Reviewer response for version 1
The article 'Thousands of exon skipping events differentiate among splicing patterns in sixteen human tissues' presents a systematic analysis of alternative splicing of the Illumina Body Map RNA-seq set, probably the most complete set of RNA-seq data to date. 
This data set consists of 160M reads each for 16 tissues, each from a different individual.
From the standpoint of a reviewer I consider this article to be of very good quality, and have very much enjoyed reviewing it. 
There are a few suggestions I hope could help improve this work.
- P3. pp.2: 
Has alternative splicing profiling been attempted before? 
If so, could this please be shown in the background section? 
If not, how does this technique specifically differ from what has been done before? 
Some more context would be appreciated.
- P3. pp.3: 
What is the effect of comparing tissues from 16 different individuals? 
I would expect that the genetic variation of each individual would have some effects in the actual AS patterns observed when compared. 
I see that these samples belong to people with different ethnic backgrounds and ages. 
I would be interested to know what the authors think about how different results would be if all 16 tissues had been from one individual.
- I tried to compile ASprofile on a mac and I got this error: 
libc.h:15:20: error: malloc.h: No such file or directory I solved this by changing this line with #include <stdlib.h>. 
Perhaps you might want to add these lines, so that mac users do not encounter the problem: 
#if !defined(__APPLE__) #include <malloc.h> #endif
- Although the license for ASprofile is available in the Zenodo page, it might also be a good idea to mention it somewhere in the article. 
Not mentioning a license may make some users uneasy, even if it says it is open source.
- In S1, how many of the mapped reads were properly paired?
- Why did you use such old versions of Ensembl genes (Ensembl 61, February 2011), UCSC Genes, CCDS genes and H-DBAs? 
I also find that the TopHat (v1.3.3) and Cufflinks (v0.9.3) versions are quite old. 
The current version for TopHat is 2.0.9 and the current version for Cufflinks is 2.1.1. 
The current version of Ensembl is version 73, September 2013. 
The usage of such old versions concerns me a little, particularly those of the gene annotations, given that a lot of the results that are presented in this work rely heavily on the comparison of AS profiles against those annotations. 
Some of the results might be different if a newer version of the annotations were up-to-date.
- P5. pp.5: 
The example of a novel event in CHTOP does not provide clear evidence as to how many reads support the novel exon. 
Please provide some numbers.
- P7. pp1: 
Please could you provide evidence for the novel putative intron retention event located in the chr7:123269489-123270019 region?
- In Figure S7.B, I would appreciate some text describing the biological significance of having the 100 bin in the x-axis with the greatest bars. 
Overall I am unable to understand what this figure means.
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