It's more an empirical question rather than a theoretical one, and short-read sequencing wouldn't be as popular as it is if it didn't work out most of the time.

It's more an empirical question rather than a theoretical one, and short-read sequencing wouldn't be as popular as it is if it didn't work out most of the time. I don't have all the exact numbers handy, but 76bp will uniquely map about 80-90% of potential reads, just with single ends. A high proportion of reads can be mapped uniquely even down to 25 or 30bp. There are some 'mappability' tracks available in the UCSC browser if you're curious about a particular region. http://hgdownload.cse.ucsc.edu/goldenPath/hg18/encodeDCC/wgEncodeMapability/ http://hgdownload.cse.ucsc.edu/goldenPath/hg18/encodeDCC/wgE... Of course there are repetitive and low complexity regions that can't be sequenced at all with these read lengths, or which haven't yet been properly sequenced or assembled at all even with much longer reads. I'm not aware of a paper that has fully explicated how read-length and the structure of the reads affects mappability (especially with pairs or reads with multiple gaps), though it's certainly something that all the people building the instruments (and the mapping algorithms) have thought about a quite a lot.