Human genomic disease variants: A neutral evolutionary explanation

Many perspectives on the role of evolution in human health include nonempirical assumptions concerning the adaptive evolutionary origins of human diseases. Evolutionary analyses of the increasing wealth of clinical and population genomic data have begun to challenge these presumptions. In order to systematically evaluate such claims, the time has come to build a common framework for an empirical and intellectual unification of evolution and modern medicine. We review the emerging evidence and provide a supporting conceptual framework that establishes the classical neutral theory of molecular evolution (NTME) as the basis for evaluating disease- associated genomic variations in health and medicine. For over a decade, the NTME has already explained the origins and distribution of variants implicated in diseases and has illuminated the power of evolutionary thinking in genomic medicine. We suggest that a majority of disease variants in modern populations will have neutral evolutionary origins (previously neutral), with a relatively smaller fraction exhibiting adaptive evolutionary origins (previously adaptive). This pattern is expected to hold true for common as well as rare disease variants. Ultimately, a neutral evolutionary perspective will provide medicine with an informative and actionable framework that enables objective clinical assessment beyond convenient tendencies to invoke past adaptive events in human history as a root cause of human disease.

• Publication year

  2012

• Venue

  Genome Research

• Publication date

  2012-06-04

• Fields of study

  Biology, Medicine, Philosophy

• Identifiers
  DOI 10.1101/gr.133702.111PMID 22665443PMCID 3409252
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Computational Molecular Evolution

  2013cited by this paper
• Evolutionary meta-analysis of association studies reveals ancient constraints affecting disease marker discovery.

  2012cited by this paper
• Rare and common variants: twenty arguments

  2012cited by this paper
• A Systematic Survey of Loss-of-Function Variants in Human Protein-Coding Genes

  2012influential reference
• Genome-wide Association Studies

  2012cited by this paper
• Crohn's disease risk alleles on the NOD2 locus have been maintained by natural selection on standing variation.

  2012cited by this paper
• Demographic history and rare allele sharing among human populations

  2011influential reference
• Improving the assessment of the outcome of nonsynonymous SNVs with a consensus deleteriousness score, Condel.

  2011cited by this paper
• The functional spectrum of low-frequency coding variation

  2011influential reference
• Ranking insertion, deletion and nonsense mutations based on their effect on genetic information

  2011cited by this paper
• Coalescence-Time Distributions in a Serial Founder Model of Human Evolutionary History

  2011cited by this paper
• Natural Selection Affects Multiple Aspects of Genetic Variation at Putatively Neutral Sites across the Human Genome

  2011influential reference
• Phylomedicine: an evolutionary telescope to explore and diagnose the universe of disease mutations.

  2011influential reference
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  2011cited by this paper
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• Clan genomics and the complex architecture of human disease.

  2011cited by this paper
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  2011cited by this paper
• Classic Selective Sweeps Were Rare in Recent Human Evolution

  2011influential reference
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  2010influential reference
• Ancestry and disease in the age of genomic medicine.

  2010cited by this paper
• Faculty Opinions recommendation of Colloquium paper: human adaptations to diet, subsistence, and ecoregion are due to subtle shifts in allele frequency.

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• The UCSC Genome Browser database: update 2011

  2010cited by this paper
• Human adaptations to diet, subsistence, and ecoregion are due to subtle shifts in allele frequency

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• Single-nucleotide evolutionary constraint scores highlight disease-causing mutations

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• A method and server for predicting damaging missense mutations

  2010cited by this paper
• Single-molecule sequencing: sequence methods to enable accurate quantitation.

  2010cited by this paper
• Genetic architecture of a complex trait and its implications for fitness and genome-wide association studies

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  2010cited by this paper
• Positive selection drives population differentiation in the skeletal genes in modern humans.

  2010cited by this paper
• Evolutionary perspectives on health and medicine

  2010influential reference
• The neutral theory of molecular evolution in the genomic era.

  2010influential reference
• The (non)malignancy of cancerous amino acidic substitutions

  2010cited by this paper
• Rare Variants Create Synthetic Genome-Wide Associations

  2010cited by this paper
• Somatic gene mutation and human disease other than cancer: an update.

  2010cited by this paper
• Clinical assessment incorporating a personal genome.

  2010cited by this paper
• Making evolutionary biology a basic science for medicine

  2010cited by this paper
• Identification of deleterious mutations within three human genomes.

  2009cited by this paper
• Genetic Variation and Recent Positive Selection in Worldwide Human Populations: Evidence from Nearly 1 Million SNPs

  2009cited by this paper
• MtSNPscore: a combined evidence approach for assessing cumulative impact of mitochondrial variations in disease

  2009cited by this paper
• Genetics and the understanding of selection

  2009cited by this paper
• Next generation tools for the annotation of human SNPs

  2009cited by this paper
• Estimating the rate of adaptive molecular evolution in the presence of slightly deleterious mutations and population size change.

  2009cited by this paper
• Single-molecule sequencing of an individual human genome

  2009influential reference
• Evolution of a malaria resistance gene in wild primates

  2009cited by this paper
• Spatial patterns of variation due to natural selection in humans

  2009cited by this paper
• Signals of recent positive selection in a worldwide sample of human populations.

  2009cited by this paper
• Positional conservation and amino acids shape the correct diagnosis and population frequencies of benign and damaging personal amino acid mutations.

  2009influential reference
• Detecting ancient admixture and estimating demographic parameters in multiple human populations.

  2009cited by this paper
• Sequence and Structure Signatures of Cancer Mutation Hotspots in Protein Kinases

  2009cited by this paper
• Potential etiologic and functional implications of genome-wide association loci for human diseases and traits

  2009cited by this paper
• Similarly Strong Purifying Selection Acts on Human Disease Genes of All Evolutionary Ages

  2009cited by this paper
• The Role of Geography in Human Adaptation

  2009cited by this paper
• Darwinian and demographic forces affecting human protein coding genes.

  2009cited by this paper
• 20 years of human mtDNA pathologic point mutations: carefully reading the pathogenicity criteria.

  2009cited by this paper
• Large Allele Frequency Differences between Human Continental Groups are more Likely to have Occurred by Drift During range Expansions than by Selection

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• Targeted Capture and Massively Parallel Sequencing of Twelve Human Exomes

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• Evolution of the human lifespan and diseases of aging: Roles of infection, inflammation, and nutrition

  2009cited by this paper
• Genome-wide association studies: what do they teach us about asthma and chronic obstructive pulmonary disease?

  2009cited by this paper
• The Human Gene Mutation Database: providing a comprehensive central mutation database for molecular diagnostics and personalised genomics

  2009cited by this paper
• Decanalization and the origin of complex disease

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• The UCSC Genome Browser database: update 2010

  2009cited by this paper
• Finding the missing heritability of complex diseases

  2009influential reference
• Cancer‐associated mutations are preferentially distributed in protein kinase functional sites

  2009cited by this paper
• Faculty Opinions recommendation of Targeted capture and massively parallel sequencing of 12 human exomes.

  2009cited by this paper
• Adaptive evolution of young gene duplicates in mammals.

  2009cited by this paper
• Evolution in Health and Disease

  2008cited by this paper
• The diploid genome sequence of an Asian individual

  2008cited by this paper
• The Catalogue of Somatic Mutations in Cancer (COSMIC)

  2008cited by this paper
• The complete genome of an individual by massively parallel DNA sequencing

  2008cited by this paper
• Proportionally more deleterious genetic variation in European than in African populations

  2008influential reference
• Assessing the Evolutionary Impact of Amino Acid Mutations in the Human Genome

  2008influential reference
• Evolutionary origins of the obesity epidemic: natural selection of thrifty genes or genetic drift following predation release?

  2008cited by this paper
• A Catalog of Neutral and Deleterious Polymorphism in Yeast

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• Thrifty genes for obesity, an attractive but flawed idea, and an alternative perspective: the ‘drifty gene’ hypothesis

  2008cited by this paper
• Molecular Evolution and Phylogenetics

  2008cited by this paper
• Natural selection on genes that underlie human disease susceptibility.

  2008influential reference
• Worldwide population differentiation at disease-associated SNPs

  2008cited by this paper
• Divergence and Polymorphism Under the Nearly Neutral Theory of Molecular Evolution

  2008cited by this paper
• Genome-wide association studies: potential next steps on a genetic journey.

  2008cited by this paper
• African genetic diversity: implications for human demographic history, modern human origins, and complex disease mapping.

  2008cited by this paper
• International Seminars in Surgical Oncology Angiopoietins Lack of Prognostic Significance in Ductal Mammary Carcinoma Background

  2007cited by this paper
• Recent human effective population size estimated from linkage disequilibrium.

  2007cited by this paper
• A Practical Genome Scan for Population-Specific Strong Selective Sweeps That Have Reached Fixation

  2007influential reference
• Localizing Recent Adaptive Evolution in the Human Genome

  2007cited by this paper
• The frailty of adaptive hypotheses for the origins of organismal complexity

  2007influential reference
• Distinguishing cancer-associated missense mutations from common polymorphisms.

  2007cited by this paper

• Uncovering genetic variation in humoral inborn errors of immunity in African populations: insights from the African genome variation database.

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• Nutrigenomics and redox regulation: Concepts relating to the Special Issue on nutrigenomics

  2023cites this paper
• Balancing selection on genomic deletion polymorphisms in humans

  2022cites this paper
• Regionally enriched rare deleterious exonic variants in the UK and Ireland

  2022cites this paper
• Genome-wide analysis of schizophrenia and multiple sclerosis identifies shared genomic loci with mixed direction of effects.

  2022cites this paper
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• Pregnancy as a Factor of Adaptive Human Evolution. The Role of Natural Selection in the Origin of Preeclampsia

  2021cites this paper
• Hypothetical novel simulations to explain the evolutionary survival of the hypo-reproductive extreme tail in the complex human diversity

  2021cites this paper
• Somatic selection distinguishes oncogenes and tumor suppressor genes

  2019cites this paper
• Genome-wide analysis indicates association between heterozygote advantage and healthy aging in humans

  2019cites this paper
• Genome-Wide Association Studies (GWAS)

  2019cites this paper
• Developmental social vulnerability as the intrinsic origin of psychopathology: A paradigm shift from disease entities to psychiatric derivatives within human diversity.

  2019cites this paper
• Bayesian estimation of genetic regulatory effects in high-throughput reporter assays

  2019cites this paper
• Dysfunction, Disease, and the Limits of Selection

  2018cites this paper
• Neutral Theory, Disease Mutations, and Personal Exomes

  2018cites this paper
• The origin of human complex diversity : Stochastic epistatic modules and the intrinsic compatibility between distributional robustness and phenotypic changeability

  2018cites this paper
• γ2 GABAAR Trafficking and the Consequences of Human Genetic Variation

  2018cites this paper
• The origin of complex human diversity: Stochastic epistatic modules and the intrinsic compatibility between distributional robustness and phenotypic changeability

  2018cites this paper
• Next-generation sequencing analyses in human disease and population genomics

  2018cites this paper
• Dysfunction, Disease, and the Limits of Selection

  2017cites this paper
• Properties of human disease genes and the role of genes linked to Mendelian disorders in complex disease aetiology

  2017cites this paper
• De novo mutational profile in RB1 clarified using a mutation rate modeling algorithm

  2017cites this paper
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  2017cites this paper
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  2017cites this paper
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  2017cites this paper
• Protein Conformational Dynamics In Genomic Analysis

  2016cites this paper
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  2016cites this paper
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  2016cites this paper
• Evolution‐informed modeling improves outcome prediction for cancers

  2016cites this paper
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  2016cites this paper
• Understanding rare and common diseases in the context of human evolution

  2016cites this paper
• Atlas of human diseases influenced by genetic variants with extreme allele frequency differences

  2016cites this paper
• A Molecular Evolutionary Reference for the Human Variome.

  2016cites this paper
• Evolution of Obesity

  2015cites this paper
• [Blood groups - minuses and pluses. Do the blood group antigens protect us from infectious diseases?].

  2015cites this paper
• Using Disease-Associated Coding Sequence Variation to Investigate Functional Compensation by Human Paralogous Proteins

  2015cites this paper
• Conformational dynamics of nonsynonymous variants at protein interfaces reveals disease association

  2015cites this paper
• PaPI: pseudo amino acid composition to score human protein-coding variants

  2015cites this paper
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  2015cites this paper
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• Disease consequences of human adaptation

  2013cites this paper
• Evolutionary perspectives on the obesity epidemic: adaptive, maladaptive, and neutral viewpoints.

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• A phylomedicine approach to understanding the evolution of auditory sensory perception and disease in mammals

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  2012cites this paper