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Human chromosome 16 features one of the highest levels of segmentally duplicated sequence among the human autosomes. We report here the 78,884,754 base pairs of finished chromosome 16 sequence, representing over 99.9% of its euchromatin. Manual annotation revealed 880 protein-coding genes confirmed by 1,670 aligned transcripts, 19 transfer RNA genes, 341 pseudogenes and three RNA pseudogenes. These genes include metallothionein, cadherin and iroquois gene families, as well as the disease genes for polycystic kidney disease and acute myelomonocytic leukaemia. Several large-scale structural polymorphisms spanning hundreds of kilobase pairs were identified and result in gene content differences among humans. Whereas the segmental duplications of chromosome 16 are enriched in the relatively gene-poor pericentromere of the p arm, some are involved in recent gene duplication and conversion events that are likely to have had an impact on the evolution of primates and human disease susceptibility.

rom the beginning, a primary objective of the Human Genome Project (HGP) was to generate a highly accurate reference sequence for the human genome. This sequence is now essentially complete and is available in its entirety as a reference for biomedical researchers. High-through- put genome sequencing has created a fundamental shift in the paradigm for biological research. Whereas gene discovery once drove DNA sequencing, now the sequencing of entire genomes drives gene discovery. As such, it is essential that the scientific community be informed about the accuracy of this reference sequence and of its fidelity to the biological templates from which it was derived.

Chromosome 5 is one of the largest human chromosomes and contains numerous intrachromosomal duplications, yet it has one of the lowest gene densities. This is partially explained by numerous gene-poor regions that display a remarkable degree of noncoding conservation with non-mammalian vertebrates, suggesting that they are functionally constrained. In total, we compiled 177.7 million base pairs of highly accurate finished sequence containing 923 manually curated protein-coding genes including the protocadherin and interleukin gene families. We also completely sequenced versions of the large chromosome-5-specific internal duplications. These duplications are very recent evolutionary events and probably have a mechanistic role in human physiological variation, as deletions in these regions are the cause of debilitating disorders including spinal muscular atrophy.

Chromosome 19 has the highest gene density of all human chromosomes, more than double the genome-wide average. The large clustered gene families, corresponding high G + C content, CpG islands and density of repetitive DNA indicate a chromosome rich in biological and evolutionary significance. Here we describe 55.8 million base pairs of highly accurate finished sequence representing 99.9% of the euchromatin portion of the chromosome. Manual curation of gene loci reveals 1,461 protein-coding genes and 321 pseudogenes. Among these are genes directly implicated in mendelian disorders, including familial hypercholesterolaemia and insulin-resistant diabetes. Nearly one-quarter of these genes belong to tandemly arranged families, encompassing more than 25% of the chromosome. Comparative analyses show a fascinating picture of conservation and divergence, revealing large blocks of gene orthology with rodents, scattered regions with more recent gene family expansions and deletions, and segments of coding and non-coding conservation with the distant fish species Takifugu.

As the final sequencing of the human genome has now been completed, we present the results of the largest examination of the quality of the finished DNA sequence. The completed study covers the major contributing sequencing centres and is based on a rigorous combination of laboratory experiments and computational analysis.

There has arisen considerable interest in the study of dopamine D2/3 agonist binding sites by positron emission tomography (PET), based on the claim that agonist sites represent a functional subset of the total number of sites labeled by more conventional antagonist ligands. To test the basis of this claim, we used quantitative autoradiography to measure the abundance of binding sites of a dopamine D2/3 agonist ([3H]NPA) and an antagonist ([3H]raclopride) in cryosections of rat brain. Saturation binding studies revealed that the Bmax for [3H]NPA was nearly identical to that of [3H]raclopride in dorsal brain regions, but was 25% less in the ventral striatum and 56% less in the olfactory tubercle. We also tested the displacement of the two ligands by the hallucinogen LSD, which is known to have dopamine agonist properties. Whereas displacement of [3H]raclopride by increasing LSD concentrations was monophasic, displacement of [3H]NPA was biphasic, suggesting an action of LSD via a subset of dopamine D2/3 agonist binding sites. Addition of the stable GTP analogue Gpp(NH)p to the medium abolished 90% of the [3H]NPA binding, and increased [3H]raclopride binding by 10%, with a shift to the right in the LSD competition curve, suggesting retention of endogenous dopamine in washed cryostat sections. Thus [3H]NPA and [3H]raclopride binding sites have nearly identical abundances in rat dorsal striatum, but are distinct in the ventral striatum, and with respect to their displacement by LSD.

rom the beginning, a primary objective of the Human Genome Project (HGP) was to generate a highly accurate reference sequence for the human genome. This sequence is now essentially complete and is available in its entirety as a reference for biomedical researchers. High-through- put genome sequencing has created a fundamental shift in the paradigm for biological research. Whereas gene discovery once drove DNA sequencing, now the sequencing of entire genomes drives gene discovery. As such, it is essential that the scientific community be informed about the accuracy of this reference sequence and of its fidelity to the biological templates from which it was derived.