The Sequence of the Human Genome¶
Why this mattered¶
TBD
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 approximately 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.
Related¶
- cite → Emergence of Scaling in Random Networks — The human genome paper invokes scale-free network ideas to discuss the organization of biological interaction and genomic systems.
- cite → Basic local alignment search tool — The human genome paper uses BLAST sequence alignment to identify genes and compare genomic sequences.
- cite → Identification of common molecular subsequences — The human genome paper builds on Smith-Waterman local alignment as a foundational method for detecting conserved molecular subsequences.
- cite → DNA sequencing with chain-terminating inhibitors — The human genome paper depends on Sanger chain-termination sequencing as the core technology enabling reference genome assembly.
- cite ← Initial sequencing and analysis of the human genome — Both papers report draft human genome sequences, linking the public consortium assembly to Celera's parallel whole-genome shotgun sequence.
- enables ← Basic local alignment search tool — BLAST enabled rapid sequence similarity search, supporting annotation and validation of assembled regions in the Human Genome Project.
- enables ← Identification of common molecular subsequences — Smith-Waterman local alignment enabled rigorous subsequence comparison, underpinning sequence assembly and annotation methods used for the human genome.
- enables ← DNA sequencing with chain-terminating inhibitors — Sanger chain-termination sequencing enabled the base-calling technology used to generate the Human Genome Project's reference sequence.