Abstract
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.
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