Table 1 Major developments and landmarks in human genetics and genomics, 1977 to date

1977

Sanger dideoxynucleotide/chain termination sequencing method developed

Mammalian genes shown to contain introns

1978

First report of characterisation of gross gene deletions responsible for human inherited disease (α- and β-thalassaemia) by Southern blotting

1979

First single base-pair substitution causing a human inherited disease (β-thalassaemia) characterized by DNA sequencing

1980

Construction of a genetic linkage map in humans using restriction fragment length polymorphisms

1990

Initiation of the Human Genome Project (HGP)

1992

Second-generation linkage map of the human genome

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

Genome-wide association studies (GWAS) approach for genetic studies of complex diseases first proposed

2001

Completion of draft DNA sequences of the human genome by the International Human Genome Sequencing Consortium (IHGSC) and Celera Genomics

International SNP Map Working Group identifies 1.42 million SNPs in the human genome

Genetic architecture of complex diseases subjected to intense debate

Linkage disequilibrium (LD) patterns documented between SNPs in regions of the human genome

2003

Initiation of the International HapMap Project

First whole-genome SNP genotyping array - Affymetrix GeneChip 10K

2004

IHGSC publishes the 'finished version' of the DNA sequence of the human genome

Initiation of the ENCODE project

Discovery of hundreds of copy number variations (CNVs) in the human genome

Database of Genomic Variants (DGV) established to catalogue CNVs

First new-generation sequencing (NGS) technology - Roche 454 GS 20 System

2005

Completion of the International HapMap Phase I Project

First proper GWAS using a commercial whole-genome SNP genotyping array

2005-present

Rapid developments of whole-genome and custom SNP genotyping arrays and technologies

Rapid developments of sequencing technologies

2006

Discovery of more than 1,000 regions of homozygosity > 1 megabase (Mb) in the genomes of outbred populations

First comprehensive map of CNVs in the HapMap populations

An initial map of insertion and deletion variants in the human genome

Illumina sequencing platform commercially marketed

2007

The first human diploid genome (Craig Venter's genome) sequenced by the Sanger sequencing method

Completion of the International HapMap Phase II Project and extension to Phase III

Genome-wide detection and characterisation of positive selection in human populations

Completion of the ENCODE project

Explosion of GWAS publications ('Year of GWAS'), approximately 100 new GWASs

'Human Genetic Variation' considered to be the 'Breakthrough of The Year' in 2007 by Science

Sequence capture or enrichment methods and technologies developed

Pervasive transcription documented

Demonstration of paired-end mapping (PEM) to detect structural variation using NGS technologies

Demonstration of ChIP-Seq to map transcription factor binding sites

Demonstration of ChIP-Seq to interrogate histone modifications

Life Technologies SOLiD sequencing platform commercially marketed

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)

2007-Present

Microarray-based methods increasingly supplanted by sequencing-based approaches such as ChIP-Seq, RNA-Seq, Methyl-Seq and CNV-Seq

2008

First human diploid genome (James Watson's genome) sequenced by NGS technologies

First whole cancer genome (acute myeloid leukaemia [AML]) sequenced

Initiation of the 1000 Genomes Project

Vast majority of human genes shown to undergo alternative splicing (RNA-Seq)

Large scale mapping and sequencing of structural variation using a clone-based method

Demonstration of depth-of-coverage approach to detect CNVs using NGS technologies

First GWAS meta-analysis using imputation methods

The issue of 'missing heritability' in GWASs recognised

2009

Feasibility of exome sequencing approach to identify a causal mutation for a Mendelian disorder first demonstrated

Exome sequencing as a useful tool for diagnostic application demonstrated

Third generation sequencing (TGS; single molecule sequencing) technology introduced --Heliscope Single Molecule Sequencer (Helicos Biosciences) commercially marketed

First human diploid genome sequenced by TGS technology

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

Large intergenic non-coding RNAs (lincRNAs) found to represent a novel category of evolutionarily conserved RNAs

Direct single molecule RNA sequencing without prior conversion of RNA to cDNA

First human DNA methylomes at base resolution

Comprehensive mapping of long-range chromatin interactions

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

More than 17 million SNPs in the human genome catalogued in the SNP Database (dbSNP; http://www.ncbi.nlm.nih.gov/projects/SNP/)

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

1,048 microRNAs found in the human genome

Completion of the International HapMap Phase III Project

Completion of pilot phase of the 1000 Genomes Project

Second generation whole-genome SNP genotyping array (with SNP selection from the 1000 Genomes Project) launched

Cost of whole-genome sequencing (at several tenfold of sequencing coverage depth) reduced to less than $5,000

Metagenomic sequencing of human gut microbes accomplished using NGS technologies

Exome sequencing study identifies causal mutations and genes for previously unexplained Mendelian disorders

GWAS meta-analysis involving total sample size of > 249,000

Comprehensive mapping of CNVs using high-resolution tiling oligonucleotide microarrays (42 million probes)

Characterisation of 20 sequenced human genomes to evaluate the prospects for identifying rare functional variants

Neanderthal genome sequenced

The genome of an extinct Palaeo-Eskimo sequenced

Exome sequencing of 200 individuals identifies an excess of low-frequency non-synonymous coding variants

International Cancer Genome Consortium (ICGC) launched

Largest GWAS of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls performed

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'

Comprehensive mapping of copy number variations based on whole-genome DNA sequencing data

Developments of other TGS technologies, such as single-molecule real-time sequencing and nanopore sequencing, are on the horizon

New addition to the NGS market -- the Ion Torrent Personal Genome Machine (PGM), produced by Life Technologies (Carlsbad, CA)

Single-cell sequencing to infer tumour evolution