Examples using R and 1000 genomes data
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README.md

1000_genomes_examples

Topic-specific web-pages

The following pages are generated by the R markdown files in the repository:

Genomic ranges example

http://bwlewis.github.io/1000_genomes_examples/ranges.html

PCA examples

Additional notes on the PCA examples:

And here are some informal performance reults on a few systems:

Introduction

The 1000 Genomes project (http://www.1000genomes.org/) is an amazing public resource coordinated by the NIH. It's a "deep catalog of human genetic variation" for more than 2500 people, all carefully curated, organized and published on the web.

Because of the size and complexity of the data, and because of the significant interest in understanding human genetics, these data are often used as examples of "big data" analysis. Typical examples of this kind of thing can be found in the Google genomics project https://github.com/googlegenomics and the Spark ADAM project https://github.com/bigdatagenomics/adam.

That's cool and all, but...

my personal opinion is that folks get too worked up over "big data" solutions and sometimes too focused on distributed system implementation details (Spark, etc.) when simple tools like R work just fine.

I am very impressed by a recent article by Michael Isard, Frank McSherry and Derek Murray (summarized http://www.frankmcsherry.org/graph/scalability/cost/2015/01/15/COST.html). In that article, McSherry and his coauthors show that careful thinking about some network analysis problems let them run better on a laptop than on a 128 CPU core cluster using a few common "big data" computing frameworks.

This note presents a few simple but useful examples using the 1000 genomes data in the spirit of Isard, McSherry and Murray. The examples are often used to showcase big data analysis frameworks. This note shows how they can sometimes be easily and efficiently solved on a decent laptop.

Variant data

The examples use "variant call format" (VCF) files following an NCBI-specific format available from links shown in the code snippets below. Loosely, "variants" are places on the genome that commonly vary from a reference genome in a cataloged way. Variants include single-nucleotide polymorphisms (a.k.a. SNPs, basically a single base change along the genome) and larger "structural" alterations. The 1000 genomes project catalogs about 81 million variants.

Variant data are stored in files by chromosome. Each file contains a set of header lines beginning with the # character, followed by one line per variant. Full file format details are described in www.1000genomes.org/wiki/analysis/variant%20call%20format/vcf-variant-call-format-version-41.

Variant data files for each chromosome are available from ftp://ftp-trace.ncbi.nih.gov/1000genomes/ftp/release/20130502/. The file format used is nicely described in this article: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3137218/pdf/btr330.pdf.

Discounting the header lines, a variant line in the data files consists of some information columns about the variant followed by one column for each sample (person) that indicates if they exhibit the variant on either or both chromosomes. For example, part of a typical line (showing only the first 5 columns and 10-15 columns) looks like:

zcat ALL.chr20.phase3_shapeit2_mvncall_integrated_v5.20130502.genotypes.vcf.gz | sed /^#/d | cut -f "1-5,10-15" | head -n 1

20      60343   .       G       A   ...    0|0     0|0     0|0     0|0     0|0     0|0

This variant is on chromosome 20 at position 60343. The reference nucleotide is G and the variant is A. Note that in some cases, more than one possibility may be listed in which case the variants are numbered 1,2,3,... Columns 10-15 show that none of the first 6 people in the database have this variant on either chromosome 0|0. Someone with the G to A variant on the 2nd strand of DNA will display 0|1, for example.

The file format is somewhat complex. Numerous full-featured VCF file parsers exist for R, see for example the http://bioconductor.org project. But the simple exmaple analyses considered in this project don't need to read VCF files in full generality, and we can also benefit from the knowledge that the 1000 genomes project follows a somewhat restricted VCF subset. I wrote the really simple 32-line C parser program https://github.com/bwlewis/1000_genomes_examples/blob/master/parse.c to take advantage of these observations and load a subset of VCF data from the 1000 genomes project into R pretty quickly.

The simple parser program turns VCF files into tab-separated output with four or three columns: variant number (just the line offset in file), sample number (person), alternate number on first strand or haploid alternate, optional alternate number on 2nd strand (diploid). For example chromosome 20 again:

cc parse.c
zcat ALL.chr20.phase3_shapeit2_mvncall_integrated_v5.20130502.genotypes.vcf.gz  | sed /^#/d  | cut  -f "10-" | ./a.out | head

1       898     0       1
2       1454    0       1
3       462     0       1
3       463     1       0

The output says that person 898 has variant number 1 (the first listed) for chromosome 20 present on the 2nd strand of DNA. And person 1454 has variant number 2 present on the 2nd strand of DNA, and so on.

For our purposes in the following examples, this simple C parser quickly converts the 1000 genomes VCF data into a variant number by person number table.

The 1000 genomes project also includes ethnicity and some other phenotypic data about each of the more than 2500 people whose genomes are represented. Those data are available from: ftp://ftp.1000genomes.ebi.ac.uk/vol1/ftp/technical/working/20130606_sample_info/20130606_g1k.ped and are easy to directly read into R.

Next steps

See the following vignettes for copy-and-pasteable example analyses on variant data that you can run yourself.

Genomic ranges example

http://bwlewis.github.io/1000_genomes_examples/ranges.html

PCA examples

Across the whole genome: http://bwlewis.github.io/1000_genomes_examples/PCA_whole_genome.html

Smaller example across just one chromosome: http://bwlewis.github.io/1000_genomes_examples/PCA.html