3. Crossbow GATCACAGGTCTATCACCCTATTAACCACTCACGGGAGCTCTCCATGCATTTGGTATTTTCGTCTGGGGGGTATGCACGCGATAGCATTGCGAGACGCTGGAGCCGGAGCACCCTATGTCGCAGTATCTGTCTTTGATTCCTGCCTCATCCTATTATTTATCGCACCTACGTTCAATATT GTCGCAGTA N CTGTCT ||||||||| |||||| GTCGCAGTA T CTGTCT GGATCT G CGATATACC |||||| ||||||||| GGATCT - CGATATACC AATCTGATCTTATTTT |||||||||||||||| AATCTGATCTTATTTT ATATATATATATATAT |||||||||||||||| ATATATATATATATAT TCTCTCCCA NN AGAGC ||||||||| ||||| TCTCTCCCA GG AGAGC Align Aggregate Reference Call: HET A, G p-value: 0.0023 GTCGCAGTATCTGTCT GTCGCAGTATCTGT NN TGTCGCAGTATCTGTC TATGTCGCAGTATCTG TAT A TCGCAGTATCT T TAT A TCGCAGTATCTG N AT A TCGCAGTAT N TG CCCTAT A TCGCAGTAT A CACCCTATGTCGCA A CACCCTAT C TCGCA A CACCCTATGTCGCA GA - CACCCTATGTCGC CCGGA - CACCCTAT A T CCGGA - CACCCTAT A T GCCGGA - CACCCTATG Statistics Parallel by read Handled by Hadoop Parallel by genome bin

4. Myrna Gene 1 GATCACAGGTCTATCACCCTATTAACCACTCACGGGAGCTCTCCATGCATTTGGTATTTTCGTCTGGGGGGTATGCACGCGATAGCATTGCGAGACGCTGGAGCCGGAGCACCCTATGTCGCAGTATCTGTCTTTGATTCCTGCCTCATCCTATTATTTATCGCACCTACGTTCAATATT GTCGCAGTATCTGTCT GTCGCAGTATCTGTCT GTCGCAGTATCTGTCT GTCGCAGTATCTGTCT TGTCGCAGTATCTGTC TATGTCGCAGTATCTG TATATCGCAGTATCTG TATATCGCAGTATCTG TATATCGCAGTATCTG CCCTATATCGCAGTAT AGCACCCTATGTCGCA AGCACCCTATATCGCA AGCACCCTATGTCGCA GAGCACCCTATGTCGC CCGGAGCACCCTATAT CCGGAGCACCCTATAT GCCGGAGCACCCTATG GTCGCAGTA N CTGTCT ||||||||| |||||| GTCGCAGTA T CTGTCT GGATCT G CGATATACC |||||| ||||||||| GGATCT - CGATATACC AATCTGATCTTATTTT |||||||||||||||| AATCTGATCTTATTTT ATATATATATATATAT |||||||||||||||| ATATATATATATATAT TCTCTCCCA NN AGAGC ||||||||| ||||| TCTCTCCCA GG AGAGC Align Gene 1 differentially expressed?: YES p-value: 0.0012 TGTCGCAGTATCTGTC AGCACCCTATGTCGCA GCCGGAGCACCCTATG GTCGCAGTA N CTGTCT ||||||||| |||||| GTCGCAGTA T CTGTCT GGATCT G CGATATACC |||||| ||||||||| GGATCT - CGATATACC AATCTGATCTTATTTT |||||||||||||||| AATCTGATCTTATTTT ATATATATATATATAT |||||||||||||||| ATATATATATATATAT TCTCTCCCA NN AGAGC ||||||||| ||||| TCTCTCCCA GG AGAGC Sample A Sample B Align Aggregate Aggregate Overlap Aggregate Normalize Aggregate Normalize Aggregate Statistics Parallel by read Handled by Hadoop Parallel by genome bin Handled by Hadoop Parallel by sample Handled by Hadoop Parallel by gene

5. Myrna Table 1 . Timing and cost for a Myrna experiment with 1.1 billion 35 bp unpaired reads from the Pickrell et al study as input. Costs are approximate and based on the pricing as of this writing, that is, $0.68 per extra-large high-CPU EC2 node per hour in the Northern Virginia zone and $0.78 in other zones, plus a $0.12 per-node-per-hour surcharge for Elastic MapReduce in all zones. Times can vary subject to, for example, congestion and Internet traffic conditions. Data transfer adds about 1hr:15m, $11 Myrna Runtime, Cost for 1.1 billion reads from Pickrell et al study EC2 Nodes 1 master, 10 workers 1 master, 20 workers 1 master, 40 workers Worker CPU cores 80 160 320 Wall clock time 4h:20m 2h:32m 1h:38m Cluster setup 4m 4m 3m Align 2h:56m 1h:31m 54m Overlap 52m 31m 16m Normalize 6m 7m 6m Statistics 9m 6m 6m Summarize & Postprocess 13m 14m 13m Approximate cost (N. Virginia / Elsewhere) $44.00 / $49.50 $50.40 / $56.70 $65.60 / $73.80

6. Myrna 71% 55%

7. Bet-hedging architecture Cloud driver script Wrapper bowtie Wrapper soapsnp Postprocess Hadoop Wrapper bowtie Wrapper soapsnp Postprocess Hadoop Singleton driver script Wrapper bowtie Wrapper soapsnp Postprocess Perl, fork, sort Hadoop driver script Cloud mode Hadoop mode Single-computer mode

9. Crossbow Data transfer adds about 1hr:15m, $28

10. Crossbow 43% 58%