Genomic Instability Evolutionary Footprints on Human Health: Driving Forces or Side Effects?

Abstract

In this work, we propose a comprehensive perspective on genomic instability comprising not only the accumulation of mutations but also telomeric shortening, epigenetic alterations and other mechanisms that could contribute to genomic information conservation or corruption. First, we present mechanisms playing a role in genomic instability across the kingdoms of life. Then, we explore the impact of genomic instability on the human being across its evolutionary history and on present-day human health, with a particular focus on aging and complex disorders. Finally, we discuss the role of non-coding RNAs, highlighting future approaches for a better living and an expanded healthy lifespan.

Keywords: DNA repair; aging; evolutionary genetics; genomic instability; human complex disorder; ncRNA; neurodegenerative diseases.

Figure 1

Sources contributing to genomic instability. ncRNA = non-coding RNA; TE = transposable element. This figure was generated using BioRender.

Figure 2

Common DNA damaging agents, types of genomic scars caused by different damage sources, and damage repair mechanisms. BER = base-excision repair; FA = Fanconi anaemia; HR = homologous recombination; MMR = mismatch repair; NER = nucleotide excision repair; NHEJ = nonhomologous end-joining; PAH = polycyclic aromatic hydrocarbons, ROS = reactive oxygen species; SSBR = single-strand break repair; UV = ultra-violet. This figure was generated using BioRender.

Figure 3

Schematic representation of the evolution of repair systems across the tree of life from the last universal common ancestor (LUCA) to today’s domains of life. Vertical branches indicate possible horizontal transfer of genes involved in the repair mechanisms.

Figure 4

Nuclear and mitochondrial DNA repair mechanisms. BER: Base Excision Repair; DSBR: Double Strand Break Repair; MMR: Mismatch Repair; NER: Nucleotide Excision Repair; SSBR: Single Strand Break Repair; N: Nucleus/Nuclear; M: Mitochondrion/Mitochondrial. This figure was generated using BioRender.

Figure 5

(A) Timeline of the activities of the primary transposable elements which had a fundamental role in the evolution of present-day humans. (B) Main transposable elements in the human genome reported in chronological order of activity. Genome = the percentage of human genome identified as TE type; Pathways = pathways in which TEs have been shown to play a role; Diseases = diseases in which TEs have been reported to be implicated. HERVs = Human Endogenous Retroviruses; L1 = Long Interspersed Nuclear Elements 1; LTR = Long Terminal Repeats; Myr = millions of years; SVA = SINE-R-VNTR-Alu. This figure was generated using BioRender.

Figure 6

Graphical representation of social dynamics changes that had repercussions on the populations genetic level. In the past, people lived in isolated groups composed of a small number of individuals (ancient society), and only recently have people started gathering in larger cities (modern society). The modern ability to prevent the impact of selective pressures determined the maintenance of variants that in a natural setup would have been filtered out, thus possibly causing late-onset diseases.