Genetics of autoimmune diseases: insights from population genetics

Human genetic diversity is the result of population genetic forces. This genetic variation influences disease risk and contributes to health disparities. Autoimmune diseases (ADs) are a family of complex heterogeneous disorders with similar underlying mechanisms characterized by immune responses against self. Collectively, ADs are common, exhibit gender and ethnic disparities, and increasing incidence. As natural selection is an important influence on human genetic variation, and immune function genes are enriched for signals of positive selection, it is thought that the prevalence of AD risk alleles seen in different population is partially the result of differing selective pressures (for example, due to pathogens). With the advent of high-throughput technologies, new analytical methodologies and large-scale projects, evidence for the role of natural selection in contributing to the heritable component of ADs keeps growing. This review summarizes the genetic regions associated with susceptibility to different ADs and concomitant evidence for selection, including known agents of selection exerting selective pressure in these regions. Examples of specific adaptive variants with phenotypic effects are included as an evidence of natural selection increasing AD susceptibility. Many of the complexities of gene effects in different ADs can be explained by population genetics phenomena. Integrating AD susceptibility studies with population genetics to investigate how natural selection has contributed to genetic variation that influences disease risk will help to identify functional variants and elucidate biological mechanisms. As such, the study of population genetics in human population holds untapped potential for elucidating the genetic causes of human disease and more rapidly focusing to personalized medicine.

[1]  Anna Ramírez-Soriano,et al.  Evolutionary dynamics of the human ABO gene , 2008, Human Genetics.

[2]  M. Oosting,et al.  Evolutionary and Functional Analysis of Celiac Risk Loci Reveals SH 2 B 3 as a Protective Factor against Bacterial Infection , 2010 .

[3]  Pardis C Sabeti,et al.  Natural Selection in a Bangladeshi Population from the Cholera-Endemic Ganges River Delta , 2013, Science Translational Medicine.

[4]  Glinda S Cooper,et al.  Recent insights in the epidemiology of autoimmune diseases: improved prevalence estimates and understanding of clustering of diseases. , 2009, Journal of autoimmunity.

[5]  J. Pritchard,et al.  A Map of Recent Positive Selection in the Human Genome , 2006, PLoS biology.

[6]  M. Bockarie,et al.  A human complement receptor 1 polymorphism that reduces Plasmodium falciparum rosetting confers protection against severe malaria , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[7]  J. Engelken,et al.  Evolutionary and functional evidence for positive selection at the human CD5 immune receptor gene. , 2012, Molecular biology and evolution.

[8]  S. Normark,et al.  Attachment of Helicobacter pylori to human gastric epithelium mediated by blood group antigens. , 1993, Science.

[9]  David B. Witonsky,et al.  CYP3A variation and the evolution of salt-sensitivity variants. , 2004, American journal of human genetics.

[10]  A. Rienzo Population genetics models of common diseases , 2006 .

[11]  P. Hedrick,et al.  Strong balancing selection at HLA loci: evidence from segregation in South Amerindian families. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[12]  M. Feldman,et al.  Worldwide Human Relationships Inferred from Genome-Wide Patterns of Variation , 2008 .

[13]  K. Kidd,et al.  Crohn's disease risk alleles on the NOD2 locus have been maintained by natural selection on standing variation. , 2012, Molecular biology and evolution.

[14]  P. Katzmarzyk,et al.  Climatic influences on human body size and proportions: ecological adaptations and secular trends. , 1998, American journal of physical anthropology.

[15]  N. Jablonski,et al.  The evolution of human skin coloration. , 2000, Journal of human evolution.

[16]  Vikas Bansal,et al.  Clinical Implications of Human Population Differences in Genome-Wide Rates of Functional Genotypes , 2012, Front. Gene..

[17]  W. Potts,et al.  Major Histocompatibility Complex Heterozygote Superiority during Coinfection , 2003, Infection and Immunity.

[18]  M. Oosting,et al.  Evolutionary and functional analysis of celiac risk loci reveals SH2B3 as a protective factor against bacterial infection. , 2010, American journal of human genetics.

[19]  N. Bresolin,et al.  Balancing selection is common in the extended MHC region but most alleles with opposite risk profile for autoimmune diseases are neutrally evolving , 2011, BMC Evolutionary Biology.

[20]  F. Balloux,et al.  Signatures of historical demography and pathogen richness on MHC class I genes , 2011, Immunogenetics.

[21]  Leena Peltonen,et al.  Identification of a variant associated with adult-type hypolactasia , 2002, Nature Genetics.

[22]  M. Clerici,et al.  The hygiene hypothesis: an evolutionary perspective. , 2010, Microbes and infection.

[23]  Jun Wang,et al.  A Neutrality Test for Detecting Selection on DNA Methylation Using Single Methylation Polymorphism Frequency Spectrum , 2014, Genome biology and evolution.

[24]  Ruslan Medzhitov,et al.  Evolution of Inflammatory Diseases , 2012, Current Biology.

[25]  Laurent Duret,et al.  Biased gene conversion and the evolution of mammalian genomic landscapes. , 2009, Annual review of genomics and human genetics.

[26]  Holly M. Mortensen,et al.  Convergent adaptation of human lactase persistence in Africa and Europe , 2007, Nature Genetics.

[27]  L. Quintana-Murci,et al.  Natural selection has driven population differentiation in modern humans , 2008, Nature Genetics.

[28]  John D Reveille,et al.  End‐Stage Renal Disease in African Americans With Lupus Nephritis Is Associated With APOL1 , 2014, Arthritis & rheumatology.

[29]  N. Bresolin,et al.  Genetic adaptation of the human circadian clock to day-length latitudinal variations and relevance for affective disorders , 2014, Genome Biology.

[30]  R. Nielsen,et al.  Signatures of Environmental Genetic Adaptation Pinpoint Pathogens as the Main Selective Pressure through Human Evolution , 2011, PLoS genetics.

[31]  A. Di Rienzo,et al.  Population Genetic Analysis of the Uncoupling Proteins Supports a Role for UCP3 in Human Cold Resistance , 2010, Molecular biology and evolution.

[32]  Alexander A. Morgan,et al.  Analysis of the Genetic Basis of Disease in the Context of Worldwide Human Relationships and Migration , 2013, PLoS genetics.

[33]  N. Bresolin,et al.  Crohn's disease loci are common targets of protozoa-driven selection. , 2013, Molecular biology and evolution.

[34]  D. Altshuler,et al.  A map of human genome variation from population-scale sequencing , 2010, Nature.

[35]  Jian Lu,et al.  Human Expression QTLs Are Enriched in Signals of Environmental Adaptation , 2013, Genome biology and evolution.

[36]  M. Hochberg,et al.  Ecology Drives the Worldwide Distribution of Human Diseases , 2004, PLoS biology.

[37]  S. Tishkoff,et al.  Biased gene conversion skews allele frequencies in human populations, increasing the disease burden of recessive alleles. , 2014, American journal of human genetics.

[38]  L. Quintana-Murci,et al.  The evolutionary landscape of cytosolic microbial sensors in humans. , 2012, American journal of human genetics.

[39]  Jeremiah D. Degenhardt,et al.  Targets of balancing selection in the human genome. , 2009, Molecular biology and evolution.

[40]  Donald W. Bowden,et al.  Association of Trypanolytic ApoL 1 Variants with Kidney Disease in African Americans , 2010 .

[41]  D. P. Strachan,et al.  Hay fever, hygiene, and household size. , 1989, BMJ.

[42]  Pardis C. Sabeti,et al.  Natural selection and infectious disease in human populations , 2014, Nature Reviews Genetics.

[43]  Laurent Duret,et al.  The Impact of Recombination on Nucleotide Substitutions in the Human Genome , 2008, PLoS genetics.

[44]  Carlos D Bustamante,et al.  Ascertainment bias in studies of human genome-wide polymorphism. , 2005, Genome research.

[45]  S. Tishkoff,et al.  Recent human adaptation: genomic approaches, interpretation and insights , 2013, Nature Reviews Genetics.

[46]  K. Tokunaga,et al.  Evolutionary Analysis of Classical HLA Class I and II Genes Suggests That Recent Positive Selection Acted on DPB1*04∶01 in Japanese Population , 2012, PloS one.

[47]  Jonathan K. Pritchard,et al.  Adaptations to Climate-Mediated Selective Pressures in Humans , 2011, PLoS genetics.

[48]  Ryan D. Hernandez,et al.  Natural selection on protein-coding genes in the human genome , 2005, Nature.

[49]  Kenneth G. C. Smith,et al.  Systemic lupus erythematosus-associated defects in the inhibitory receptor FcγRIIb reduce susceptibility to malaria , 2007, Proceedings of the National Academy of Sciences.

[50]  A. Chakravarti,et al.  Differential Susceptibility to Hypertension Is Due to Selection during the Out-of-Africa Expansion , 2005, PLoS genetics.

[51]  Chung-I Wu,et al.  An ancient balanced polymorphism in a regulatory region of human major histocompatibility complex is retained in Chinese minorities but lost worldwide. , 2006, American journal of human genetics.

[52]  C. Vasconcelos,et al.  Fetal outcome in autoimmune diseases. , 2012, Autoimmunity reviews.

[53]  Asan,et al.  Sequencing of 50 Human Exomes Reveals Adaptation to High Altitude , 2010, Science.

[54]  Laurent Excoffier,et al.  Evidence for polygenic adaptation to pathogens in the human genome. , 2013, Molecular biology and evolution.

[55]  Xiaofeng Zhu,et al.  Genome-wide comparison of African-ancestry populations from CARe and other cohorts reveals signals of natural selection. , 2011, American journal of human genetics.

[56]  A. Aderem,et al.  A stop codon polymorphism of Toll-like receptor 5 is associated with resistance to systemic lupus erythematosus. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[57]  L. Excoffier,et al.  Molecular analysis of the beta-globin gene cluster in the Niokholo Mandenka population reveals a recent origin of the beta(S) Senegal mutation. , 2002, American journal of human genetics.

[58]  A. Clark,et al.  Population genetic tools for dissecting innate immunity in humans , 2013, Nature Reviews Immunology.

[59]  Miles Parkes,et al.  Genetic insights into common pathways and complex relationships among immune-mediated diseases , 2013, Nature Reviews Genetics.

[60]  Ryan D. Hernandez,et al.  Classic Selective Sweeps Were Rare in Recent Human Evolution , 2011, Science.

[61]  P. Luisi,et al.  Balancing immunity and tolerance: genetic footprint of natural selection in the transcriptional regulatory region of HLA-G , 2014, Genes and Immunity.

[62]  Kevin Marsh,et al.  Common variation in the ABO glycosyltransferase is associated with susceptibility to severe Plasmodium falciparum malaria. , 2008, Human molecular genetics.

[63]  J. Todd,et al.  Rare Variants of IFIH1, a Gene Implicated in Antiviral Responses, Protect Against Type 1 Diabetes , 2009, Science.

[64]  W. Loomis Skin-Pigment Regulation of Vitamin-D Biosynthesis in Man , 1967, Science.

[65]  C. Ober,et al.  Evidence of balancing selection at the HLA-G promoter region. , 2005, Human molecular genetics.

[66]  Joseph K. Pickrell,et al.  Signals of recent positive selection in a worldwide sample of human populations. , 2009, Genome research.

[67]  Ryan D. Hernandez,et al.  Evolutionary Processes Acting on Candidate cis-Regulatory Regions in Humans Inferred from Patterns of Polymorphism and Divergence , 2009, PLoS genetics.

[68]  R M May,et al.  Coevolution of hosts and parasites , 1982, Parasitology.

[69]  C. Chambers,et al.  State of the art: Reproduction and pregnancy in rheumatic diseases. , 2015, Autoimmunity reviews.

[70]  C. Tyler-Smith,et al.  Human genomic regions with exceptionally high levels of population differentiation identified from 911 whole-genome sequences , 2014, Genome Biology.

[71]  Xi Jiang,et al.  Human susceptibility and resistance to Norwalk virus infection , 2003, Nature Medicine.

[72]  J. M. Smith,et al.  The hitch-hiking effect of a favourable gene. , 1974, Genetical research.

[73]  D. F. Roberts Body weight, race and climate. , 1953, American journal of physical anthropology.

[74]  N. Bresolin,et al.  Population Genetics of IFIH 1 : Ancient Population Structure , Local Selection , and Implications for Susceptibility to Type 1 Diabetes , 2011 .

[75]  F. Klironomos,et al.  How epigenetic mutations can affect genetic evolution: model and mechanism. , 2013, BioEssays : news and reviews in molecular, cellular and developmental biology.

[76]  Manik Kuchroo,et al.  Common risk alleles for inflammatory diseases are targets of recent positive selection. , 2013, American journal of human genetics.

[77]  Sharon R Grossman,et al.  Integrating common and rare genetic variation in diverse human populations , 2010, Nature.

[78]  David C. Wilson,et al.  Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease , 2012, Nature.

[79]  W. Leonard,et al.  Climatic influences on basal metabolic rates among circumpolar populations , 2002, American journal of human biology : the official journal of the Human Biology Council.

[80]  A. Siepel,et al.  Probabilities of Fitness Consequences for Point Mutations Across the Human Genome , 2014, Nature Genetics.

[81]  Carlos D Bustamante,et al.  Localizing Recent Adaptive Evolution in the Human Genome , 2007, PLoS genetics.

[82]  A. Di Rienzo Population genetics models of common diseases. , 2006, Current opinion in genetics & development.

[83]  L. Quintana-Murci,et al.  From evolutionary genetics to human immunology: how selection shapes host defence genes , 2010, Nature Reviews Genetics.

[84]  Joshua M Akey,et al.  Where do we go from here? Constructing genomic maps of positive selection in humans: , 2009 .

[85]  Joseph K. Pickrell,et al.  Evolutionary Dynamics of Human Toll-Like Receptors and Their Different Contributions to Host Defense , 2009, PLoS genetics.

[86]  R. Cagliani,et al.  Pathogen-Driven Selection in the Human Genome , 2013, International Journal of Evolutionary Biology.

[87]  E. Parra,et al.  Exploring signatures of positive selection in pigmentation candidate genes in populations of East Asian ancestry , 2013, BMC Evolutionary Biology.

[88]  R. Hardwick,et al.  Evolutionary history of copy-number-variable locus for the low-affinity Fcγ receptor: mutation rate, autoimmune disease, and the legacy of helminth infection. , 2012, American journal of human genetics.

[89]  Jan Hillert,et al.  MHC2TA is associated with differential MHC molecule expression and susceptibility to rheumatoid arthritis, multiple sclerosis and myocardial infarction , 2005, Nature Genetics.

[90]  Pardis C Sabeti,et al.  Detecting recent positive selection in the human genome from haplotype structure , 2002, Nature.

[91]  Keith C. Cheng,et al.  SLC24A5, a Putative Cation Exchanger, Affects Pigmentation in Zebrafish and Humans , 2005, Science.

[92]  P. Kwok,et al.  Carriers of rare missense variants in IFIH1 are protected from psoriasis. , 2010, The Journal of investigative dermatology.

[93]  Pardis C Sabeti,et al.  Genome-wide detection and characterization of positive selection in human populations , 2007, Nature.

[94]  C. Winkler,et al.  Association of Trypanolytic ApoL1 Variants with Kidney Disease in African Americans , 2010, Science.

[95]  Raphael Zidovetzki,et al.  A Comprehensive Analysis of Shared Loci between Systemic Lupus Erythematosus (SLE) and Sixteen Autoimmune Diseases Reveals Limited Genetic Overlap , 2011, PLoS genetics.

[96]  F. Balloux,et al.  Pathogen-Driven Selection and Worldwide HLA Class I Diversity , 2005, Current Biology.

[97]  M. Kanai,et al.  Rare Variants of IFIH 1 , a Gene Implicated in Antiviral Responses , Protect Against Type 1 Diabetes , 2009 .

[98]  Deborah A Nickerson,et al.  Allele Frequency Matching Between SNPs Reveals an Excess of Linkage Disequilibrium in Genic Regions of the Human Genome , 2006, PLoS genetics.

[99]  L. Excoffier,et al.  Molecular Analysis of the β-Globin Gene Cluster in the Niokholo Mandenka Population Reveals a Recent Origin of the βS Senegal Mutation , 2002 .

[100]  A. McGrogan,et al.  Pregnancy losses in women with Type 1 or Type 2 diabetes in the UK: an investigation using primary care records , 2014, Diabetic medicine : a journal of the British Diabetic Association.

[101]  O. Doumbo,et al.  Blood group O protects against severe Plasmodium falciparum malaria through the mechanism of reduced rosetting , 2007, Proceedings of the National Academy of Sciences.

[102]  K. Michaud,et al.  Effects of infertility, pregnancy loss, and patient concerns on family size of women with rheumatoid arthritis and systemic lupus erythematosus , 2012, Arthritis care & research.

[103]  Eric S. Lander,et al.  Identifying Recent Adaptations in Large-Scale Genomic Data , 2013, Cell.

[104]  John C. Marioni,et al.  Deciphering the genetic architecture of variation in the immune response to Mycobacterium tuberculosis infection , 2012, Proceedings of the National Academy of Sciences.

[105]  N. Bresolin,et al.  Population genetics of IFIH1: ancient population structure, local selection, and implications for susceptibility to type 1 diabetes. , 2010, Molecular biology and evolution.

[106]  Q. Lu,et al.  Heritability versus the role of the environment in autoimmunity. , 2012, Journal of autoimmunity.

[107]  N. Bresolin,et al.  Widespread balancing selection and pathogen-driven selection at blood group antigen genes. , 2009, Genome research.

[108]  C. Langefeld,et al.  Genes Associated with SLE Are Targets of Recent Positive Selection , 2014, Autoimmune diseases.

[109]  K. Honda,et al.  The microbiome in infectious disease and inflammation. , 2012, Annual review of immunology.

[110]  Mark Daly,et al.  What have we learned from six years of GWAS in autoimmune diseases, and what is next? , 2012, Current opinion in immunology.

[111]  Pardis C Sabeti,et al.  Genetic signatures of strong recent positive selection at the lactase gene. , 2004, American journal of human genetics.

[112]  M. Nei,et al.  Pattern of nucleotide substitution at major histocompatibility complex class I loci reveals overdominant selection , 1988, Nature.

[113]  Kosuke M. Teshima,et al.  Natural Selection on Genes that Underlie Human Disease Susceptibility , 2008, Current Biology.

[114]  N. Mulder,et al.  Population-specific common SNPs reflect demographic histories and highlight regions of genomic plasticity with functional relevance , 2014, BMC Genomics.