How many harmful mutations do you carry?

According to a new article in Nature (full text for subscribers only), the answer depends on your ancestry: Europeans carry more potentially fitness-reducing mutations than individuals from Africa.

The authors support this claim with sequencing data from more than 10,000 genes, obtained from 20 individuals of European ancestry and 15 African-Americans. As far as I can tell the same data were used in a 2005 Nature paper by the same group to address a completely different question, which I note simply because getting two Nature papers from the same data is a rare and wondrous thing!

Here, the authors examine the patterns of genetic variation within the protein-coding regions of their 10,000 genes. This variation can be broken down into two major classes: variations that don't change the sequence of the encoded protein, and are thus unlikely to affect fitness; and variations which do alter protein sequence. The protein-changing variants were further classified into three groups, based on how likely they are to disrupt the function of the encoded protein: benign, possibly damaging, or probably damaging.

The authors find some potentially interesting differences between the European and African samples: although the total amount of variation is substantially lower in Europeans, the proportion of it that rates as potentially harmful is higher. This is consistent with the notion that modern Europeans are derived from a relatively small population that migrated out of Africa between 50 and 100 thousand years ago. This "bottleneck" resulted in a loss of genetic variation, while the subsequent expansion as Europeans colonised new and fertile lands resulted in variants that have slightly negative effects on fitness "surfing" to disproportionately high frequencies.

The differences between the populations is actually pretty small, and this interpretation of the data is controversial (as noted in a Nature news article). But I'll leave that debate for another blogger - what interests me right now are the implications of these results for future analysis of large-scale sequencing data.

The article notes that the average individual in their data was heterozygous (that is, carried one "good" copy and one "bad" copy) for more than 400 possibly or probably damaging variants, and homozygous (that is, carried two "bad" copies) for more than 90 of these variants. Bearing in mind that these data are based on around half of the genes contained in our genome, this means that when you have your entire genome sequenced (as we are all likely to, at some point in the next twenty or so years) you will find that you carry one copy of more than 800 potentially damaging variants, and two copies of almost 200.

Among these potentially damaging variants there will be massive differences in the risk of disease for you and for your children: many will have little or no effect on health even if you carry two bad copies, whereas some may be severe enough to cause serious disease even if you carry only one bad copy (like a Huntington's disease mutation).

We know from studies of inbreeding that all of the variants will add up to around two to five "lethal equivalents" - which could mean five variants that would each be 100% lethal if you happened to carry two copies, or 500 variants that each carry a 1% chance of death (with a more likely scenario being somewhere in between!). With our current understanding of molecular and cellular biology we can confidently predict the final effects on health of only a tiny fraction of these variations - and that's not even considering the substantial proportion of potentially nasty variation occurring outside protein-coding regions, for which it is currently essentially impossible to predict function. Within five to ten years, we will have the capacity to cheaply sequence your entire genome and find all of these variations, but we will be unable to predict the likely health impacts of the vast majority of them.

It's hard enough providing genetic counselling for a family carrying one serious disease mutation. How will counsellors deal with a patient carrying around 1,000 potentially deleterious mutations, most of which we don't really understand?

Added in edit: Those interested in further exploration of the implications of these data for recent human evolution should check out John Hawks. Thomas Mailund also has an excellent post discussing this paper in detail.

Lohmueller, K.E., Indap, A.R., Schmidt, S., Boyko, A.R., Hernandez, R.D., Hubisz, M.J., Sninsky, J.J., White, T.J., Sunyaev, S.R., Nielsen, R., Clark, A.G., Bustamante, C.D. (2008). Proportionally more deleterious genetic variation in European than in African populations. Nature, 451(7181), 994-997. DOI: 10.1038/nature06611