This observation, and the potential for rare CVs to explain much of the remaining additive genetic variation not tagged by SNPs, are together potentially consistent with a model of purifying selection of varying strength: CVs of small effect are under weak to nonexistent purifying selection and drift to high frequencies whereas CVs of larger effect are under increasingly strong purifying selection and kept rare because of it (Figure 1). Finally, although we have argued that much of the remaining variation in traits that has

not been explained by SNPs is likely to be due to rare CVs, there are several alternative explanations for selleck chemicals llc the discrepancy. For example, it is possible that family studies have over-estimated additive genetic variation,

meaning that little additive genetic variation remains to be explained and that rare variants thereby account for little trait variation. Forthcoming methods that use whole-genome sequencing data or shared identical-by-descent haplotypes, both of which can measure or tag rare CVs, should be able to put the rare variant debate largely to rest by directly estimating the importance of rare CVs. We have presented evidence from schizophrenia that is generally consistent LDK378 supplier with underlying CVs on average being under purifying selection and their frequencies being maintained by mutation–selection balance. Findings on human personality [6•] and other behavioral traits appear generally consistent

with this, although datasets are smaller and conclusions more tentative. However, the substantial proportion of variation accounted for by common CVs suggests that the highest frequency/smallest effect CVs may be selectively neutral or nearly neutral. These findings are not contradictory. It is important to recognize that the mutation–selection Acetophenone and the neutral mutation-drift models are not qualitatively distinct; they exist on the same continuum defined by the strength of purifying selection. To date, there is no convincing evidence that balancing selection plays an important role in maintaining the genetic variation in behavioral traits, and outside of the MHC region, genome-wide scans suggest a limited role for balancing selection in general 55, 56 and 57]. Nevertheless, absence of evidence does not necessarily equate to evidence for absence, and future findings could challenge this conclusion. Large whole-genome sequencing datasets will greatly expand our ability to understand the importance of rare variants in complex traits and inform our understanding of the evolutionary processes involved in maintaining traits’ genetic variation. Nevertheless, attempting to understand the evolutionary roots of genetic variation in traits will remain inherently difficult because selection acts on total ‘net fitness’ rather than fitness with respect to any given trait.