The plasticity of the genome complicates genetic causation, but should be investigated from a functional perspective. Specific adaptive hypotheses are referenced in the target article, but it is also necessary to explain how the integrity of the genome is maintained despite processes that tend towards its diversification and degradation. These include the accumulation of deleterious changes and intra-genomic conflict

Benjamin J. A. Dickins

Hastings

Dickins, BJA

Nottingham Trent Institutional Repository (IRep)

Behavioral and Brain Sciences Is genomics bad for you?--Manuscript Draft-- Manuscript Number:Full Title: Is genomics bad for you?Short Title: Commentary on CharneyArticle Type: Commentary ArticleCorresponding Author: Benjamin Dickins, Ph.D.Penn State UniversityUNITED STATESCorresponding Author SecondaryInformation:Corresponding Author's Institution: Penn State UniversityCorresponding Author's SecondaryInstitution:First Author: Benjamin Dickins, Ph.D.First Author Secondary Information:Order of Authors: Benjamin Dickins, Ph.D.Order of Authors Secondary Information:Abstract: The plasticity of the genome complicates genetic causation, but should be investigatedfrom a functional perspective. Specific adaptive hypotheses are referenced in thetarget article, but it is also necessary to explain how the integrity of the genome ismaintained despite processes that tend towards its diversification and degradation.These include the accumulation of deleterious changes and intra-genomic conflict.Powered by Editorial Manager® and Preprint Manager® from Aries Systems Corporation1. Evan Charney 2. Abstract: 59; Main text: 995; References: 723; Entire document: 1833 3. Is genomics bad for you? 4. Benjamin JA Dickins 5. The Pennsylvania State University 6. Biology Department, 302 Wartik Laboratory, University Park, PA 16802, USA 7. +1 814 863 2185 8. ben@bx.psu.edu 9. http://www.bendickins.com/  10: Abstract The plasticity of the genome complicates genetic causation, but should be investigated from a functional perspective. Specific adaptive hypotheses are referenced in the target article, but it is also necessary to explain how the integrity of the genome is maintained despite processes that tend towards its diversification and degradation. These include the accumulation of deleterious changes and intra-genomic conflict.  11. Main text Most of the phenomena Charney terms “neo-genetic” entail changes to the genetic substrate and are therefore classifiable as kinds of mutation. Epigenetic marks differ because they influence gene expression, not sequence. Somatic mutations during development can lead to genetic mosaicism while epigenetic modifications presumably underlie cellular differentiation (Ng and Gurdon, 2008). Mutations in the germline can lead to non-Mendelian inheritance of portions of the genome (reviewed in Burt and Trivers, 2006), while epigenetic changes can create unusual patterns of expression such as polar overdominance (Cockett et al., 1996). Charney argues that these peculiarities undermine genotype to phenotype maps implicit in the statistical frameworks of behavior genetics. Rather than venture criticism, I here expand on the theoretical challenge presented by one aspect of mutation, simply that of its ubiquity.  Mutations can be understood as products either of necessity or chance. Charney sʼ emphasis on adaptive phenotypic plasticity is apposite. To the extent that mutations are functional they are instances of adaptedness per se, rather than drivers of adaptation (for an explanation of this perspective see Dickins and Dickins, 2008). Charney also describes well the manner in which adventitious changes are harnessed through somatic hypermutation in the immune system. But he says “stochasticity continually threatens to undermine the order imposed by biological systems”. This is surely so: severe and multifarious mutations affecting the genome within lineages (at least some of which are associated with behavioural dysfunction: e.g., Stewart et al., 2011) would seem to threaten extinction. How, for example, does a brain maintain its function or a population of organisms preserve its genomic integrity, despite frequent aneuploidy?  Let us consider only “conventional” mutations, viz. single nucleotide changes or Commentary ArticleClick here to download Commentary Article: DickinscommentaryonCharneyfinal.rtf indels (insertions and deletions), of the kind that can be associated with Mendelian disorders. Many such mutations are deleterious, and even mildly deleterious mutations can lead to extinction when they accumulate under the influence of genetic drift (Muller, 1964). Even assuming an infinite population size, mutation accumulation can lead to population extinction with a probability that depends not on the average effect size of mutations but upon their rate of occurrence and on the intrinsic fecundity of individuals (Bull et al., 2007). Humans have slow life histories (Robson and Wood, 2008), a low effective population size (Yu et al., 2004) and a relatively high mutation rate (Kondrashov, 2003; Lynch, 2010) although they benefit from recombination. Given the proportion of de novo mutations expected to be deleterious, and with advances in medical care that plausibly entail a relaxation of negative selection, these parameters have led to concerns about population fitness in the medium term (Lynch, 2010; but see Keightley, 2012). Low frequency alleles with relatively large effect sizes may also underlie at least some of the missing heritability in genome wide association studies (Manolio et al., 2009), thereby contributing to the burden of disease at this time.  The reduction in the mean fitness of a population caused by mutations (the mutation load) is attenuated when the fitness of an individual depends on others around it; this is so-called soft selection (Wallace, 1975). Alternatively germline viability selection can expurgate deleterious alleles, an observation made plausible in humans by the seemingly high rate of “occult” pregnancies (Edmonds et al., 1982), with many aborted concepti manifesting aneuploidies (Macklon et al., 2002). The occurrence of mitotic and meiotic cell divisions in the germline of “sexual” species has significant population genetic consequences (Hastings, 1991). For example, when germline selection is soft this can favour the evolution of “anti-robustness” in which genotypes readily suffer reduced fitness when mutated (Archetti, 2009). Anti-robust genotypes are also expected in regenerative tissues for theoretical reasons (Krakauer and Plotkin, 2002) paradoxically contributing to robustness at the level of the organism.  Emerging evidence supports purifying selection in the mammalian mitochondrial genome (Fan et al., 2008; Stewart et al., 2008), which is probably facilitated by a germline bottleneck in copy number. We are beginning to understand how cell lineages behave in mammalian oogenesis (Reizel et al., 2012), but important details are unresolved. In the male germline, recent evidence suggests positive selection for specific genetic disorders (Goriely et al., 2003; Choi et al., 2012). One response to these preliminary data is to conceive of ‘disease’ as an outcome of a breakdown in the regulation and control of deleterious mutations. Focussing on the regulation of mitochondrial function one colourful review elaborates such a “quality-control” perspective (Braschi and McBride, 2010). Although Charney suggests that transposon activation in the brain might be positively associated with neural plasticity and flexibility, it may prove necessary to consider how neural networks buffer themselves from the deleterious effects of mutations or even how behaviour itself might modulate mutational effects.  Some of the phenomena Charney describes might threaten stability, not because of their passive accumulation, but because they are selected for independently of their effect on the rest of the genome. For example transposons active in the germline increase their contribution to posterity by over-replication, but can damage genes if they “jump” close by or into them. When intragenomic conflict occurs, and a component of the genome acts against the wider coalition, the evolution of repressors is favoured by natural selection (Burt and Trivers, 2006). Aspects of meiosis such as reduction division and recombination may have evolved to restrain selfish genetic elements.  Many forms of epigenetic regulation were revealed during research into genomic imprinting. Imprinted gene expression can be explained by conflict between paternally and maternally derived alleles within offspring (Haig and Westoby, 1989) or as a consequence of maternal-foetal co-adaptation (Keverne and Curly, 2008). From the conflict perspective imprinted gene expression does not benefit the organism, but potentially creates problems in the event of epigenetic dsyregulation or mutation (due to haploinsufficiency at the expressing allele). Aberrant patterns of imprinted gene expression are implicated in intrauterine growth restriction (Tycko, 2006), but recent screens (reviewed in Kelsey, 2011) have suggested abundant imprinted expression in the brain. Trivers (2000) has also outlined ways in which intragenomic conflict can manifest itself in the behaviour of individuals.  12. References Archetti M. (2009) "Survival of the steepest: hypersensitivity to mutations as an adaptation to soft selection." Journal of Evolutionary Biology 22(4): 740-50  Braschi E, McBride HM. (2010) "Mitochondria and the culture of the Borg: understanding the integration of mitochondrial function within the reticulum, the cell, and the organism." Bioessays 32(11): 958-66  Bull JJ, Sanjuán R, Wilke CO. (2007) "Theory of lethal mutagenesis for viruses." Journal of Virology 81(6): 2930-9  Burt A and Trivers RL. (2006) "Genes in Conflict: The Biology of Selfish Genetic Elements". The Belknap Press.  Choi SK, Yoon SR, Calabrese P, Arnheim N. (2012) "Positive Selection for New Disease Mutations in the Human Germline: Evidence from the Heritable Cancer Syndrome Multiple Endocrine Neoplasia Type 2B." PLoS Genetics 8(2): e1002420  Cockett NE, Jackson SP, Shay TL, Farnir F, Berghmans S, Snowder GD, Nielsen DM,  Dickins TE and Dickins BJA. (2008) "Mother nature's tolerant ways: why non-genetic inheritance has nothing to do with evolution." New Ideas in Psychology 26: 41-54  Edmonds DK, Lindsay KS, Miller JF, Williamson E, Wood PJ. (1982) "Early embryonic mortality in women." Fertility and Sterility 38: 447-53  Fan W, Waymire KG, Narula N, Li P, Rocher C, Coskun PE, Vannan MA, Narula J, Macgregor GR, Wallace DC. (2008) "A mouse model of mitochondrial disease reveals germline selection against severe mtDNA mutations." Science 319(5865): 958-62  Georges M. (1996) "Polar overdominance at the ovine callipyge locus." Science 273(5272): 236-8  Goriely A, McVean GA, Röjmyr M, Ingemarsson B, Wilkie AO. (2003) "Evidence for selective advantage of pathogenic FGFR2 mutations in the male germ line." Science 301(5633): 643-6  Haig, D. and Westoby, M. (1989) "Parent-Specific Gene Expression and the Triploid Endosperm." American Naturalist 134: 147-55  Hastings IM. (1991) "Germline selection: population genetic aspects of the sexual/asexual life cycle." Genetics 129(4): 1167-76  Keightley PD. (2012) "Rates and fitness consequences of new mutations in humans." Genetics 190(2): 295-304  Kelsey G. (2011) “Epigenetics and the brain: transcriptome sequencing reveals new depths to genomic imprinting.” Bioessays 33(5): 362-7  Keverne EB, Curley JP. (2008) “Epigenetics, brain evolution and behaviour.” Frontiers in Neuroendocrinology 29(3): 398-412  Kondrashov AS. (2003) "Direct estimates of human per nucleotide mutation rates at 20 loci causing Mendelian diseases." Human mutation 21(1): 12-27  Krakauer DC, Plotkin JB. (2002) "Redundancy, antiredundancy, and the robustness of genomes." Proceedings of the National Academy of the United States of America 99(3): 1405-9  Lynch L. (2010) "Rate, molecular spectrum, and consequences of human mutation." Proceedings of the National Academy of the United States of America 107(3): 961-8  Macklon NS, Geraedts JP, Fauser BC. (2002) "Conception to ongoing pregnancy: the 'black box' of early pregnancy loss." Human Reproduction Update 8(4): 333-43  Manolio TA, Collins FS, Cox NJ, Goldstein DB, Hindorff LA, Hunter DJ, McCarthy MI, Ramos EM, Cardon LR, Chakravarti A, Cho JH, Guttmacher AE, Kong A, Kruglyak L, Mardis E, Rotimi CN, Slatkin M, Valle D, Whittemore AS, Boehnke M, Clark AG, Eichler EE, Gibson G, Haines JL, Mackay TF, McCarroll SA, Visscher PM. (2009) "Finding the missing heritability of complex diseases." Nature 461(7265): 747-53  Muller HJ. (1964) "The relation of recombination to mutational advance." Mutation Research 1: 2-9  Ng RK and Gurdon JB. (2008) "Epigenetic inheritance of cell differentiation status." Cell Cycle 7(9): 1173-7  Reizel Y, Itzkovitz S, Adar R, Elbaz J, Jinich A, Chapal-Ilani N, Maruvka YE,  Nevo N, Marx Z, Horovitz I, Wasserstrom A, Mayo A, Shur I, Benayahu D, Skorecki K, Segal E, Dekel N, Shapiro E. (2012) "Cell lineage analysis of the Mammalian female germline." PLoS Genetics 8(2): e1002477  Robson SL and Wood B. (2008) "Hominin life history: reconstruction and evolution." Journal of Anatomy 212: 394-425  Stewart JB, Freyer C, Elson JL, Wredenberg A, Cansu Z, Trifunovic A, Larsson NG. (2008) "Strong purifying selection in transmission of mammalian mitochondrial DNA." PLoS Biology 6(1): e10  Stewart LR, Hall AL, Kang S-H L, Shaw CA, Beaudet AL. (2011) "High frequency of known copy number abnormalities and maternal duplication 15q11-q13 in patients with combined schizophrenia and epilepsy." BMC Medical Genetics 12: 154  Trivers R. (2000) “The elements of a scientific theory of self-deception.” Annals of the New York Academy of Sciences 907: 114-31  Tycko B. (2006) “Imprinted genes in placental growth and obstetric disorders.” Cytogenetic and Genome Research 113(1-4): 271-8  Wallace B. (1975) "Hard and soft selection revisited." Evolution 29: 465-73  Yu N, Jensen-Seaman MI, Chemnick L, Ryder O, Li W-H. (2004) "Nucleotide diversity in gorillas." Genetics 166: 1375-83 

[Open peer commentary] Is genomics bad for you?

AbstractThe plasticity of the genome complicates genetic causation but should be investigated from a functional perspective. Specific adaptive hypotheses are referenced in the target article, but it is also necessary to explain how the integrity of the genome is maintained despite processes that tend towards its diversification and degradation. These include the accumulation of deleterious changes and intragenomic conflict.</jats:p

Crossref

Behavioral and Brain Sciences

Is genomics bad for you?

http://irep.ntu.ac.uk/id/eprint/7852/1/4367_Dickins.pdf

[Open peer commentary] Is genomics bad for you?

Abstract

Similar works

Full text

Available Versions

Nottingham Trent Institutional Repository (IRep)

Crossref