important traits have already been identified or are close to being identified, and some of them have been applied in farm animal breeding programs by marker-assisted selection.     

Molecular-genetic maps for group 1 chromosomes of Triticeae species and their relation to chromosomes in rice and oat

Group 1 chromosomes of the Triticeae tribe have been studied extensively because many important genes have been assigned to them. In this paper, chromosome 1 linkage maps of Triticum aestivum, T. tauschii, and T. monococcum are compared with existing barley and rye maps to develop a consensus map for Triticeae species and thus facilitate the mapping of agronomic genes in this tribe. The consensus map that was developed consists of 14 agronomically important genes, 17 DNA markers that were derived from known-function clones, and 76 DNA markers derived from anonymous clones. There are 12 inconsistencies in the order of markers among seven wheat, four barley, and two rye maps. A comparison of the Triticeae group 1 chromosome consensus map with linkage maps of homoeologous chromosomes in rice indicates that the linkage maps for the long arm and the proximal portion of the short arm of group 1 chromosomes are conserved among these species. Similarly, gene order is conserved between Triticeae chromosome 1 and its homoeologous chromosome in oat. The location of the centromere in rice and oat chromosomes is estimated from its position in homoeologous group 1 chromosomes of Triticeae.     

Comparative maps: adding pieces to the mammalian jigsaw puzzle

Comparative maps display the chromosomal location of homologous genes in different species and highlight genetic segments that are conserved in evolution. These maps are used to study chromosomal changes that occurred during the divergence of mammalian lineages, to identify candidates for hereditary disease genes, and to facilitate mapping in other species. Recently, physical mapping in regions of known conserved linkage has revealed previously undetected chromosomal changes that may provide clues to understanding chromosomal structure and function and evolutionary processes. The availability of these data in electronically accessible formats is critical to the growth and analysis of comparative maps.     

An expanded comparative map of bovine chromosome 27 targeting dairy form QTL regions

At present, the density of genes on the bovine maps is extremely limited and current resolution of the human-bovine comparative map is insufficient for selection of candidate genes controlling many economic traits of interest in dairy cattle. This study describes the chromosomal mapping of 10 selected gene-associated markers to bovine linkage and radiation hybrid maps to improve the breakpoint resolution in the human-bovine comparative map near two previously identified quantitative trait loci for the linear type trait, dairy form. Two regions of conserved synteny not previously described are reported between the telomeric region of bovine chromosome 27 (BTA27) and human chromosome 3 (HSA3) p24 region and between the HSA4q34.1 region and BTA8. These data increase the number of genes positioned on the bovine gene maps, refine the human-bovine comparative map, and should improve the efficiency of candidate gene selection for the dairy form trait in cattle.     

Analysis of recombination and gene distribution in the 2L1.0 region of wheat (Triticum aestivum L.) and barley (Hordeum vulgare L.)

Both wheat and barley belong to tribe Triticeae and are closely related. High-density detailed comparison of physical and genetic linkage maps revealed that wheat genes are present in physically small gene-rich regions (GRRs). One of the largest GRRs is located around fraction length 1.0 of the long arm of wheat homoeologous group 2 chromosomes termed the "2L1.0 region." The main objective of this study was to analyze the structural and functional organization of the 2L1.0 region in barley in comparison to wheat. Using the 29 physically mapped RFLP markers for the region, wheat and barley consensus genetic linkage maps of the 2L1.0 region were generated by combining information from 18 wheat and 7 barley genetic linkage maps. Comparative analysis using these consensus maps and other available wheat and barley mapping resources identified 227 DNA markers and ESTs for the region. The region accounted for 58% of the genes and 68% of the arm's recombination in wheat. However, the corresponding region in barley accounted for about 42% of the genes and 81% of the recombination. The kb/cM ratio for the region was 122 in barley compared to 244 in wheat. Distribution of genes and recombination varied between the two species even though the gene order and density were similar.     

A human genome map of comparative anchor tagged sequences.

Effective comparative mapping inference utilizing developing gene maps of animal species requires the inclusion of anchored reference loci that are homologous to genes mapped in the more "gene-dense" mouse and human maps. Nominated anchor loci, termed comparative anchor tagged sequences (CATS), have been ordered in the mouse linkage map, but due to the dearth of common polymorphisms among human coding genes have not been well represented in human linkage maps. We present here an ordered framework map of 314 comparative anchor markers in humans based on mapping analysis in the Genebridge 4 panel of radiation hybrid cell lines, plus empirically optimized CATS PCR primers which detect these markers. The ordering of these homologous gene markers in human and mouse maps provides a framework for comparative gene mapping of representative mammalian species.     

Sequence diversity in 36 candidate genes for cardiovascular disorders.

Two strategies involving whole-genome association studies have been proposed for the identification of genes involved in complex diseases. The first one seeks to characterize all common variants of human genes and to test their association with disease. The second one seeks to develop dense maps of single-nucleotide polymorphisms (SNPs) and to detect susceptibility genes through linkage disequilibrium. We performed a molecular screening of the coding and/or flanking regions of 36 candidate genes for cardiovascular diseases. All polymorphisms identified by this screening were further genotyped in 750 subjects of European descent. In the whole set of genes, the lengths explored spanned 53.8 kb in the 5' regions, 68.4 kb in exonic regions, and 13 kb in the 3' regions. The strength of linkage disequilibrium within candidate regions suggests that genomewide maps of SNPs might be efficient ways to identify new disease-susceptibility genes, provided that the maps are sufficiently dense. However, the relatively large number of polymorphisms within coding and regulatory regions of candidate genes raises the possibility that several of them might be functional and that the pattern of genotype-phenotype association might be more complex than initially envisaged, as actually has been observed in some well-characterized genes. These results argue in favor of both genomewide association studies and detailed studies of the overall sequence variation of candidate genes, as complementary approaches.     

Polytene chromosomal maps of 11 Drosophila species: the order of genomic scaffolds inferred from genetic and physical maps

The sequencing of the 12 genomes of members of the genus Drosophila was taken as an opportunity to reevaluate the genetic and physical maps for 11 of the species, in part to aid in the mapping of assembled scaffolds. Here, we present an overview of the importance of cytogenetic maps to Drosophila biology and to the concepts of chromosomal evolution. Physical and genetic markers were used to anchor the genome assembly scaffolds to the polytene chromosomal maps for each species. In addition, a computational approach was used to anchor smaller scaffolds on the basis of the analysis of syntenic blocks. We present the chromosomal map data from each of the 11 sequenced non-Drosophila melanogaster species as a series of sections. Each section reviews the history of the polytene chromosome maps for each species, presents the new polytene chromosome maps, and anchors the genomic scaffolds to the cytological maps using genetic and physical markers. The mapping data agree with Muller's idea that the majority of Drosophila genes are syntenic. Despite the conservation of genes within homologous chromosome arms across species, the karyotypes of these species have changed through the fusion of chromosomal arms followed by subsequent rearrangement events.     

Physical Mapping of Genetic Markers on the Short Arm of Chromosome 5

The deletion of the short arm of chromosome 5 is associated with the cri-du-chat syndrome. In addition, loss of this portion of a chromosome is a common cytogenetic marker in a number of malignancies. However, to date, no genes associated with these disorders have been identified. Physical maps are the first step in isolating causative genes, and genes involved in autosomal recessive disorders are now routinely mapped through the identification of linked markers. Extensive genetic maps based upon polymorphic short tandem repeats (STRs) have provided researchers with a large number of markers to which such disorders can be genetically mapped. However, the physical locations of many of these STRs have not been determined. Toward the goal of integrating the human genetic maps with the physical maps, a 5p somatic cell hybrid deletion mapping panel that was derived from patients with 5p deletions or translocations was used to physically map 47 STRs that have been used to construct genetic maps of 5p. These data will be useful in the localization of disease genes that map to 5p and may be involved in the etiology of the cri-du-chat syndrome.     

Genomic structure, mapping, and expression analysis of the mammalian Lunatic, Manic, and Radical fringe genes

The three members of the mammalian fringe gene family, Manic fringe (Mfng), Radical fringe (Rfng), and Lunatic fringe (Lfng), were identified on the basis of their similarity to Drosophila fringe (fng) and their participation in the evolutionarily conserved Notch receptor signaling pathway. Fringe genes encode pioneer secretory proteins with weak similarity to glycosyltransferases. Both expression patterns and functional studies support an important role for Fringe genes in patterning during embryonic development and an association with cellular transformation. We have now further characterized the expression and determined the chromosomal localization and genomic structure of the mouse Mfng, Rfng, and Lfng genes; the genomic structure and conceptual open reading frame of the human RFNG gene; and the refined chromosomal localization of the three human fringe genes. The mouse Fringe genes are expressed in the embryo and in adult tissues. The mouse and human Fringe family members map to three different chromosomes in regions of conserved synteny: Mfng maps to mouse Chr 15, and MFNG maps to human Chr 22q13.1 in the region of two cancer-associated loci; Lfng maps to mouse Chr 5, and LFNG maps to human Chr 7p22; Rfng maps to mouse Chr 11, and RFNG maps to human Chr 17q25 in the minimal region for a familial psoriasis susceptibility locus. Characterization of the genomic loci of the Fringe gene family members reveals a conserved genomic organization of 8 exons. Comparative analysis of mammalian Fringe genomic organization suggests that the first exon is evolutionarily labile and that the Fringe genes have a genomic structure distinct from those of previously characterized glycosyltransferases. Received: 19 February 1999 / Accepted: 22 February 1999