After the completion of a draft human genome sequence, the International Human Genome Sequencing Consortium has proceeded to finish and annotate each of the 24 chromosomes comprising the human genome. Here we describe the sequencing and analysis of human chromosome 3, one of the largest human chromosomes. Chromosome 3 comprises just four contigs, one of which currently represents the longest unbroken stretch of finished DNA sequence known so far. The chromosome is remarkable in having the lowest rate of segmental duplication in the genome. It also includes a chemokine receptor gene cluster as well as numerous loci involved in multiple human cancers such as the gene encoding FHIT, which contains the most common constitutive fragile site in the genome, FRA3B. Using genomic sequence from chimpanzee and rhesus macaque, we were able to characterize the breakpoints defining a large pericentric inversion that occurred some time after the split of Homininae from Ponginae, and propose an evolutionary history of the inversion.
Small cell lung cancer (SCLC) has been associated with a deletion of the short arm of chromosome 3. One SCLC cell line, H748, has an interstitial deletion of chromosome 3p and shows allele loss for the DNF15S2 locus detected by the probe lambda H3. Conservation of DNF15S2 sequences in mouse indicated that this human genomic fragment may contain coding sequences. Screening of a normal lung cDNA library with chromosome 3-specific fragments of the lambda H3 probe resulted in the isolation of 18 positive clones. The cDNA clones detect an additional DNA polymorphism that is in linkage disequilibrium with the HindIII polymorphism of the DNF15S2 locus. Sequence analysis indicated that the DNF15S2 locus could potentially code for a previously unreported protein of 67 kDa which has 26 cysteine residues. DNF15S2 is part of the coding region of a 3.3-kb mRNA expressed in lung. Northern analysis indicated that this mRNA was not detectable in one of five SCLC lines. This SCLC line, H128, also lacks the enzyme aminoacylase 1.