A big memory example: Genome imputation

(Note: you cannot actually “follow along” with this example, as it involves human genetic data that I am not at liberty to share)

Processing speed is not the only limiting factor in terms of computational resources: memory can also be critical. Here, I illustrate a project I was involved in that involved large amounts of data and for which the critical consideration requiring the use of the Neon cluster was its larger memory capacity.

The example involves genome imputation, which I will now briefly describe. A (relatively) inexpensive way of carrying out a genome-wide study is to use a hybridization chip that probes the genome at a large number of markers. A more expensive way is to sequence the entire genome. A cost-effective compromise is pay for the chip, but use imputation to fill in the gaps between the markers. This is made possible by endeavors like the 1000 Genomes Project, which has (so far) sequenced the genomes of 2,504 individuals and made those sequences available to the public.

The classical model of genetics is that each human has two copies of each portion of the genome, and that, during reproduction, parents pass one of those copies at random to their children. This is, for the most part, true, but these random transmissions do not occur independently – transmissions on the same chromosome are correlated. That correlation is fairly complicated, as it depends on a genetic phenomenon known as crossover:

There are various ways of imputing genomes, but the most accurate rely on hidden Markov models (HMMs) to infer the unknown genetic blocks (known as “haplotypes”) belonging to individuals in the sample:

Essentially, the observed genotypes (GO) provide information about the hidden haplotypes (Z), which in turn allow us to infer the unobserved genotypes (GU) with reasonable accuracy. Hidden Markov models themselves are not terribly computer-intensive to fit; it’s the sheer size of genetic data that makes genome imputation computer-intensive and in particular, memory-intensive. In particular, imputation for the SOPHIA project (in collaboration with Profs. Ryckman and Saftlas in Epidemiology) involved nearly 80 Gb of data (some from the actual SOPHIA samples, some from the 1000 Genomes Project, some of it imputed).

I use a program called MaCH (for Markov Chain Haplotyping) to perform the imputation. I won’t go through all the details, but just so you can see how the same ideas of scripting and qsub arrays can be put to use in this problem, I’ll share the commands for step 1 of the imputation process (it’s more computationally efficient to do the calculations in two steps: the first step is called “pre-phasing”; the second step is the actual imputation). The script is:

File: phase 
mach1 -d chr$SGE_TASK_ID.dat -p chr$SGE_TASK_ID.ped --rounds 20 --states 200 --interim 5 --phase --sample 5 --prefix chr$SGE_TASK_ID.haps > phase$SGE_TASK_ID.log
cut -f 1 -d " " chr$SGE_TASK_ID.haps.erate | sed -n '1!p' > chr$SGE_TASK_ID.snps
rm chr$SGE_TASK_ID.haps.sample*
rm chr$SGE_TASK_ID.haps.prelim*

Which we run with:

> 
qsub -t 1-22 phase

This runs the hidden Markov model separately on each chromosome 1-22 (i.e., simultaneously phasing all 22 chromosomes, one processor per chromosome). The process took overnight (about 12 hours), but that’s a lot better than 22 nights!

Breaking up the problem in this way is natural to genetics, but the same general principle of data splitting is widely applied in many other fields involving “big data”.

Image credits: My crossover picture comes from the Noor lab at Duke; my HMM illustration is from Nihar Shah at Berkeley.