Genomic Mosaicism Formed by Somatic Variation in the Aging and Diseased Brain

Over the past 20 years, analyses of single brain cell genomes have revealed that the brain is composed of cells with myriad distinct genomes: the brain is a genomic mosaic, generated by a host of DNA sequence-altering processes that occur somatically and do not affect the germline. As such, these sequence changes are not heritable. Some processes appear to occur during neurogenesis, when cells are mitotic, whereas others may also function in post-mitotic cells. Here, we review multiple forms of DNA sequence alterations that have now been documented: aneuploidies and aneusomies, smaller copy number variations (CNVs), somatic repeat expansions, retrotransposons, genomic cDNAs (gencDNAs) associated with somatic gene recombination (SGR), and single nucleotide variations (SNVs). A catch-all term of DNA content variation (DCV) has also been used to describe the overall phenomenon, which can include multiple forms within a single cell’s genome. A requisite step in the analyses of genomic mosaicism is ongoing technology development, which is also discussed. Genomic mosaicism alters one of the most stable biological molecules, DNA, which may have many repercussions, ranging from normal functions including effects of aging, to creating dysfunction that occurs in neurodegenerative and other brain diseases, most of which show sporadic presentation, unlinked to causal, heritable genes.

Genomic Variation, Evolvability, and the Paradox of Mental Illness

Twentieth-century genetics was hard put to explain the irregular behavior of neuropsychiatric disorders. Autism and schizophrenia defy a principle of natural selection; they are highly heritable but associated with low reproductive success. Nevertheless, they persist. The genetic origins of such conditions are confounded by the problem of variable expression, that is, when a given genetic aberration can lead to any one of several distinct disorders. Also, autism and schizophrenia occur on a spectrum of severity, from mild and subclinical cases to the overt and disabling. Such irregularities reflect the problem of missing heritability; although hundreds of genes may be associated with autism or schizophrenia, together they account for only a small proportion of cases. Techniques for higher resolution, genomewide analysis have begun to illuminate the irregular and unpredictable behavior of the human genome. Thus, the origins of neuropsychiatric disorders in particular and complex disease in general have been illuminated. The human genome is characterized by a high degree of structural and behavioral variability: DNA content variation, epistasis, stochasticity in gene expression, and epigenetic changes. These elements have grown more complex as evolution scaled the phylogenetic tree. They are especially pertinent to brain development and function. Genomic variability is a window on the origins of complex disease, neuropsychiatric disorders, and neurodevelopmental disorders in particular. Genomic variability, as it happens, is also the fuel of evolvability. The genomic events that presided over the evolution of the primate and hominid lineages are over-represented in patients with autism and schizophrenia, as well as intellectual disability and epilepsy. That the special qualities of the human genome that drove evolution might, in some way, contribute to neuropsychiatric disorders is a matter of no little interest.

DNA content variation and SNP diversity within a single population of asexual snails

A growing body of research suggests that many clonal populations maintain genetic diversity even without occasional sexual reproduction. The purpose of our study was to document variation in SNP diversity, DNA content, and pathogen susceptibility in clonal lineages of the New Zealand freshwater snail, Potamopyrgus antipodarum. We studied snails that were collected from multiple field sites around a single lake (Lake Alexandrina), as well as isofemale clonal lineages that had been isolated and maintained in the laboratory. We used the KASP method to genotype our samples at 46 nuclear SNP sites, and we used flow cytometry to estimate DNA content. We found high levels of SNP diversity, both in our field samples and in our clonal laboratory lines. We also found evidence of high variation in DNA content among clones, even among clones with identical genotypes across all SNP sites. Controlled pathogen exposures of the laboratory populations revealed variation in susceptibility among distinct clonal genotypes, which was independent of DNA content. Taken together, these results show high levels of diversity among asexual snails, especially for DNA content, and they suggest rapid genome evolution in asexuals.

Nuclear DNA content variation within four species of Asian catfish of family Pangasidae and their two interspecific hybrids by flow cytometry

Nuclear DNA content (NDC) of species or population is believed to have been formed naturally by many mechanisms such chromosomal mutation, insertion and deletion, transposable element, and duplication. Additionally, hybridizations and species’ phylogenetic relationship may also contribute to the NDC diversity. This study was aimed to investigate the profile of NDC in four species Asian catfishes of the genera Pangasius including Pangasionodon hypophthalmus, Pangasius djambal, Pangasius nasusutus, Pangasius nieuwenhuisii, interspecific hybrid of female P. hypophthalmus and male P. djambal (Hybrid HD), and female P. hypophthalmus and male P. nasutus (Hybrid HN). Red blood cells (RBC) were taken from the respective species/groups and NDC measurement was performed in an Attune acoustic flowcytometer (ABI) using DAPI staining and chicken, Gallus domesticus, RBC was used as size reference. The results showed that the mean NDC of P. hypophthalmus, P. djambal. P. nasusutus, P. nieuwenhuisii, were 0.960±0.0254 pg, 1.017±0.0510 pg, 1.000±0.0410 pg, 1.074±0.0231 pg, which are within the range of NDC in the other catfish families The NDC values of Hybrid HD and Hybrid HN were1.005±0.0358 and 0.956± 0.0089, respectively. Among the pure line species, the NDC of P. hypophthalmus was the lowest and was different (P<0.05) from those of P. djambal and P. nieuwenhuisii but was not different (P>0.05) from that of the P. nasutus. The NDC of both Hybrid HD and Hybrid HN were not different form their respective parental lines. However, the NDC profiles of both hybrids were different in that the NDC of the former was in between while the latter was below their respective parental lines. Phylogenetically, the NDC diversity within Pangasiid catfish in this study was independent of their phylogenetic relationship based on cytoplasmic and nuclear markers. Keywords: Flow cytometry, nuclear DNA content, P.hypophthalmus, P. djambal, P. nasutus, P. nieuwenhuisii, interspecific hybrid.