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In search of rare human variants

The 1000 Genomes Project has completed its pilot phase, sequencing the whole genomes of 179 individuals and characterizing all the protein-coding sequences of many others. Welcome to the third phase of human genomics.

The goal of the 1000 Genomes Project is to find most of the variants in the human genome that have a frequency of at least 1% in the populations studied. The consortium of researchers participating in the project now reports the results of its pilot phase.
But first let’s take a step back. A decade ago, the reference copy of the human genome was sequenced. Although that project is undoubtedly one of the greatest scientific achievements of our time, its potential societal impact will be fully realized only if genomic regions that are responsible for various traits of medical importance, such as response to a drug or susceptibility to a disease, can be identified. After the initial sequencing of the human genome, therefore, a second phase of human genomics emerged, focusing on identifying genomic variations responsible for hereditary diseases and other medically relevant traits. Such genomewide association studies (GWAS) are based on examining the genomes of thousands of individuals for correlations between the presence of genomic variants and the trait of interest.
Many successes have come out of GWAS, but there has also been some disappointment that perhaps the pickings from these studies have been too slim. For instance, although certain disorders — including obesity, diabetes and cardiovascular disease — are known to have a strong genetic component, their associated genomic variants detected through GWAS cannot explain most of the experimentally identified genetic effects found in affected families. Human geneticists call this problem the ‘missing heritability’.
There are many possible explanations for the missing heritability, the most popular being the effect of rare variants. GWAS are based on examining a battery of different variants across the genome. Until recently, however, the cost of including both common and rare variants in such studies was prohibitively high, pushing the focus towards identifying common variants that occur at a relatively high frequency in the population. Consequently, if many rare variants, rather than a few common ones, are responsible for a disease, the rare variants would have been missed in most GWAS.

See More : Nature Magazine 2010
https://www.nature.com/nature/journal/v467/n7319/full/4671050a.html" target="_blank">https://www.nature.com/nature/journal/v467/n7319/full/4671050a.html