ABSTRACT
MOTIVATION: The identification of orthologous gene pairs is generally based on sequence similarity. Gene pairs that are mutually 'best hits' between the genomes being compared are asserted to be orthologs. Although this method identifies most orthologous gene pairs with high confidence, it will miss a fraction of them, especially genes in duplicated gene families. In addition, the approach depends heavily on the completeness and quality of gene annotation. When the gene sequences are not correctly represented the approach is unlikely to find the correct ortholog. To overcome these limitations, we have developed an approach to identify orthologous gene pairs using shared chromosomal synteny and the annotation of protein function. RESULTS: Assembled mouse and human genomes were used to identify the regions of conserved synteny between these genomes. 'Syntenic anchors' are conserved non-repetitive locations between mouse and human genomes. Using these anchors, we identified blocks of sequences that contain consistently ordered anchors between the two genomes (syntenic blocks). The synteny information has been used to help us identify orthologous gene pairs between mouse and human genomes. The approach combines the mutual selection of the best tBlastX hits between human and mouse transcripts, and inferring gene orthologous relationships based on sharing syntenic anchors, collocating in the same syntenic blocks and sharing the same annotated protein function. Using this approach, we were able to find 19,357 orthologous gene pairs between human and mouse genomes, a 20% increase in the number of orthologs identified by conventional approaches.
Subject(s)
Algorithms , Chromosome Mapping/methods , Chromosomes, Mammalian/genetics , Pattern Recognition, Automated/methods , Proteins/genetics , Sequence Alignment/methods , Sequence Analysis, DNA/methods , Animals , Conserved Sequence , Evolution, Molecular , Genetic Linkage/genetics , Genome , Humans , Mice , Sequence Homology, Nucleic AcidABSTRACT
DNA sequence and annotation of the entire human chromosome 7, encompassing nearly 158 million nucleotides of DNA and 1917 gene structures, are presented. To generate a higher order description, additional structural features such as imprinted genes, fragile sites, and segmental duplications were integrated at the level of the DNA sequence with medical genetic data, including 440 chromosome rearrangement breakpoints associated with disease. This approach enabled the discovery of candidate genes for developmental diseases including autism.
Subject(s)
Chromosomes, Human, Pair 7/genetics , Sequence Analysis, DNA , Animals , Autistic Disorder/genetics , Chromosome Aberrations , Chromosome Fragile Sites , Chromosome Fragility , Chromosome Mapping , Computational Biology , Congenital Abnormalities/genetics , CpG Islands , DNA, Complementary , Databases, Genetic , Euchromatin/genetics , Expressed Sequence Tags , Gene Duplication , Genes, Overlapping , Genetic Diseases, Inborn/genetics , Genomic Imprinting , Humans , In Situ Hybridization, Fluorescence , Limb Deformities, Congenital/genetics , Mice , Molecular Sequence Data , Mutation , Neoplasms/genetics , Pseudogenes , RNA/genetics , Retroelements , Williams Syndrome/geneticsABSTRACT
The high degree of similarity between the mouse and human genomes is demonstrated through analysis of the sequence of mouse chromosome 16 (Mmu 16), which was obtained as part of a whole-genome shotgun assembly of the mouse genome. The mouse genome is about 10% smaller than the human genome, owing to a lower repetitive DNA content. Comparison of the structure and protein-coding potential of Mmu 16 with that of the homologous segments of the human genome identifies regions of conserved synteny with human chromosomes (Hsa) 3, 8, 12, 16, 21, and 22. Gene content and order are highly conserved between Mmu 16 and the syntenic blocks of the human genome. Of the 731 predicted genes on Mmu 16, 509 align with orthologs on the corresponding portions of the human genome, 44 are likely paralogous to these genes, and 164 genes have homologs elsewhere in the human genome; there are 14 genes for which we could find no human counterpart.
