1000 Genomes Project

The 1000 Genomes Project (abbreviated as 1KGP), launched in January 2008, was an international research effort to establish by far the most detailed catalogue of human genetic variation. Scientists planned to sequence the genomes of at least one thousand anonymous participants from a number of different ethnic groups within the following three years, using newly developed technologies which were faster and less expensive. In 2010, the project finished its pilot phase, which was described in detail in a publication in the journal Nature. In 2012, the sequencing of 1092 genomes was announced in a Nature publication. In 2015, two papers in Nature reported results and the completion of the project and opportunities for future research. Many rare variations, restricted to closely related groups, were identified, and eight structural-variation classes were analyzed. The 1000 Genomes Project (abbreviated as 1KGP), launched in January 2008, was an international research effort to establish by far the most detailed catalogue of human genetic variation. Scientists planned to sequence the genomes of at least one thousand anonymous participants from a number of different ethnic groups within the following three years, using newly developed technologies which were faster and less expensive. In 2010, the project finished its pilot phase, which was described in detail in a publication in the journal Nature. In 2012, the sequencing of 1092 genomes was announced in a Nature publication. In 2015, two papers in Nature reported results and the completion of the project and opportunities for future research. Many rare variations, restricted to closely related groups, were identified, and eight structural-variation classes were analyzed. The project unites multidisciplinary research teams from institutes around the world, including China, Italy, Japan, Kenya, Nigeria, Peru, the United Kingdom, and the United States. Each will contribute to the enormous sequence dataset and to a refined human genome map, which will be freely accessible through public databases to the scientific community and the general public alike. By providing an overview of all human genetic variation, the consortium will generate a valuable tool for all fields of biological science, especially in the disciplines of genetics, medicine, pharmacology, biochemistry, and bioinformatics. Since the completion of the Human Genome Project, advances in human population genetics and comparative genomics have made it possible to gain increasing insight into the nature of genetic diversity. However, we are just beginning to understand how processes like the random sampling of gametes, structural variations (insertions/deletions (indels), copy number variations (CNV), and retroelements), single-nucleotide polymorphisms (SNPs), and natural selection have shaped the level and pattern of variation within species and also between species. The random sampling of gametes during sexual reproduction leads to genetic drift — a random fluctuation in the population frequency of a trait — in subsequent generations and would result in the loss of all variation in the absence of external influence. It is postulated that the rate of genetic drift is inversely proportional to population size, and that it may be accelerated in specific situations such as bottlenecks, where the population size is reduced for a certain period of time, and by the founder effect (individuals in a population tracing back to a small number of founding individuals). Anzai et al. demonstrated that indels account for 90.4% of all observed variations in the sequence of the major histocompatibility locus (MHC) between humans and chimpanzees. After taking multiple indels into consideration, the high degree of genomic similarity between the two species (98.6% nucleotide sequence identity) drops to only 86.7%. For example, a large deletion of 95 kilobases (kb) between the loci of the human MICA and MICB genes, results in a single hybrid chimpanzee MIC gene, linking this region to a species-specific handling of several retroviral infections and the resultant susceptibility to various autoimmune diseases. The authors conclude that instead of more subtle SNPs, indels were the driving mechanism in primate speciation. Besides mutations, SNPs and other structural variants such as copy-number variants (CNVs) are contributing to the genetic diversity in human populations. Using microarrays, almost 1,500 copy number variable regions, covering around 12% of the genome and containing hundreds of genes, disease loci, functional elements and segmental duplications, have been identified in the HapMap sample collection. Although the specific function of CNVs remains elusive, the fact that CNVs span more nucleotide content per genome than SNPs emphasizes the importance of CNVs in genetic diversity and evolution. Investigating human genomic variations holds great potential for identifying genes that might underlie differences in disease resistance (e.g. MHC region) or drug metabolism. Natural selection in the evolution of a trait can be divided into three classes. Directional or positive selection refers to a situation where a certain allele has a greater fitness than other alleles, consequently increasing its population frequency (e.g. antibiotic resistance of bacteria). In contrast, stabilizing or negative selection (also known as purifying selection) lowers the frequency or even removes alleles from a population due to disadvantages associated with it with respect to other alleles. Finally, a number of forms of balancing selection exist; those increase genetic variation within a species by being overdominant (heterozygous individuals are fitter than homozygous individuals, e.g. G6PD, a gene that is involved in both Hemolytic anaemia and malaria resistance) or can vary spatially within a species that inhabits different niches, thus favouring different alleles. Some genomic differences may not affect fitness. Neutral variation, previously thought to be “junk” DNA, is unaffected by natural selection resulting in higher genetic variation at such sites when compared to sites where variation does influence fitness.