Finding a disease-causing mutation is like finding a needle in a haystack. Or rather like finding one needle in hundreds of haystacks. As in: it’s really difficult. Because the genome is a BIG place, and you’re looking for one small change*. So how do you go about finding such a change?
Basically, there are two strategies:
1. Take a lucky (or well-educated) guess. Sometimes you have a hunch where to look, for example because you know other cases where doctors and scientists have found mutations in exactly the same place. It’s like picking a single haystack out of many, focusing all your attention on that region, hoping you are right and that you’ll find something.
2. Bite the bullet and look at every single haystack really, really carefully. In scientific terms this means that you sequence the whole genome, and then comb through the mutations you find, to see if you can identify one that could be disease-causing. Sometimes, this might be your only option, if you don’t really know where to look.
Which method is better?
Both methods have their pros and cons. Obviously, the lucky guess option (looking at only a small part of the genome) is much cheaper. But even if you’re an expert of a given disease your best guess might not be good enough. That’s when the unbiased approach comes in handy: looking at the whole genome (combing through all the haystacks) is more expensive (about 10-100x more), but you might find things in unexpected places, where you otherwise would not have looked. Also, you use a different technology for the “lucky-guess-sequencing” and the “all-haystacks” sequencing, and the per-unit cost is less for the “all-haystack” method. Therefore, if you have many potential lucky guesses, it is often the same cost to sequence the whole genome and then focus your analysis on the lucky guesses. This way, if you don’t find anything in your lucky-guess-haystacks you can still look at the other ones, too.
*Actually, for the mutation aficionados amongst you: it is of course possible that we’re not looking for a single small change (a point mutation), but a single large change (a structural variant, like a large deletion or duplication or inversion). We know that there are many developmental disorders that are caused by structural variants, so we’ll also be keeping an eye out for those, too.