Once #221 and #230 are closed, we should underline the changes since initial submission as requested:

In order to facilitate review of the revised manuscript please provide a point-by-point rebuttal and underline any additions to the text or areas with other significant changes. Please ensure that the revised version is as concise as possible, and that it conforms to our format requirements (see http://www.nature.com/nmeth for our Guide to Authors). We shall return to the issue of format and presentation in the event that the manuscript is accepted for publication.