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Saturday, May 14, 2011

Height, breeding values and selection

I can't wait to read this paper. The results were reported on the blog Genetic Inference, based on a talk at Biology of Genomes 2011.

A few comments:

1. Although known alleles for height only account for 5-10% of variance (out of the expected 80-90%), it is very plausible that loci of smaller effect or MAF (minor allele frequency) account for the "missing heritability". We still lack sufficient statistics to detect most of the individual loci of this type, but it's a matter of time. See beautiful paper from Visscher's group. The results described below suggest that loci just below the (arbitrary) significance threshold currently in use might also be height associated. There is a whole distribution of loci with smaller effect sizes and MAF that are just waiting to be discovered -- we have only found the tip of the iceberg.

2. Even with only a fraction of total additive variance identified, one can still make estimates of breeding value for groups by simply computing the prevalence of known associated loci in each group. How indicative these (large effect/MAF) loci are of the actual breeding values can't be answered a priori, but I would bet they are a good indicator, and this seems to be the case for height.

3. If the results on selection hold up this will be clear evidence for differential selection between groups of a quantitative trait (as opposed to lactose or altitude tolerance, which are controlled by small sets of loci). We may soon be able to conclude that there has been enough evolutionary time for selection to work within European populations on a trait that is controlled by hundreds (probably thousands) of loci.

4. With luck we might get to this level of analysis for g in the next 5-10 years. (I originally wrote 3-5 years but one of my more sober collaborators convinced me that would be quite unlikely!)

5. Understanding the evolution and distribution of quantitative traits like height and g at this level is an important milestone in scientific history.

It's amazing to see scientific and technological progress verify models that you've had in your head since age 12 :-)

Genetic Inference: ... Europeans differ systematically in their height, and these differences correlate with latitude. The average Italian is 171cm, whereas the average Swede is a full 4cm taller. Are these differences genetic? Have they been under evolutionary selection in recent human history?

Michael Turchin gave some pretty convincing answers to these questions, using genetic data from the 129 thousand individuals in the GIANT consortium. He compared the frequencies of alleles that are known to increase height, and found that they are more common in Northern Europe. Interestingly, he found the same relationship for alleles that have weaker evidence for height association, showing that there are still a large number of common height variants hiding in the genome, which are also more frequent in Northern Europe.

Height differences are thus heritable, but have they been under evolutionary selection? Or are these differences merely down to genetic drift? This can also be tested using the GIANT data, which shows significant statistical evidence of selection on height variants in recent history. On top of that, the magnitude of the selection is correlated with the effect size of the height variant, providing strong evidence that these variants are being selected specifically for their impact on height.

This is a textbook example of how an evolutionary study should be done; you show a phenotypic difference exists, that it is heritable, and that it is under selection. This opens the question as to why height has been selected in Northern Europe (or shortness in Southern Europe). Could the same data be used to test specific hypotheses there?

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