More Quantification of Human Nuclear DNA Mutation Rates

Nuclear DNA is essentially a big complicated molecule, and stuck in the middle of the dynamic environment of the cell it accumulates damage due to reactions with other molecules. Near all of this damage is repaired quickly, but only near all. So we accumulate somewhat random mutations scattered across our cells as we age. There is some debate over whether this is actually a cause of general age-related degeneration over the present human life span versus only a cause of cancer.

This paper looks at human mutation rates in the exome, a classification that includes only small fraction of our DNA, but which is thought to encompass most of the important known mutations associated with various diseases. There is thus an energetic community that studies this small part of the genome:

The inability of genomic variants to fully explain known or suspected inherited and spontaneous components of a wide variety of diseases may indicate that there may be additional undiscovered factors that complicate analysis. These factors include the number and rapidity with which one accumulates genomic variants, which if known could be compensated for, like ethnicity and sex. Genetic characterization of aging, therefore, may hold a key to questions regarding the importance of acquired somatic variants, variation in aging within a population, and their role in human diseases. Adding time and the accompanying mosaic changes as variables may enhance the accuracy and utility of population-scale analysis of human traits and disease.

In an attempt to begin to address this gap, we hypothesized that the inherited genome is not static but rather dynamic with time with individual experiences punctuating genomes differently. To test this hypothesis we used exome sequencing of normal epithelial samples from three healthy individuals serially collected at different ages in their life. We found the human genome to be dynamic, acquiring a varying number of mutations with age (5,000 to 50,000 in 9 to 16 years). These mutations span across 3,000 to 13,000 genes, which commonly showed association with Wnt signaling and Gonadotropin releasing hormone receptor pathways, and indicated for individuals a specific and significant enrichment for increased risk for diabetes, kidney failure, cancer, Rheumatoid arthritis, and Alzheimer's disease - conditions usually associated with aging.

[This demonstrates] that the exome of an individual is dynamic and constantly experiences environmental and evolutionary pressures and over time enriches for deleterious variants. This finding indicates that the accumulation of somatic variants and possibly the rate of accumulation will contribute to how an individual ages, and prompting age-related diseases. It challenges our existing approach in population-scale sequencing studies and establishes "age" as an important variable that must be accounted for in the analysis and interpretation of any given human genome. These observations are supportive of new paradigm, "Multiple genomes per individual".



So this makes it seem that mutation over time *is* one of the fundamental drivers of aging: many genes are mutating over time (and that's just in the exome).

I wonder if the genetic drift *between* cells is also a significant factor. Essentially, cells within the body become more foreign to each other over time.

Posted by: John at June 19th, 2014 8:28 PM

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