Mutational Load and the Functional Fraction of the Human Genome

Area of Science:

• Genomics
• Evolutionary Biology
• Population Genetics

Background:

• The functional fraction of the human genome is debated, with sequence divergence suggesting ~15% and the ENCODE project indicating 80% functional regions.
• Understanding the genome's functional fraction is crucial for evolutionary and practical applications.

Purpose of the Study:

• To investigate if mutational load imposes a limit on the functional fraction of the human genome.
• To characterize the distribution of fitness in a large, finite, diploid population at mutation-selection equilibrium.

Main Methods:

• Analysis of fitness distribution at mutation-selection equilibrium in a large population (N=10^9).
• Modeling the variance of log fitness as 'nus', where 'n' is the number of functional sites, 'u' is the deleterious mutation rate, and 's' is the selection coefficient.
• Calculating the likely fitness of the fittest individual in the population.

Main Results:

• The fitness of the fittest individual in a large population is approximately e^(5nus).
• The functional fraction is unlikely to be substantially limited by mutational load.
• Any potential limit on the functional fraction is highly dependent on the selection coefficients of deleterious mutations.

Conclusions:

• Mutational load does not appear to significantly constrain the functional fraction of the human genome.
• The ENCODE project's findings of a large functional genome are not strongly contradicted by mutational load considerations.
• Further research should focus on the specific selection coefficients of mutations to refine estimates of functional genome limits.