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We are what we… aren't? Cataloguing deletions and insertions in the human genome

Until recently, scientists studying whole human genomes focused primarily on variations among the four nucleotides, or "letters", that make up our DNA. Differences in the sequence, or spelling, of these regions are responsible for diversity among individuals and ethnic groups, and the cause of many diseases. But they're not the only source of human variation. Odd, but not uncommon, blips of missing or added material--called short insertions and deletions, or "indels"-- in between stretches of similarity were not regularly cataloged due in part to technological limitations.

A recent study in Genome Research lead by Stanford geneticist Stephen Montgomery, PhD, has now done just that. Montgomery, along with senior author Gerton Lunter, PhD, from the Wellcome Trust Centre for Human Genetics in the United Kingdoms, found that indels may be a major source of human genetic variation.  According to Montgomery:

In this study, we were able to leverage advances in sequencing technology to systematically characterize this abundant but lesser explored class of human genetic variation. Understanding indels will be essential to further more-complete interpretation of individual genomes.  With this rich catalog of indels, we are now able to identify frequently mutated genes and implicate these variants as causal agents that influence gene expression and complex disorders.

Indels have already been implicated in some disorders such as Huntington's disease, in which repeated expansions of a short, three-nucleotide stretch increase the severity and decrease the age of onset of the disease. The researchers used data from the 1000 Genomes Project to compare the location and prevalence of more than 1.6 million indels in 179 individuals from three populations. Intriguingly, they found that over half of the indels occur in just four percent of the genome--often in regions where the nucleotide sequence encourages the DNA replication machinery to stutter and slip rather than plodding along tamely.

The study highlights an important class of human genetic variation that, until now, has been largely overlooked, and the researchers are eager to learn how indels have affected human evolution and contribute to disease.

As Lunter explains on the Wellcome Centre's blog today:

Having a comprehensive and uniform collection of indels has enabled us to better understand the evolutionary pressures that shape this important class of human variation and to refine our understanding of the evolution and structure of the human genome.

Adds Montgomery:

We can now increase our understanding of the mutational forces which give rise to these variants and define and influence the structure of the genome.  We plan to use the results of this study to further the integration of indels into studies that seek to understand the character of the genomes, gene expression and the origins of diverse genetic disease.

Previously Scientists announce the completion of the ENCODE project, a massive genome encyclopedia and Humans share history - and a fair amount of genetic material - with Neanderthals

Photo by Wellcome Images

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