Relating pathogenic loss-of-function mutations in humans to their evolutionary fitness costs.

Scientists studied genetic mutations that cause severe developmental conditions including autism. They found that harmful mutations in certain genes have been naturally selected against over many generations because they reduce survival and reproduction. Children with autism and other developmental conditions carry more of these highly harmful mutations than the general population. The study found differences between boys and girls with autism, and between families with one affected child versus multiple affected children.

This population genetics study analyzed loss-of-function (LOF) mutations in 17,318 autosomal and 679 X-linked genes from 56,855 individuals to understand the evolutionary fitness costs of pathogenic mutations. The researchers found that causal LOF variants for severe diseases occur in 'mutation intolerant' genes with fitness costs typically above 1%. X-linked genes showed the highest fitness costs, followed by autosomal genes. Individuals with six severe developmental disorders carried an excess of highly deleterious mutations (fitness effects >10%) that are typically only a few generations old.

The proportion of highly deleterious mutations varied by disease onset age and study design, with autism showing differences between simplex versus multiplex families and female versus male probands.

Findings may improve genetic variant interpretation by incorporating evolutionary fitness costs. Could enhance genetic counseling by explaining inheritance patterns and recurrence risks. The sex and family structure differences in autism may inform personalized genetic testing strategies.

Study design influence on mutation detection rates suggests potential ascertainment bias. The model relies on population genetic assumptions that may not hold across all populations. Clinical implications are inferred from evolutionary fitness effects rather than direct clinical outcomes.

Causal loss-of-function (LOF) variants for Mendelian and severe complex diseases are enriched in 'mutation intolerant' genes. We show how such observations can be interpreted in light of a model of mutation-selection balance and use the model to relate the pathogenic consequences of LOF mutations at present to their evolutionary fitness effects. To this end, we first infer posterior distributions for the fitness costs of LOF mutations in 17,318 autosomal and 679 X-linked genes from exome sequences in 56,855 individuals. Estimated fitness costs for the loss of a gene copy are typically above 1%; they tend to be largest for X-linked genes, whether or not they have a Y homolog, followed by autosomal genes and genes in the pseudoautosomal region.

We compare inferred fitness effects for all possible de novo LOF mutations to those of de novo mutations identified in individuals diagnosed with one of six severe, complex diseases or developmental disorders. Probands carry an excess of mutations with estimated fitness effects above 10%; as we show by simulation, when sampled in the population, such highly deleterious mutations are typically only a couple of generations old. Moreover, the proportion of highly deleterious mutations carried by probands reflects the typical age of onset of the disease. The study design also has a discernible influence: a greater proportion of highly deleterious mutations is detected in pedigree than case-control studies, and for autism, in simplex than multiplex families and in female versus male probands.

Thus, anchoring observations in human genetics to a population genetic model allows us to learn about the fitness effects of mutations identified by different mapping strategies and for different traits.