28 October 2010

1000 Genomes Project: First results

Scientists have announced the completion of the pilot phase of the "1000 genomes" project. The goal of the project, launched in 2008, is to describe the variability of human DNA in different populations. During the pilot phase, scientists conducted full or partial sequencing of the genomes of about 800 people and described many new genetic variations, as well as quantified to what extent we genetically differ from each other.

A huge international consortium worked on the project, sequencing was carried out on the basis of nine research centers. The data are presented by the European Molecular Biology Laboratory of the European Bioinformatics Institute (EMBL-EBI) and the National Center for Biotechnological Informatics of the USA (US National Center for Biotechnology Information (NCBI) in open access on the website 1000genomes.org .

More genomes – less accuracyThe purpose of the pilot phase was to develop and compare several strategies for sequencing multiple genomes.

The pilot phase includes three separate projects. First: the genome of 179 people was completely sequenced with a small overlap of 2-6 passes (this means less data accuracy). Of these, 59 belong to the Yoruba population in Nigeria, 60 residents of Utah are of European descent and 30 are Japanese. Second: the genome of six people from two families (Yoruba and descendants of Europeans from Utah), each consisting of parents and a daughter, was completely sequenced with high (x42) overlap (with high accuracy). And third: the genome of 679 people from seven populations in Africa, Europe and Asia was partially sequenced. For this purpose, 8140 exons (coding sites) from 906 genes were selected.

One of the main goals of biology and medicine is to understand the relationship between genotype and phenotype: the signs of an organism that are encoded in DNA. In the years that have passed since the decoding of the nucleotide sequence of the first human genome, a lot of data on the genetic variability of different people has appeared. A database on single-nucleotide polymorphisms (SNP), insertions and deletions (excisions) in the DNA sequence, and frequencies of various genetic variations in different populations (HapMap Project) has been created.

SNP (snips) are mutations affecting only one nucleotide. Snips are very often associated with certain characteristic features (that is, one variant is associated with one type of manifestation of the trait, and the other with another), so it is convenient to use them for diagnosis and comparison of sequences among themselves.

These data stimulated the discovery of many genes associated with various diseases – more than a thousand such sites were found in five years. Despite this, scientists say, there is still no deep understanding of the contribution of genetics to the human phenotype.

What new have geneticists learnedDuring the pilot project, scientists decoded 4.9 terabytes of information encoded in DNA.

They described 15 million SNPs, 1 million nucleotide insertions and deletions, 20 thousand large variations in the structure of DNA. There are many of them that have not been described before. For example, 8 million new SNPs.

The complete sequencing of the genomes of the two families allowed not only to identify all genetic variations in their members, but also to trace how these variations are transmitted to the next generation. In this part of the project alone, scientists found 5.9 million SNPs, 605 thousand insertions and deletions, and over 14 thousand large structural variations. The family project allowed us to estimate the rate of occurrence of new mutations in germ cells – it is approximately 10-8 per couple of bases per generation.

The population of Africans showed the greatest number of variations (including new ones). Among Africans, scientists found 63% and 44% of new SNPs (in the first and third projects), and among Europeans – 33% and 22%. This indicates a greater genetic diversity of the African population.

The researchers also isolated about 1,000 genes duplicated in most people, and in some cases the number of copies ranged from 5 to 368 per person. A comparison of the new data with the results of studying the genomes of chimpanzees, gorillas and orangutans showed that humans have several more copies of genes associated with the functioning and development of the brain.

How much do we differThe researchers calculated that among the individual differences in the genome, an average of 10-12 thousand SNPs lead to differences in the proteins encoded by the genes.

Individual differences amount to an average of 190-210 small nucleotide insertions and deletions, 80-100 stop codons" (combinations of nucleotides that stop protein synthesis). It turned out that each person has an average of 250-300 variations that disrupt the work of genes. And most importantly, each person carries an average of 50-100 mutations associated with hereditary diseases (they are in the Gene Mutation Database, HGMD).

According to the authors, their work allows us to at least begin to understand how the human genome was formed under the influence of natural selection. Having assessed the degree of discrepancy between populations, scientists came to the conclusion that most local (to local environmental conditions) adaptations occurred with a change in the frequency of existing mutations, and not with the appearance of new ones. Already, the data obtained will allow us to more accurately localize the genes associated with various diseases.

The full "1000 genomes" project, which is scheduled to be completed in 2012, will include sequencing with low overlap (of the order of x4) and deep sequencing of coding sections of 2500 genomes from all continents. Scientists expect that the project will describe 95% of the variability occurring in populations with a frequency of at least 1%. The total cost of the project is estimated from 30-50 to 120 million dollars.

An article outlining the results of the pilot phase (Peter H. Sudmant et al., Diversity of Human Copy Number Variation and Multicopy Genes) has been published in open access in the latest issue of Science; the October special issue of the journal Nature (also in open access) is entirely devoted to the project "1000 genomes".

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