Table 1.

Major developments and landmarks in human genetics and genomics, 1977 to date

Year	Development	References
1977	Sanger dideoxynucleotide/chain termination sequencing method developed	[38]
	Mammalian genes shown to contain introns	[50]
1978	First report of characterisation of gross gene deletions responsible for human inherited disease (α- and β-thalassaemia) by Southern blotting	[51]
1979	First single base-pair substitution causing a human inherited disease (β-thalassaemia) characterized by DNA sequencing	[52]
1980	Construction of a genetic linkage map in humans using restriction fragment length polymorphisms	[53]
1990	Initiation of the Human Genome Project (HGP)	[54]
1992	Second-generation linkage map of the human genome	[55]
1996	The Human Gene Mutation Database (HGMD), an attempt to collate known (published) gene lesions responsible for human inherited disease, established and made available at http://www.hgmd.org	[56]
	Genome-wide association studies (GWAS) approach for genetic studies of complex diseases first proposed	[57]
2001	Completion of draft DNA sequences of the human genome by the International Human Genome Sequencing Consortium (IHGSC) and Celera Genomics	[1,2]
	International SNP Map Working Group identifies 1.42 million SNPs in the human genome	[58]
	Genetic architecture of complex diseases subjected to intense debate	[59,60]
	Linkage disequilibrium (LD) patterns documented between SNPs in regions of the human genome	[61,62]
2003	Initiation of the International HapMap Project	[63]
	First whole-genome SNP genotyping array - Affymetrix GeneChip 10K	[17]
2004	IHGSC publishes the 'finished version' of the DNA sequence of the human genome	[64]
	Initiation of the ENCODE project	[65]
	Discovery of hundreds of copy number variations (CNVs) in the human genome	[26,27]
	Database of Genomic Variants (DGV) established to catalogue CNVs	[27]
	First new-generation sequencing (NGS) technology - Roche 454 GS 20 System	[29,30]
2005	Completion of the International HapMap Phase I Project	[66]
	First proper GWAS using a commercial whole-genome SNP genotyping array	[3]
2005-present	Rapid developments of whole-genome and custom SNP genotyping arrays and technologies	[18]
	Rapid developments of sequencing technologies	[31,33]
2006	Discovery of more than 1,000 regions of homozygosity > 1 megabase (Mb) in the genomes of outbred populations	[28]
	First comprehensive map of CNVs in the HapMap populations	[22]
	An initial map of insertion and deletion variants in the human genome	[67]
	Illumina sequencing platform commercially marketed	[29,30]
2007	The first human diploid genome (Craig Venter's genome) sequenced by the Sanger sequencing method	[68]
	Completion of the International HapMap Phase II Project and extension to Phase III	[69]
	Genome-wide detection and characterisation of positive selection in human populations	[70]
	Completion of the ENCODE project	[71]
	Explosion of GWAS publications ('Year of GWAS'), approximately 100 new GWASs	[4]
	'Human Genetic Variation' considered to be the 'Breakthrough of The Year' in 2007 by Science	[4]
	Sequence capture or enrichment methods and technologies developed	[72-74]
	Pervasive transcription documented	[75]
	Demonstration of paired-end mapping (PEM) to detect structural variation using NGS technologies	[76]
	Demonstration of ChIP-Seq to map transcription factor binding sites	[77]
	Demonstration of ChIP-Seq to interrogate histone modifications	[78]
	Life Technologies SOLiD sequencing platform commercially marketed	[29,30]
	A community resource project launched to sequence large-insert clones from many individuals, systematically discovering and resolving these complex variants at the DNA sequence level (The Human Genome Structural Variation Working Group)	[79]
2007-Present	Microarray-based methods increasingly supplanted by sequencing-based approaches such as ChIP-Seq, RNA-Seq, Methyl-Seq and CNV-Seq	[39,41,80,81]
2008	First human diploid genome (James Watson's genome) sequenced by NGS technologies	[46]
	First whole cancer genome (acute myeloid leukaemia [AML]) sequenced	[82]
	Initiation of the 1000 Genomes Project	[83]
	Vast majority of human genes shown to undergo alternative splicing (RNA-Seq)	[84,85]
	Large scale mapping and sequencing of structural variation using a clone-based method	[86]
	Demonstration of depth-of-coverage approach to detect CNVs using NGS technologies	[87]
	First GWAS meta-analysis using imputation methods	[88]
	The issue of 'missing heritability' in GWASs recognised	[89]
2009	Feasibility of exome sequencing approach to identify a causal mutation for a Mendelian disorder first demonstrated	[12]
	Exome sequencing as a useful tool for diagnostic application demonstrated	[90]
	Third generation sequencing (TGS; single molecule sequencing) technology introduced --Heliscope Single Molecule Sequencer (Helicos Biosciences) commercially marketed	[91]
	First human diploid genome sequenced by TGS technology	[92]
	Latest assembly of the human genome (Genome Reference Consortium, release GRCh37, February 2009), Genebuild published by Ensembl (database version 56.37a) includes 23,616 protein-coding genes, 6,407 putative RNA genes and 12,346 pseudogenes	http://www.ensembl.org/Homo_sapiens/Info/StatsTable
	Large intergenic non-coding RNAs (lincRNAs) found to represent a novel category of evolutionarily conserved RNAs	[93,94]
	Direct single molecule RNA sequencing without prior conversion of RNA to cDNA	[95]
	First human DNA methylomes at base resolution	[96]
	Comprehensive mapping of long-range chromatin interactions	[97,98]
2010	Number of disease-causing/disease-associated germline mutations collated in the Human Gene Mutation Database exceeds 100,000 in > 3,700 different nuclear genes	[99,100]
	More than 17 million SNPs in the human genome catalogued in the SNP Database (dbSNP; http://www.ncbi.nlm.nih.gov/projects/SNP/)	[101]
	As of 2nd November 2010, DGV catalogued 66,741 CNVs, 953 inversions and 34,229 insertions and deletions (indels) (100 base pairs (bp) -- 1 kilobase (kb) from 42 published studies	http://projects.tcag.ca/variation/
	1,048 microRNAs found in the human genome	miRBase, Release 16.0: September 2010, http://www.mirbase.org/
	Completion of the International HapMap Phase III Project	[21]
	Completion of pilot phase of the 1000 Genomes Project	[102]
	Second generation whole-genome SNP genotyping array (with SNP selection from the 1000 Genomes Project) launched	http://www.illumina.com/applications/gwas.ilmn
	Cost of whole-genome sequencing (at several tenfold of sequencing coverage depth) reduced to less than $5,000	[44]
	Metagenomic sequencing of human gut microbes accomplished using NGS technologies	[103]
	Exome sequencing study identifies causal mutations and genes for previously unexplained Mendelian disorders	[13,14]
	GWAS meta-analysis involving total sample size of > 249,000	[104]
	Comprehensive mapping of CNVs using high-resolution tiling oligonucleotide microarrays (42 million probes)	[105]
	Characterisation of 20 sequenced human genomes to evaluate the prospects for identifying rare functional variants	[106]
	Neanderthal genome sequenced	[107]
	The genome of an extinct Palaeo-Eskimo sequenced	[108]
	Exome sequencing of 200 individuals identifies an excess of low-frequency non-synonymous coding variants	[109]
	International Cancer Genome Consortium (ICGC) launched	[110]
	Largest GWAS of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls performed	[111]
2011	As of 13th May 2011, 874 publications and 4,327 SNPs documented in the National Human Genome Research Institute (NHGRI) 'A Catalog of Published Genome-wide Association Studies'	http://www.genome.gov/gwastudies/
	Comprehensive mapping of copy number variations based on whole-genome DNA sequencing data	[112]
	Developments of other TGS technologies, such as single-molecule real-time sequencing and nanopore sequencing, are on the horizon	[32]
	New addition to the NGS market -- the Ion Torrent Personal Genome Machine (PGM), produced by Life Technologies (Carlsbad, CA)	http://www.iontorrent.com/
	Single-cell sequencing to infer tumour evolution	[113]