Over at Genomes Unzipped Dr. Daniel MacArthur has a review up of a paper in Science where he is first author (note for grad students and aspiring post-docs, Dr. MacArthur is starting a new lab, where he posted an ungated version of the paper). He hits all the salient points, so I will cover two issues, a general and a specific.
As Dr. MacArthur notes we’re entering the era of whole-genome sequencing for humans. There is going to be a lot of gold in the coming avalanche of data, but this gold will be dwarfed by the amount of ‘fool’s gold’. On the face of it this makes total sense. When you go out and sequence billions of base pairs there will be technical errors, and those errors are likely to be confused with biological errors (i.e., genuine malfunctions in the genome, as opposed to malfunctions in the genome technology!). Technology is still technology, and until we get artificial intelligence we need to have a human check. MacArthur warns against the temptation to take on face value those researchers who are naive or unethical in attempting to pass on results which they should know are likely false positives to beef up their publication counts.
Second, the results themselves suggest that the average human has ~100 loss-of-function mutations. These mutations are generally in genes which seem relatively redundant and less critical to human function, implying strong selective constraint on the emergence of these variants. They’re at low frequency, and likely distinct from person to person. But just because loss-of-function mutations don’t kill you, it doesn’t mean they don’t have some phenotypic effect. I would not be surprised if variation across siblings of the distribution of loss-of-function mutations correlate well with indicators of overall physiological “fitness.” Second, it seems likely that many of these loss-of-function mutations can come to the fore in importance after our reproductive years. In other words, over a substantial proportion of the modern human life! So understanding our individual patterns of loss-of-function mutations may be important, even if in general they confirm that yes, we do not exhibit extremely deleterious congential diseases which strike us down in our prime.