Biology:Isochore (genetics)

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In genetics, an isochore is a large region of genomic DNA (greater than 300 kilobases) with a high degree of uniformity in GC content; that is, guanine (G) and cytosine (C) bases. The distribution of bases within a genome is non-random: different regions of the genome have different amounts of G-C base pairs, such that regions can be classified and identified by the proportion of G-C base pairs they contain. Bernardi and colleagues first noticed the compositional non-uniformity of vertebrate genomes using thermal melting and density gradient centrifugation.[1] [2] [3] The DNA fragments extracted by the gradient centrifugation were later termed "isochores",[4] which was subsequently defined as "very long (much greater than 200 KB) DNA segments" that "are fairly homogeneous in base composition and belong to a small number of major classes distinguished by differences in guanine-cytosine (GC) content".[3] Subsequently, the isochores "grew" and were claimed to be ">300 kb in size."[5] [6] The theory proposed that the isochore composition of genomes varies markedly between "warm-blooded" (homeotherm) vertebrates and "cold-blooded" (poikilotherm) vertebrates[3] and later became known as the isochore theory.

The thermodynamic stability hypothesis

The isochore theory purported that the genome of "warm-blooded" vertebrates (mammals and birds) are mosaics of long isochoric regions of alternating GC-poor and GC-rich composition, as opposed to the genome of "cold-blooded" vertebrates (fishes and amphibians) that were supposed to lack GC-rich isochores.[3][7] [8] [9] [10] [11] These findings were explained by the thermodynamic stability hypothesis, attributing genomic structure to body temperature. GC-rich isochores were purported to be a form of adaptation to environmental pressures, as an increase in genomic GC-content could protect DNA, RNA, and proteins from degradation by heat. [3][4] Despite its attractive simplicity, the thermodynamic stability hypothesis has been repeatedly shown to be in error [12] [13] [14] .[15] [16] [17] [18] [19] Many authors showed the absence of a relationship between temperature and GC-content in vertebrates,[17][18] while others showed the existence of GC-rich domains in "cold-blooded" vertebrates such as crocodiles, amphibians, and fish.[14][20] [21] [22]


Principles of the isochore theory

The isochore theory was the first to identify the nonuniformity of nucleotide composition within vertebrate genomes and predict that the genome of "warm-blooded" vertebrates such as mammals and birds are mosaic of isochores (Bernardi et al. 1985). The human genome, for example, was described as a mosaic of alternating low and high GC content isochores belonging to five compositional families, L1, L2, H1, H2, and H3, whose corresponding ranges of GC contents were said to be <38%, 38%-42%, 42%-47%, 47%-52%, and >52%, respectively.[23]

The main predictions of the isochore theory are that:

  • GC content of the third codon position (GC3) of protein coding genes is correlated with the GC content of the isochores embedding the corresponding genes.[23]
  • The genome organization of warm-blooded vertebrates is a mosaic of mostly GC-rich isochores.[24][25]
  • Genome organization of cold-blooded vertebrates is characterized by low GC content levels and lower compositional heterogeneity than warm-blooded vertebrates. Homogeneous domains do not reach the high GC levels attained by the genomes of warm-blooded vertebrates.[24][25]

The neutralist-selectionist controversy

Two opposite explanations that endeavored to explain the formations of isochores were vigorously debated as part of the neutralist-selectionist controversy. The first view was that isochores reflect variable mutation processes among genomic regions consistent with the neutral model.[26] [27] Alternatively, isochores were posited as a result of natural selection for certain compositional environment required by certain genes.[28] Several hypotheses derive from the selectionist view, such as the thermodynamic stability hypothesis [6][29] and the biased gene conversion hypothesis.[27] Thus far, none of the theories provides a comprehensive explanation to the genome structure, and the topic is still under debate.

The rise and fall of the isochore theory

The isochore theory became one of the most useful theories in molecular evolution for many years. It was the first and most comprehensive attempt to explain the long-range compositional heterogeneity of vertebrate genomes within an evolutionary framework. Despite the interest in the early years in the isochore model, in recent years, the theory’s methodology, terminology, and predictions have been challenged.

Because this theory was proposed in the 20th century before complete genomes were sequenced, it could not be fully tested for nearly 30 years. In the beginning of the 21st century, when the first genomes were made available it was clear that isochores do not exist in the human genome[30] nor in other mammalian genomes.[31] When failed to find isochores, many attacked the very existence of isochores.[30][32] [33] [34] [35] The most important predictor of isochores, GC3 was shown to have no predictable power [36] [37] to the GC content of nearby genomic regions, refuting findings from over 30 years of research, which were the basis for many isochore studies. Isochore-originators replied that the term was misinterpreted [23][38] [39] as isochores are not "homogeneous" but rather fairly homogeneous regions with a heterogeneous nature (especially) of GC-rich regions at the 5 kb scale,[40] which only added to the already growing confusion. The reason for this ongoing frustration was the ambiguous definition of isochores as long and homogeneous, allowed some researchers to discover "isochores" and others to dismiss them, although both camps used the same data.

The unfortunate side effect of this controversy was an "arms race" in which isochores are frequently redefined and relabeled following conflicting findings that failed to reveal "mosaic of isochores."[23][32][34] The unfortunate outcomes of this controversy and the following terminological-methodological mud were the loss of interest in isochores by the scientific community. When the most important core-concept in isochoric literature, the thermodynamic stability hypothesis, was rejected, the theory lost its appeal. Even today, there is no clear definition to isochores nor is there an algorithm that detects isochores.[41] Isochores are detected manually by visual inspection of GC content curves ,[42] however because this approach lacks scientific merit and is difficult to replicate by independent groups, the findings remain disputed.

The compositional domain model

As the study of isochores was de facto abandoned by most scientists, an alternative theory was proposed to describe the compositional organization of genomes in accordance with the most recent genomic studies. The Compositional Domain Model depicts genomes as a medley of short and long homogeneous and nonhomogeneous domains.[35] The theory defines "compositional domains" as genomic regions with distinct GC-contents as determined by a computational segmentation algorithm.[35] The homogeneity of compositional domains is compared to that of the chromosome on which they reside using the F-test, which separated them into compositionally homogeneous domains and compositionally nonhomogeneous domains based on the outcome of test. Compositionally homogeneous domains that are sufficiently long (≥ 300 kb) are termed isochores or isochoric domains. These terms are in accordance with the literature as they provide clear distinction between isochoric- and nonisochoric-domains.

A comprehensive study of the human genome unraveled a genomic organization where two-thirds of the genome is a mixture of many short compositionally homogeneous domains and relatively few long ones. The remaining portion of the genome is composed of nonhomogeneous domains. In terms of coverage, only 1% of the total number of compositionally homogeneous domains could be considered "isochores" which covered less than 20% of the genome.[35]

Since its inception the theory received wide attention and was extensively used to explain findings emerging from over dozen new genome sequencing studies.[31][43] [44] [45] [46] [47] [48] [49] [50] However, many important questions remain open, such as which evolutionary forces shaped the structure of compositional domains and the ways they differ between different species.

References

  1. ↑ Macaya, Thiery, and Bernardi (1976). "An approach to the organization of eukaryotic genomes at a macromolecular level". Journal of Molecular Biology 108 (1): 237–254. doi:10.1016/S0022-2836(76)80105-2. PMID 826644. 
  2. ↑ Thiery, Macaya, and Bernardi (1976). "An analysis of eukaryotic genomes by density gradient centrifugation". Journal of Molecular Biology 108 (1): 219–235. doi:10.1016/S0022-2836(76)80104-0. PMID 826643. 
  3. ↑ 3.0 3.1 3.2 3.3 3.4 Bernardi et al. (1985). "The mosaic genome of warm-blooded vertebrates". Science 228 (4702): 953–958. doi:10.1126/science.4001930. PMID 4001930. Bibcode: 1985Sci...228..953B. 
  4. ↑ 4.0 4.1 Cuny et al. (1981). "The major components of the mouse and human genomes: Preparation, basic properties and compositional heterogeneity". European Journal of Biochemistry 115 (2): 227–233. doi:10.1111/j.1432-1033.1981.tb05227.x. PMID 7238506. 
  5. ↑ Salinas et al. (1987). "Nonrandom distribution of MMTV proviral sequences in the mouse genome". Nucleic Acids Res 15 (7): 3009–3022. doi:10.1093/nar/15.7.3009. PMID 3031617. 
  6. ↑ 6.0 6.1 Bernardi (1993). "The vertebrate genome: isochores and evolution". Molecular Biology and Evolution 10 (1): 186–204. doi:10.1093/oxfordjournals.molbev.a039994. PMID 8450755. 
  7. ↑ Bernardi (1995). "The human genome: organization and evolutionary history". Annual Review of Genetics 29: 445–476. doi:10.1146/annurev.ge.29.120195.002305. PMID 8825483. 
  8. ↑ Bernardi, Hughes, and Mouchiroud (1997). "The major compositional transitions in the vertebrate genome". Journal of Molecular Evolution 44 Suppl 1 (S1): S44–51. doi:10.1007/PL00000051. PMID 9071011. Bibcode: 1997JMolE..44S..44B. 
  9. ↑ Robinson, Gautier, and Mouchiroud (1997). "Evolution of isochores in rodents". Molecular Biology and Evolution 14 (8): 823–828. doi:10.1093/oxfordjournals.molbev.a025823. PMID 9254920. 
  10. ↑ Galtier and Mouchiroud; Mouchiroud, D (1998). "Isochore evolution in mammals: a human-like ancestral structure". Genetics 150 (4): 1577–1584. doi:10.1093/genetics/150.4.1577. PMID 9832533. 
  11. ↑ Oliver et al. (2001). "Isochore chromosome maps of eukaryotic genomes". Gene 276 (1–2): 47–56. doi:10.1016/S0378-1119(01)00641-2. PMID 11591471. 
  12. ↑ Aota and Ikemura; Ikemura, T (1986). "Diversity in G + C content at the third position of codons in vertebrate genes and its cause". Nucleic Acids Res 14 (16): 6345–6355. doi:10.1093/nar/14.16.6345. PMID 3748815. 
  13. ↑ Galtier and Lobry; Lobry, J.R. (1997). "Relationships Between Genomic G+C Content, RNA Secondary Structures, and Optimal Growth Temperature in Prokaryotes". Journal of Molecular Evolution 44 (6): 632–636. doi:10.1007/PL00006186. PMID 9169555. Bibcode: 1997JMolE..44..632G. 
  14. ↑ 14.0 14.1 Hughes, Zelus, and Mouchiroud (1999). "Warm-blooded isochore structure in Nile crocodile and turtle". Molecular Biology and Evolution 16 (11): 1521–1527. doi:10.1093/oxfordjournals.molbev.a026064. PMID 10555283. 
  15. ↑ Eyre-Walker and Hurst; Hurst, LD (2001). "The evolution of isochores". Nat Rev Genet 2 (7): 549–555. doi:10.1038/35080577. PMID 11433361. 
  16. ↑ Hurst and Merchant; Merchant, AR (2001). "High guanine-cytosine content is not an adaptation to high temperature: a comparative analysis amongst prokaryotes". Proceedings of the Royal Society B 268 (1466): 493–497. doi:10.1098/rspb.2000.1397. PMID 11296861. 
  17. ↑ 17.0 17.1 Belle, Smith, and Eyre-Walker (2002). "Analysis of the phylogenetic distribution of isochores in vertebrates and a test of the thermal stability hypothesis". Journal of Molecular Evolution 55 (3): 356–363. doi:10.1007/s00239-002-2333-1. PMID 12187388. Bibcode: 2002JMolE..55..356B. 
  18. ↑ 18.0 18.1 Ream, Johns, and Somero (2003). "Base Compositions of Genes Encoding {alpha}-Actin and Lactate Dehydrogenase-A from Differently Adapted Vertebrates Show No Temperature- Adaptive Variation in G + C Content". Molecular Biology and Evolution 20 (1): 105–110. doi:10.1093/molbev/msg008. PMID 12519912. http://mbe.oxfordjournals.org/cgi/content/abstract/20/1/105. 
  19. ↑ Belle et al. (2004). "The decline of isochores in mammals: an assessment of the GC content variation along the mammalian phylogeny". Journal of Molecular Evolution 58 (6): 653–660. doi:10.1007/s00239-004-2587-x. PMID 15461422. Bibcode: 2004JMolE..58..653B. 
  20. ↑ Hughes, Friedman, and Murray (2002). "Genomewide pattern of synonymous nucleotide substitution in two complete genomes of Mycobacterium tuberculosis". Emerging Infectious Diseases 8 (11): 1342–1346. doi:10.3201/eid0811.020064. PMID 12453367. 
  21. ↑ Costantini, Auletta, and Bernardi (2007). "Isochore patterns and gene distributions in fish genomes". Genomics 90 (3): 364–371. doi:10.1016/j.ygeno.2007.05.006. PMID 17590311. 
  22. ↑ Symonová, Majtánová, Arias-Rodriguez , Mořkovský, Kořínková, Cavin, Johnson Pokorná, Doležálková, Flajšhans, Normandeau, Ráb, Meyer, and Bernatchez (2016). "Genome Compositional Organization in Gars Shows More Similarities to Mammals than to Other Ray-Finned Fish". Journal of Experimental Zoology 328 (7): 607–619. doi:10.1002/jez.b.22719. PMID 28035749. http://nbn-resolving.de/urn:nbn:de:bsz:352-2-603ra8pvhw693. 
  23. ↑ 23.0 23.1 23.2 23.3 Bernardi (2001). "Misunderstandings about isochores. Part 1". Gene 276 (1–2): 3–13. doi:10.1016/S0378-1119(01)00644-8. PMID 11591466. 
  24. ↑ 24.0 24.1 Bernardi (2000). "Isochores and the evolutionary genomics of vertebrates". Gene 241 (1): 3–17. doi:10.1016/S0378-1119(99)00485-0. PMID 10607893. 
  25. ↑ 25.0 25.1 Bernardi (2000). "The compositional evolution of vertebrate genomes". Gene 259 (1–2): 31–43. doi:10.1016/S0378-1119(00)00441-8. PMID 11163959. 
  26. ↑ Wolfe, Sharp, and Li; Sharp; Li (1989). "Mutation rates differ among regions of the mammalian genome". Nature 337 (6204): 283–285. doi:10.1038/337283a0. PMID 2911369. Bibcode: 1989Natur.337..283W. 
  27. ↑ 27.0 27.1 Galtier et al. (2001). "GC- content evolution in mammalian genomes: the biased gene conversion hypothesis". Genetics 159 (2): 907–911. doi:10.1093/genetics/159.2.907. PMID 11693127. 
  28. ↑ Matassi, Sharp, and Gautier (1999). "Chromosomal location effects on gene sequence evolution in mammals". Current Biology 9 (15): 786–791. doi:10.1016/S0960-9822(99)80361-3. PMID 10469563. 
  29. ↑ Bernardi and Bernardi; Bernardi, G (1986). "Compositional constraints and genome evolution". Journal of Molecular Evolution 24 (1–2): 1–11. doi:10.1007/BF02099946. PMID 3104608. Bibcode: 1986JMolE..24....1B. 
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  32. ↑ 32.0 32.1 Nekrutenko and Li; Li, WH (2000). "Assessment of compositional heterogeneity within and between eukaryotic genomes". Genome Research 10 (12): 1986–1995. doi:10.1101/gr.10.12.1986. PMID 11116093. 
  33. ↑ Häring and Kypr; Kypr, J (2001). "No Isochores in the Human Chromosomes 21 and 22?". Biochemical and Biophysical Research Communications 280 (2): 567–573. doi:10.1006/bbrc.2000.4162. PMID 11162557. 
  34. ↑ 34.0 34.1 Cohen et al. (2005). "GC composition of the human genome: in search of isochores". Molecular Biology and Evolution 22 (5): 1260–1272. doi:10.1093/molbev/msi115. PMID 15728737. 
  35. ↑ 35.0 35.1 35.2 35.3 Elhaik et al. (2010). "Identifying compositionally homogeneous and nonhomogeneous domains within the human genome using a novel segmentation algorithm". Nucleic Acids Res 38 (15): e158. doi:10.1093/nar/gkq532. PMID 20571085. 
  36. ↑ Elhaik, Landan, and Graur (2009). "Can GC Content at Third- Codon Positions Be Used as a Proxy for Isochore Composition?". Molecular Biology and Evolution 26 (8): 1829–1833. doi:10.1093/molbev/msp100. PMID 19443854. 
  37. ↑ Tatarinova et al. (2010). "GC3 biology in corn, rice, sorghum and other grasses". BMC Genomics 11: 308. doi:10.1186/1471-2164-11-308. PMID 20470436. 
  38. ↑ Li et al. (2003). "Isochores merit the prefix 'iso'". Computational Biology and Chemistry 27 (1): 5–10. doi:10.1016/S1476-9271(02)00090-7. PMID 12798034. Bibcode: 2002physics...9080L. 
  39. ↑ Clay and Bernardi (2005). "How Not to Search for Isochores: A Reply to Cohen et al". Molecular Biology and Evolution 22 (12): 2315–2317. doi:10.1093/molbev/msi231. PMID 16093569. 
  40. ↑ Romiguier et al. (2010). "Contrasting GC-content dynamics across 33 mammalian genomes: Relationship with life-history traits and chromosome sizes". Genome Research 20 (8): 1001–1009. doi:10.1101/gr.104372.109. PMID 20530252. 
  41. ↑ Elhaik, Graur, and Josic (2010). "Comparative testing of DNA segmentation algorithms using benchmark simulations". Molecular Biology and Evolution 27 (5): 1015–1024. doi:10.1093/molbev/msp307. PMID 20018981. 
  42. ↑ Costantini et al. (2006). "An isochore map of human chromosomes". Genome Research 16 (4): 536–541. doi:10.1101/gr.4910606. PMID 16597586. 
  43. ↑ Robinson, Gene E.; Gibbs, Richard A.; Weinstock, George M.; Worley, Kim C.; Evans, Jay D.; Maleszka, Ryszard (2006). "Insights into social insects from the genome of the honeybee Apis mellifera". Nature 443 (7114): 931–949. doi:10.1038/nature05260. PMID 17073008. Bibcode: 2006Natur.443..931T. 
  44. ↑ Sodergren et al. (2006). "The genome of the sea urchin Strongylocentrotus purpuratus". Science 314 (5801): 941–952. doi:10.1126/science.1133609. PMID 17095691. Bibcode: 2006Sci...314..941S. 
  45. ↑ Richards, S.; Gibbs, Richard A.; Weinstock, George M.; Brown, Susan J.; Denell, Robin; Beeman, Richard W.; Gibbs, Richard; Beeman, Richard W. et al. (2008). "The genome of the model beetle and pest Tribolium castaneum". Nature 452 (7190): 949–955. doi:10.1038/nature06784. PMID 18362917. Bibcode: 2008Natur.452..949R. 
  46. ↑ Kirkness et al. (2010). "Genome sequences of the human body louse and its primary endosymbiont provide insights into the permanent parasitic lifestyle". Proceedings of the National Academy of Sciences of the United States of America 107 (27): 12168–12173. doi:10.1073/pnas.1003379107. PMID 20566863. Bibcode: 2010PNAS..10712168K. 
  47. ↑ Werren et al. (2010). "Functional and evolutionary insights from the genomes of three parasitoid Nasonia species". Science 327 (5963): 343–348. doi:10.1126/science.1178028. PMID 20075255. Bibcode: 2010Sci...327..343.. 
  48. ↑ Smith et al. (2011). "Draft genome of the globally widespread and invasive Argentine ant (Linepithema humile)". Proceedings of the National Academy of Sciences of the United States of America 108 (14): 5673–5678. doi:10.1073/pnas.1008617108. PMID 21282631. Bibcode: 2011PNAS..108.5673S. 
  49. ↑ Smith et al. (2011). "Draft genome of the red harvester ant Pogonomyrmex barbatus". Proceedings of the National Academy of Sciences of the United States of America 108 (14): 5667–5672. doi:10.1073/pnas.1007901108. PMID 21282651. Bibcode: 2011PNAS..108.5667S. 
  50. ↑ Suen et al. (2011). Copenhaver, Gregory. ed. "The genome sequence of the leaf-cutter ant Atta cephalotes reveals insights into its obligate symbiotic lifestyle". PLOS Genetics 7 (2): e1002007. doi:10.1371/journal.pgen.1002007. PMID 21347285. 

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