Rate, molecular spectrum, and consequences of human mutation

Area of Science:

• Genetics
• Evolutionary Biology
• Genomics

Background:

• Mutation is essential for evolution but also causes deleterious alleles, impacting human health.
• De novo mutations provide insights into mutation rates, molecular spectrum, and eukaryotic genome evolution.

Purpose of the Study:

• To estimate the rate and molecular spectrum of de novo mutations using databases for monogenic disorders.
• To infer the evolutionary dynamics of eukaryotic genomes, including nucleotide composition and mutation biases.
• To assess the impact of mutations on human health and long-term fitness.

Main Methods:

• Utilized recently established databases on de novo mutations for monogenic disorders.
• Compared human germline mutation rates with those of other species.
• Analyzed mutation patterns in relation to genome-wide nucleotide composition and intron function.

Main Results:

• The human per-generation mutation rate is high, but the per-cell division germline rate is relatively low compared to other species.
• A universal mutational bias toward A/T composition was observed across species.
• Mutations at splice-site residues in introns are a significant cause of human mortality.
• Genome-wide nucleotide composition appears to evolve towards a balance between selection for G/C and genetic drift, influenced by mutation biases.

Conclusions:

• Human germline mutation rates and biases have significant implications for genome evolution.
• Splice-site mutations pose a considerable threat to human health.
• Current human behaviors may lead to reduced fitness due to deleterious mutation accumulation over the next centuries, necessitating genetic interventions.