Any replacement of a DNA base –– in the single strand of viruses and prokaryotes (bacteria & archaebacteria), or in one of the paired strands of eukaryotes (plants, fungi & animals) –– results in a MUTATION. DNA mutations accumulate at a steady pace across the genome, passing from one generation to the next; this is one of the principal mechanisms by which species evolve and improve their chances of survival (via finding food, avoiding predators & reproduction). Enhanced virulence of a virus, development of bacterial resistance to an antibiotic, adaptation of a tumor to resist ongoing exposure to a chemotherapeutic drug, and evolution of a species –– are ALL examples of this evolutionary process. Because most DNA is not involved in encoding proteins or participating in critical-life regulatory DNA modules, the vast majority of mutations are “silent.” Nevertheless, on the basis of the degree of shared mutations, a genealogical relationship can be reconstructed from ancient and modern individuals –– allowing one to go back hundreds of thousands of years in human evolutionary history.
Instead of comparing individuals, in the two [attached] full articles, authors assessed the rate of DNA mutation in single cells from developing [1st article] and aging [2nd article] human brains –– revealing mutational histories in neurodevelopment, aging, and neurodegeneration. These approaches also have implications for understanding complex diseases that could result from somatic mutations that arise later in life (e.g. cancer). De novo mutations in DNA of the egg or sperm can be associated with devastating disorders affecting young individuals, because all cells in the body inherit these germline mutations.
By contrast, somatic DNA mutations sporadically occur throughout the life of an organism as a result of (environmentally-caused) DNA damage –– as well as errors in DNA replication or repair. [By “environment”, this means ionizing radiation, in utero signals, dietary and lifestyle effects, and exposure to mutagenic chemicals or metals.] When somatic mutations occur early in the life in dividing cells, they are obviously found in a large number of cellular descendants. If mutations occur in dividing cells as humans age, they are found in only a limited number of cells, resulting in tissue mutational mosaicism (see figure in attached editorial). The inheritance pattern of mutations in cells within a tissue can be used to establish a temporal, or genealogical, relationship of mutations to understand better the role of mutational mosaicism in human diseases.
Somatic mosaicism in human brain may alter function of individual neurons. Authors [attached full article 550] analyzed genomes of single cells from three human forebrains (15 to 21 weeks postconception). They detected 200-400 single-nucleotide variations (SNVs) per cell. SNVs with a frequency of more than 2% in brain were also present in spleen, confirming these mutations were pregastrulation in origin. Authors reconstructed cell lineages for the first five postzygotic cleavages and calculated a mutation rate of ~1.3 mutations per division per cell (this is a pretty small number, considering the cell’s haploid genome is more than 1 billion nucleotides). Later in development –– during neurogenesis (formation of neurons and the nervous sytem), the mutation spectrum intriguingly shifted toward oxidative damage, and the mutation rate increased. Both neurogenesis and early embryogenesis exhibited substantially more mutagenesis than adulthood. [Could this finding reflect insufficient defenses against oxidative stress during early embryogenesis?]
Based on a comparison of counts of germline SNVs –– 3,746,847 for subject 275; 3,809,591 for subject 316; 4,316,547 for subject 320; to those derived by The 1000 Genomes Project across different human subpopulations –– authors concluded that subjects 275 and 316 were of non-African origin, whereas subject 320 was of African descent. To explain this quite simply (and in papers of the Great Human Diaspora frequently described in these GEITP pages), humans of African descent have existed on the planet longer than humans of non-African origin, and therefore African DNA has been “exposed to” environmental insults longer than DNA of non-African origin.
Authors [attached full article 555] used single-cell whole-genome sequencing to perform genome-wide somatic SNV identification on DNA from 161 single neurons from prefrontal cortex and hippocampus of 15 normal individuals (aged 4 months to 82 years), as well as nine individuals affected by early-onset neurodegeneration due to genetic disorders of DNA repair (Cockayne syndrome and xeroderma pigmentosum). Somatic SNVs increased approximately linearly with age in both areas of the brain and were greater in number in patients with neurodegenerative disease. Accumulation of somatic mutations with age showed age-related, region-related, and disease-related molecular signatures –– which authors suggest might be important in other human age-associated conditions.
Science 2 Feb 2o18; 359: 550–555 & 555–559 & editorial pp 521–522