Fig 1.
Expected allele frequencies in a population, according to mutation-selection balance models.
The blue bar denotes the expected allele frequency under an infinite population size, the green bar the mean under a finite constant population, and the red bar the mean under a plausible demographic model for European populations; for this last case, the entire distribution across 100,000 simulations is shown in the grey histogram. All models assume s = 1 and h = 0, i.e., fully recessive, lethal mutations. For the finite constant population size model, we present the mean frequency for a population size of 20,000 (see S2A Fig for other choices). Population allele frequencies (q) were transformed to log10(q), and those q = 0 were set to 10−7 for visual purposes, but indicated as “0” on the X-axis. The density of the distribution is plotted on a log-scale on the Y-axis. The mutation rate u was set to 1.5 x 10−8 per bp per generation in all models.
Fig 2.
Comparison between expected and observed mean allele frequencies of recessive, lethal disease mutations.
(A) Shown are the expected and observed mean sample frequencies of disease mutations for four different mutation types. The title of the panel indicates the mutation type, followed by K, the total number of mutations of that type considered in this study, with the p-value for the difference between observed and expected mean frequencies given below. Distributions in grey are the mean sample allele frequencies across K mutations based on 100,000 simulations, and rely on a plausible demographic model for European populations [25] (see Methods). Blue bars represent the observed mean frequencies of the four mutation types, estimated from 33,370 individuals of European ancestry from ExAC. (B) Fold increase in the observed mean allele frequency in relation to the expected, as a function of the mutation rate u (on a log-scale), for each of the four mutation classes.
Fig 3.
Sample allele frequencies at the gene level.
The expectation (grey) is based on 1000 simulations, assuming no fitness decrease in heterozygotes, but allowing for compound heterozygosity (see Methods for details). The sum of allele frequencies of known recessive lethal disease mutations in each gene (purple bars) was obtained from ExAC considering 33,370 European individuals. Genes are ordered according to the two-tailed p-value (S4 Table; see Methods). Genes are bolded when they differ significantly from expectation (at the 5% level). Violin plots show the distribution of the log10 combined allele frequency of all segregating alleles obtained from simulations and boxes represent the fraction of simulations in which no deleterious allele was observed in the simulated sample at present time.
Table 1.
For a given set of parameters na (the sample size in a putative disease ascertainment study) and Fa (the average inbreeding coefficient of the population in which the study is being performed), we report the probability of a recessive, lethal mutation being ascertained, as well as the fold increase in mean allele frequencies of the ascertained cases (qa) in relation to the mean frequencies of all mutations for each mutation type (qu), based on simulations (see Methods for details).
For a similar result derived from analytical modeling, see S6 Fig. Parameters for this step of the simulation correspond to plausible scenarios for human populations with widespread inbreeding (e.g., Fa = 1/16 corresponds to offspring of first-cousin marriage). The last column in the bottom panel shows the fold increase of the mean allele frequency observed in ExAC in relation to simulations based on the Tennessen et al. [25] demographic model (see Methods). Mutation rates u per bp, per generation were obtained from a large human pedigree study [18].