Genetics as Explanation: Limits to the Human Genome Project

Abstract

Living organisms are composed of cells and all living cells contain a genome, the organism's stock of deoxyribonucleic acid (DNA). The role of the genome has been likened to a computer program that encodes the organism's development and its subsequent response to the environment. Thus, the organism and its fate can be explained by genetics, the plans written into the sequence of genomic DNA; the Human Genome Project was devised to decipher this program. However, it is now clear that the genome does not directly program the organism; the computer program metaphor has misled us. The genome is only one class of vital information that serves the organism. Indeed, we now know that the healthy individual human is an ecosystem that lives in symbiosis with hundreds of different species of bacteria – the microbiota. Metaphorically, the genome can be likened to a toolbox for accomplishing specific tasks.

Key Concepts

  • The genome does not function as a master plan or computer program for controlling the organism; the genome is the organism's servant, not its master.
  • The genome is a reservoir of DNA sequence information and a vehicle for transmitting this information; the meaning of DNA emerges from the cellular processing of this raw information into proteins and other functional molecules.
  • Complex organisms like humans live in symbiosis with a microbiota of many hundreds of micro‐organisms. The microbiota are essential to human health and the phenotype of the individual is greatly influenced by interactions with the microbiota. The body houses manyfold more DNA of microbial origin than it does the genomic DNA inherited from the parents. The individual is thus an ecosystem of diverse cellular origins.
  • DNA is only one class of vital information that serves the organism; the organism epigenetically uses, manipulates, regulates and, in the case of the immune system, creates genes.
  • The effects of a gene vary with the organism's environment; the interactions between genes and environment are not linear and, in most cases, not additive. Therefore, one cannot compute with certainty the relative contributions of genes and environment to an organism's observed features – its phenotype.
  • Metaphorically, we can think of the genome as akin to a list of words, a vocabulary, which can be used to build and express a meaningful language; like a vocabulary, a genome by itself has no functional meaning.
  • The genome is thus akin to a toolbox of DNA sequences that provide molecular tools as requested by the internal state of the organism and the state of the environment.
  • One's genes cannot explain one's being: an organism is the expression of a dynamic and ongoing interaction between the state of its environment and its internal state, which includes its past history and its toolbox of DNA sequences.

Keywords: genetics; computer program; evolution; information; complexity symbiosis

Figure 1. Genomic DNA has been viewed as a master program. According to this metaphor, the cell's DNA is considered to function like the brain of the cell; the DNA is likened to a computer program that sends orders to the hardware – the cells, organs, body and species that bear the genome and its variants. The cellular hardware performs services as ordered by the program to effect DNA replication, cell division, growth, differentiation, development, hereditary transmission and other vital functions; these in total give rise to the phenotype of the organism. The phenotype through natural selection and heredity leads to evolution of the DNA program (arrows).
Figure 2. The individual is a holobiont that includes eukaryote cells bearing genomic DNA inherited from its parents along with myriads of symbiotic microbial cells. The species of microbial cells in the microbiota bear diverse genomes; the individual phenotype is thus the expression of multiple genotypes. In addition, the individual contains a brain and an immune system that develop beyond their initial genomic information.
Figure 3. Embryonic stem cells express more segments of genomic DNA than their differentiated offspring cells do. The figure depicts the relative degree of DNA expression as the height of the vertical lines along the strand of DNA encoding the Gpi1 gene on chromosome 7 of the mouse in embryonic stem cells (ESC; upper red) and in significantly more differentiated neuronal precursor cells (NPC; lower green). It is clear that the Gpi1 locus (delineated at the bottom of the figure) is expressed to a greater degree in the ESC than in the NPC. The product of the Gpi1 gene is expressed in many blood cells and is involved in the synthesis of a glycolipid that serves to anchor proteins to the cell surface. The specific panels in the figure are part of a genome‐wide assay of gene expression using microarrays that tile the entire mouse genome.Reproduced from Efroni et al. 2008 © Elsevier.
Figure 4. The relationship between DNA, RNA and proteins, the expressed products of genomic DNA, is circular. It takes DNA and RNA to produce proteins, but it takes RNA and proteins to make genes. The circular relationship is an ongoing process strongly influence by ncRNA, symbiotic microbiota and environment. The structures and behaviours generated by the process are the meaning of the process (see the text).
Figure 5. The genome is a toolbox. The genome is envisioned as a box of DNA sequence tools that are materialised into proteins and RNA regulatory signals by expressing open reading frames, splice variants and so forth. These various expressions of DNA tools are services made in response to requests generated by the internal state of the organism and by the state of the environment. The proteins and other service molecules made using the DNA tools affect cell and body structure, cell division, growth, differentiation and other organismal functions that together generate the organism's phenotype – its observed characteristics. In contrast to the genome viewed as master program (Figure), the output of the genome generates the input that submits requests to the genome toolbox: the internal state of the organism's phenotype together with the state of the environment feeds back to generate requests to the genome toolbox. In other words, there is no master program a priori; the genome is an element in an ongoing circular loop (Figure). The phenotype, through the processes of natural selection and heredity, generates the evolution of the toolbox.
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Reference

Efroni S, Duttagupta R, Cheng J, et al. (2008) Global transcription in pluripotent embryonic stem cells. Cell Stem Cell 2: 437–447.

Further Reading

Atlan H (1987) Self‐creation of meaning. Physica Scripta 36: 563–576.

Atlan H and Koppel M (1990) The cellular computer DNA: program or data? Bulletin of Mathematical Biology 52: 3335–3348.

Atlan H (2001) Epigenesis and self‐organization: new perspectives in biology and medicine. In: Compendium A, Solomon B, Taraboulos A and Katchalski‐Katsir E (eds) Conformational Diseases, pp. 291–297. Basel: The Center for the Study of Emerging Diseases, Bialik Institute Jerusalem and Karger.

Belizário JE and Napolitano M (2015) Human microbiomes and their roles in dysbiosis, common diseases, and novel therapeutic approaches. Frontiers in Microbiology 6: 1050.

Cohen IR (2000) Tending Adam's Garden: Evolving the Cognitive Immune Self. San Diego, CA: Academic Press.

Cohen IR (2006) Informational landscapes in art, science, and evolution. Bulletin of Mathematical Biology 68: 1213–1229.

Cohen IR and Harel D (2007) Explaining a complex living system: dynamics, multi‐scaling and emergence. Journal of the Royal Society, Interface/the Royal Society 4: 175–182.

Efroni S, Harel D and Cohen IR (2005) A theory for complex systems: reactive animation. In: Paton R and McNamara L (eds) Multidisciplinary Approaches to Theory in Medicine: Studies in Multidisciplinarity, vol. 3, pp. 309–324. Amsterdam: Elsevier.

Efroni S, Duttagupta R, Cheng J, et al. (2008) Global transcription in pluripotent embryonic stem cells. Cell Stem Cell 2: 437–447.

Zilber‐Rosenberg I and Rosenberg E (2008) Role of microorganisms in the evolution of animals and plants: the hologenome theory of evolution. FEMS Microbiology Reviews 32 (5): 723–735.

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Cohen, Irun R, Atlan, Henri, and Efroni, Sol(Nov 2016) Genetics as Explanation: Limits to the Human Genome Project. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0005881.pub3]