A genomic mutational constraint map using variation in 76,156 human genomes.

The depletion of disruptive variation caused by purifying natural selection (constraint) has been widely used to investigate protein-coding genes underlying human disorders1-4, but attempts to assess constraint for non-protein-coding regions have proved more difficult. Here we aggregate, process and release a dataset of 76,156 human genomes from the Genome Aggregation Database (gnomAD)-the largest public open-access human genome allele frequency reference dataset-and use it to build a genomic constraint map for the whole genome (genomic non-coding constraint of haploinsufficient variation (Gnocchi)). We present a refined mutational model that incorporates local sequence context and regional genomic features to detect depletions of variation. As expected, the average constraint for protein-coding sequences is stronger than that for non-coding regions. Within the non-coding genome, constrained regions are enriched for known regulatory elements and variants that are implicated in complex human diseases and traits, facilitating the triangulation of biological annotation, disease association and natural selection to non-coding DNA analysis. More constrained regulatory elements tend to regulate more constrained protein-coding genes, which in turn suggests that non-coding constraint can aid the identification of constrained genes that are as yet unrecognized by current gene constraint metrics. We demonstrate that this genome-wide constraint map improves the identification and interpretation of functional human genetic variation.

The variability of male quality and female mate choice decisions: second-order stochastic dominance and the behavior of searchers under a sequential search strategy.

The strategy employed by a female to sample prospective mates determines the likelihood that a high-quality male is encountered in the search process. In general, the choosiness of females is expected to depend on the variability of quality amongst the males that are sampled. The sequential search strategy is a prominent model of search behavior that involves the use of a threshold criterion to evaluate encountered individuals. In this paper, we show that the stochastic dominance of one distribution of male quality over another at the second order is necessary and sufficient for the optimal threshold criterion to differ under two distributions of male quality when the cost to sample males is held constant and the mean quality of males under each of the distributions is identical. A difference of the variance of male quality between two distributions does not imply that one distribution stochastically dominates the other at the second order and, hence, should not, in general, be used to assess the relative variability of quality amongst prospective mates. The adjustment of the threshold criterion in response to experimental manipulations of the distribution of male quality has been inferred from induced differences of the duration of search or the number of males sampled in the search process. Here we show that such inferences are unjustified. In particular, the difference of the threshold criterion imposed by second-order stochastic dominance does not determine the distribution under which females are expected to sample a larger number of males in the search process.

Mate choice and optimal search behavior: fitness returns under the fixed sample and sequential search strategies.

The behavior of a female in search of a mate determines the likelihood that she encounters a high-quality male in the search process. The fixed sample (best-of-n) search strategy and the sequential search (fixed threshold) strategy are two prominent models of search behavior. The sequential search strategy dominates the former strategy--yields an equal or higher expected net fitness return to searchers--when search costs are nontrivial and the distribution of quality among prospective mates is uniform or truncated normal. In this paper our objective is to determine whether there are any search costs or distributions of male quality for which the sequential search strategy is inferior to the fixed sample search strategy. The two search strategies are derived under general conditions in which females evaluate encountered males by inspection of an indicator character that has some functional relationship to male quality. The solutions are identical to the original models when the inspected male attribute is itself male quality. The sequential search strategy is shown to dominate the fixed sample search strategy for all search costs and distributions of male quality. Low search costs have been implicated to explain empirical observations that are consistent with the use of a fixed sample search strategy, but under conditions in which the original models were derived there is no search cost or distribution of male quality that favors the fixed sample search strategy. Plausible alternative explanations for the apparent use of this search strategy are discussed.