Tag Archive for '1000 genomes'

Learning more from your 23andMe results with Imputation

PeterAndEliana This is a guest post by Peter Cheng and Eliana Hechter from the University of California, Berkeley.

Suppose that you’ve had your DNA genotyped by 23andMe or some other DTC genetic testing company. Then an article shows up in your morning newspaper or journal (like this one) and suddenly there’s an additional variant you want to know about. You check your raw genotypes file to see if the variant is present on the chip, but it isn’t! So what next? [Note: the most recent 23andMe chip does include this variant, although older versions of their chip do not.]

Genotype imputation is a process used for predicting, or “imputing”, genotypes that are not assayed by a genotyping chip. The process compares the genotyped data from a chip (e.g. your 23andMe results) with a reference panel of genomes (supplied by big genome projects like the 1000 Genomes or HapMap projects) in order to make predictions about variants that aren’t on the chip. If you want a technical review of imputation (and the program IMPUTE in particular), we recommend Marchini & Howie’s 2010 Nature Reviews Genetics article. However, the following figure provides an intuitive understanding of the process.

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All genomes are dysfunctional: broken genes in healthy individuals

Breakdown of the number of loss-of-function variants in a "typical" genome

I don’t normally blog here about my own research, but I’m making an exception for this paper. There are a few reasons to single this paper out: firstly, it’s in Science (!); and secondly, no fewer than five Genomes Unzipped members (me, Luke, Joe, Don and Jeff) are co-authors. For me it also represents the culmination of a fantastic postdoc position at the Wellcome Trust Sanger Institute (for those who haven’t heard on Twitter, I’ll be starting up a new research group at Massachusetts General Hospital in Boston next month).

Readers who don’t have a Science subscription can access a pre-formatted version of the manuscript here. In this post I wanted to give a brief overview of the study and then highlight what I see as some of the interesting messages that emerged from it.

First, some background

This is a project some three years in the making – the idea behind it was first conceived by my Sanger colleague Bryndis Yngvadottir and I back in 2009, and it subsequently expanded into a very productive collaboration with several groups, most notably Mark Gerstein’s group at Yale University, and the HAVANA gene annotation team at the Sanger Institute.

The idea is very simple. We’re interested in loss-of-function (LoF) variants – genetic changes that are predicted to be seriously disruptive to the function of protein-coding genes. These come in many forms, ranging from a single base change that creates a premature stop codon in the middle of a gene, all the way up to massive deletions that remove one or more genes completely. These types of DNA changes have long been of interest to geneticists, because they’re known to play a major role in really serious diseases like cystic fibrosis and muscular dystrophy.

But there’s also another reason that they’re interesting, which is more surprising: every complete human genome sequenced to date, including celebrities like James Watson and Craig Venter, has appeared to carry hundreds of these LoF variants. If those variants were all real, that would indicate a surprising degree of redundancy in the human genome. But the problem is we don’t actually know how many of these variants are real – no-one has ever taken a really careful look at them on a genome-wide scale.
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Friday Links

The Genomes Unzipped team has been quiet for the last few weeks as we prepare for a major announcement – stay tuned next week to find out more. In the meantime, here are a few things we found around the web this week.

China’s sequencing powerhouse BGI collaborated with Danish researchers to analyse the exomes (the sequences of all protein-coding genes) of 200 individuals from Denmark, in a study published in Nature Genetics. The researchers took an approach similar to that adopted by the 1000 Genomes Project, sequencing each of the individuals at fairly low depth (with each base in the exome being covered on average by 12 sequencing reads, as compared to at least 30 for a “high quality” genome), but then using a statistical approach to identify variants and infer their frequency within the population. The headline finding was that the sequenced individuals carry more rare protein-altering polymorphisms than expected; the authors conclude:

Based on our findings, we support the idea that much of the heritable variation affecting fitness is caused by low-frequency mutations, which are often overlooked in studies based on genotyping rather than resequencing.

The conclusion that much of the “missing heritability” for disease is driven by rare protein-altering mutations is plausible, but this study in and of itself doesn’t provide compelling evidence in support of it. Fortunately, more definitive studies are underway: as tens of thousands of exomes from disease patients and controls accumulate over the next two years, the contribution of rare protein-coding variants to disease (or surprising lack thereof) will soon be fairly definitively established. [DM]

Bio-IT World has an excellent special issue on “The Road to the $1000 Genome”, highlights include an article pondering the often underestimated costs of analysis of genome sequences, and an update on Hugh Reinhoff’s personal quest to find the mutation underlying his daughter’s genetic disease. The issue coincides with the launch of editor Kevin Davies’ new book The $1000 Genome, which was favourably reviewed this week at 23andMe’s blog The Spittoon. [DM]

In Science this week, John Travis takes a look at the technically and ethically challenging world of Native American genetics, focusing on the effort to sequence the nuclear genome of Lakota warrior Sitting Bull from snippets allegedly taken from the man’s hair. The story includes the unusual method by which the main researcher in the project gained approval to study the Native American’s remains:

LaPointe said the basement ceremony was required to get permission from Sitting Bull himself, who was killed in 1890. Willerslev says something odd happened at the ceremony, recalling a blue-green light that ran across his body and into his mouth. LaPointe says the spirit of Sitting Bull tested the geneticist and approved. As a result, LaPointe allowed Willerslev to cut a short section from a long braid of Sitting Bull’s still-shiny black hair and fly it back to the University of Copenhagen for analysis.

If only all ethics committee meetings were livened up by pyrotechnics… [DM]

A piece in Fortune tells the remarkable story of Hugh Martin, CEO of the massively-funded third-generation sequencing startup Pacific Biosciences, who has battled openly with cancer while guiding the company through funding rounds and towards a public share offering. [DM]

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