What genes can't tell us about lactase persistence

Gene ExpressionBy Razib KhanFeb 17, 2010 4:26 PM


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Lactase persistence results in the ability to break down the lactose sugar in milk as an adult, lactase being the enzyme which breaks down lactose. If one can not digest that sugar, and still consumes milk, then one exhibits the symptoms of lactose intolerance. Originally diagnosed as a disease it has come to light that 2/3 of the world's population is lactose intolerant, and, that this is probably the ancestral "wild type" (I would be interested if readers could name a mammal which exhibited lactase persistence aside from humans). Lactase persistence is a relatively new trait which emerged in the wake of cultural changes which were triggered by the Neolithic Revolution, primarily the domestication of cattle, goat, etc., and their utilization as a source of milk. The latter does not always entail from the former; the Gond tribe of India apparently has utilized cattle & goat for meat, but avoids drinking milk as adults (presumably they're lactose intolerant). The ability to digest milk as an adult is a phenotype has been elucidated in terms of its genetics rather well in the past ten years, at least in relation to a host of other traits of interest such as height & weight. A few genes of large effect generate a dominant phenotype whereby lactase continues to be produced into adulthood, and, there are alternative genetic architectures which can lead to this persistence. In other words, there are different instances when mutations arose which conferred lactase persistence. So as far as human genetics questions being illuminated in the "post-genomic era," lactase persistence is probably one of the successes. And yet there is much we don't know. A new paper addresses the issue by attempting to connect the dots in the holes of our knowledge, A worldwide correlation of lactase persistence phenotype and genotypes:

Results We used surface interpolation of Old World lactase persistence genotype and phenotype frequency estimates obtained from all available literature and perform a comparison between predicted and observed trait frequencies in continuous space. By accommodating additional data on sample numbers and known false negative and false positive rates for the various lactase persistence phenotype tests (blood glucose and breath hydrogen), we also apply a Monte Carlo method to estimate the probability that known lactase persistence-associated allele frequencies can explain observed trait frequencies in different regions. Conclusion Lactase persistence genotype data is currently insufficient to explain lactase persistence phenotype frequency in much of western and southern Africa, southeastern Europe, the Middle East and parts of central and southern Asia. We suggest that further studies of genetic variation in these regions should reveal additional nucleotide variants that are associated with lactase persistence.

I've tried to look at the lactase persistence data myself, and one problem is how you measure the phenotype. This isn't like height or weight, where precision is pretty good. Their method attempted to taken into account the error rates in detecting lactose intolerance, both false positives and negatives. They also had to account for the fact that they had lactase persistence data on some populations, but no genotype data. But using geographical extrapolation methods they constructed a series of maps which show the clines of both the allele and trait frequencies. Here's one which illustrates the differences between the two sets of maps, with blue being the genotype over-predicting lactase persistence, and red under-predicting:

It is clear that there is a trend toward under-prediction to a much greater magnitude than over-prediction. This makes sense when you consider the possibility that there are likely other lactase persistence alleles out there which haven't been picked up in association studies because the samples aren't representative of the world's genetic variation. Citation: BMC Evolutionary Biology 2010, 10:36doi:10.1186/1471-2148-10-36

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