A 2.91-billion base pair (bp) consensus sequence of the euchromatic portion of the human genome was generated by the whole-genome shotgun sequencing method. The 14.8-billion bp DNA sequence was generated over 9 months from 27,271,853 high-quality sequence reads (5.11-fold coverage of the genome) from both ends of plasmid clones made from the DNA of five individuals. Two assembly strategies—a whole-genome assembly and a regional chromosome assembly—were used, each combining sequence data from Celera and the publicly funded genome effort. The public data were shredded into 550-bp segments to create a 2.9-fold coverage of those genome regions that had been sequenced, without including biases inherent in the cloning and assembly procedure used by the publicly funded group. This brought the effective coverage in the assemblies to eightfold, reducing the number and size of gaps in the final assembly over what would be obtained with 5.11-fold coverage. The two assembly strategies yielded very similar results that largely agree with independent mapping data. The assemblies effectively cover the euchromatic regions of the human chromosomes. More than 90% of the genome is in scaffold assemblies of 100,000 bp or more, and 25% of the genome is in scaffolds of 10 million bp or larger. Analysis of the genome sequence revealed 26,588 protein-encoding transcripts for which there was strong corroborating evidence and an additional ∼12,000 computationally derived genes with mouse matches or other weak supporting evidence. Although gene-dense clusters are obvious, almost half the genes are dispersed in low G+C sequence separated by large tracts of apparently noncoding sequence. Only 1.1% of the genome is spanned by exons, whereas 24% is in introns, with 75% of the genome being intergenic DNA. Duplications of segmental blocks, ranging in size up to chromosomal lengths, are abundant throughout the genome and reveal a complex evolutionary history. Comparative genomic analysis indicates vertebrate expansions of genes associated with neuronal function, with tissue-specific developmental regulation, and with the hemostasis and immune systems. DNA sequence comparisons between the consensus sequence and publicly funded genome data provided locations of 2.1 million single-nucleotide polymorphisms (SNPs). A random pair of human haploid genomes differed at a rate of 1 bp per 1250 on average, but there was marked heterogeneity in the level of polymorphism across the genome. Less than 1% of all SNPs resulted in variation in proteins, but the task of determining which SNPs have functional consequences remains an open challenge.

No abstract

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.

No abstract

We undertook a systematic search for linkage in 196 affected sibling pairs (ASPs) with DSMIV schizophrenia. In stage 1 we typed 97 ASPs with 229 microsatellite markers at an average inter-marker distance of 17.26 cM. Multipoint affected sib pair analysis identified seven regions with a maximum lod score (MLS) at or above the level associated with a nominal pointwise significance of 5%, on chromosomes 2q, 4p, 10q, 15q, 18p, 20q and Xcen. In stage 2 we genotyped a further 54 markers in 196 ASPs together with parents and unaffected siblings. This allowed the regions identified in stage 1 to be typed at an average spacing of 5.15 cM, while the region of interest on chromosome 2 was typed to 9.55 cM. Analysis was performed on the whole data set. Simulation studies suggested that we would expect one multipoint MLS of 1.5 per genome scan in the absence of linkage. An MLS of 3 would be expected only once in every 20 genome scans and thus corresponds to a genome-wide significance of 0.05. We obtained three multipoint MLSs >1.5 and, on this basis, the results on chromosomes 4p, 18q and Xcen can be considered suggestive. However, none approached a genome-wide significance of 0. 05. The power of this study was >0.95 to detect a susceptibility locus of lambda(s)= 3 with a genome-wide significance of 0.05, but only 0.70 to detect a locus of lambda(s)= 2. Our results suggest that common genes of major effect (lambda(s)> 3) are unlikely to exist for schizophrenia.