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Ohno

The Robert S Boas Center for Genomics and Human Genetics ... Genetics, 4:247-265. Lewis (1951)

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Ohno

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  1. Ohno’s Evolution by Duplication andDNA Correlations Wentian Li, Ph.D The Robert S Boas Center for Genomics and Human Genetics North Shore LIJ Institute for Medical Research March 18, 2005

  2. Outline of the talk • Ohno’s evolution by gene duplication • Duplication-mutation model (expansion-modification model) • Confirmation of 1/f noise in DNA sequences as predicted by the duplication-mutation model • Duplication in bacteria genomes? • Music as the second example where the three themes converge (1/f noise - redundancy in musical composition - duplication-mutation model)

  3. Susumu Ohno (1928-2000) • Undergraduate degree in veterinary (1949) • Graduate degree in immunology (1953) • UCLA, then City of Hope National Medical Center (50s-retired) • One X-chromosome being heterochromatic(1959) • Evolution by gene duplication (1970) • Term “junk DNA” (1972) • Relating DNA with music (1986)

  4. From Evolution by Gene Duplication (1970) “Had evolution been entirely dependent upon natural selection, from a bacterium only numerous forms of bacteria would have emerged. The creation of metazoans, vertebrates, and finally mammals from unicellular organisms would have been quite impossible, for such big leaps in evolution required the creation of new gene loci with previously nonexistent function. Only the cistron [gene] that became redundant was able to escape from the relentless pressure of natural selection. By escaping, it accumulated formerly forbidden mutations to emerge as a new gene locus.”

  5. “Natural selection merely modified while redundancy created” -S. Ohno

  6. Pre-1970 works on gene duplication • Kuwada (1911), Tischler (1915) • JBS Haldane (1932), The Causes of Evolution(Harper and Bros) • Bridges’s observation of gene duplication in Drosophila (1935-36) • Serebrovsky (1938): selection is relaxed in genes that duplicate • Muntzing (1936), Tischler (1935), Nishiyama (1934) • Gulick (1944) “increases in gene count.. (to) great complexity” • Goldschmit (1940), Metz(1947), Huxley (1942): importance of.. • SG Stephens (1951), “Possible significance of duplication in evolution”, Adv. Genetics, 4:247-265. • Lewis (1951) “pseudoallelism &gene evolution” linked duplicates • S Ohno, U Wolf, NB Atkin (1968),“Evolution from fish to mammals by gene duplication”, Hereditas, 59:169-187. See Taylor & Raes (2004)

  7. More and more interests in gene duplications • http://www.nslij-genetics.org/duplicaiton/

  8. Example: two rounds of duplication (2R)

  9. The extent of duplicated genes (Dujon et al. Nature 2004)

  10. effects of duplicated genes vs. single-copy genes • Gu, et al. Nature, 421:63-66 (2003) • Yeast S. cerevisiae has ~6000 genes, about ¼ of them are part of “duplicates”, the rest exist as “singletons”. • Knocking 12.4% of one of the “duplicates” is lethal • Knocking 29% of the “singletons” is lethal • Knocking 64.3% of one of the “duplicates” has no or weak effect • Knocking 39.5% of the “duplicates” has no or weak effect

  11. Could the result be relevant to human genome? • Housekeeping genes more likely in “duplicate group” (multigene families)? • Disease genes for Mendelian diseases more likely in “singleton group”?? • Disease genes for complex diseases more likely in “duplicate group”???

  12. Some examples of disease genes

  13. the general principle of Ohno’s duplication is true, but… • Whole genome duplication (polyploidization) or regional/local/segmental duplication? [polyploids tend to be unstable] • Duplication of genes or duplication of a piece of DNA with possibly no functions? [then “gene” duplication is a by-product instead of a design] • Is redundancy caused by duplication the only source of robustness against mutations? [system robustness is another source]

  14. Redundancy, n. : repetition or excessive use of something 1. Correlation, n.: a causal, complementary, parallel or reciprocal relationship between two comparable entities 2. Correlation, n. (statistics) : the simultaneous change of two random variables The Copy and the original gene (DNA segment) are correlated in sense 1. Even after the decay and deletion of function of the copy gene, it is still correlated with the original in sense 2. [problem: not random variable] Redundancy and correlation

  15. Modeling correlation via duplication • Duplication-mutation model (expansion-modification model) W.Li, Europhysics Letters,10:395-400 (1989); W.Li, Physical Review A, 43:5240-6260 (1991) • Repeated local duplication with a fixed probability (p) • Repeated mutation with a fixed probability (q=1-p) • Sequence length continues to increase

  16. Properties of the duplication-mutation model • Although the duplication/redundancy/correlation is created locally, the correlation can actually be “propagated” to long distances • Duplication part is responsible for generating correlation, whereas the mutation part is destroying it. • When the duplication probability is large (e.g. p=0.9, q=0.1), the limiting sequence exhibits long-range correlation and power-law (scaling) behaviors, including the “1/f noise”.

  17. History behind the duplication-mutation model • Searching for long-range correlation in limit sequences generated by cellular automata (1986) • The idea of increasing the sequence length in order to generate long-range correlation (1988) • Realizing the connection between the duplication-mutation model (expansion-modification model) and Ohno’s evolution by duplication (K Kaneko, Nov 1988) • Failed attempt to detect 1/f noise in DNA sequences from GeneBank (Li, Kaneko, 1989) • Successful attempt to detect 1/f noise in DNA sequences (Li, 1991)

  18. duplication

  19. Li, Stolovitzky, Bernaola-Galvan, Oliver, Genome Research, 8:916-928 (1998)

  20. Li and Holste, Fluctuation and Noise Letters, 4:L453-L464 (2004)

  21. Li and Holste, Phys. Rev. E (2005), to appear.

  22. The general idea in duplication-mutation model seems to fit the data, but… • The local duplication and the subsequent “pushing” may be replaced by a global duplication (I.e. base duplication may be replaced by segmental duplication). • Whole-genome duplication followed by several inter-chromosome exchanges may also create redundancy and correlation • A spectrum of dynamics instead of just two (duplication and mutation)

  23. Duplication in bacteria genomes? • Zipkas & Riley (1975): pair of genes of similar function tend to be separated by 90 or 180 degrees • Lobry (1996): G-C changes sign at replication origin/termina • Eisen et al (2000): when two bacterial genomes are compared, either direct or complementary opposite, there is a cross-like match

  24. If GC-bias changes sign but has the same magnitude, two similar sequences point to opposite direction

  25. Genomewide dot plots • Base-to-base comparison • Base composition difference • Oligonucleotide composition differences • Exact match of a long (e.g. 25 bases) oligo • Protein/ORF matches (BLAST, FASTA) • “maximum unique match” (MUM) (MUMer program: http://www.tigr.org/software/mummer/)

  26. The all pervasive principle of repetitious recurrence governs not only coding sequence construction but also human endeavor in musical composition Title of a paper authored by Susumu Ohno and Midori Ohno (1996)

  27. DNA-Music connection: I • DNA sequences all exhibit 1/f spectra (no exception yet) • Musical time series all exhibit 1/f noise (both loudness and pitch, both musical signal and speech) Voss & Clarke (1975) “1/f noise in music and speech”, Nature, 258:317-318.

  28. DNA-Music connection: II • DNA sequence is redundant (full of repeats) • Musical series is also redundant (repetitive)

  29. DNA-Music connection: III • The generation/elongation of DNA sequences are driven mainly by duplication in various form (genomewide, segmental,…) • The musical composition process consists of re-usage of the main/minor themes • Can both be modeled by some form of duplication-mutation models?

  30. “We have formerly seen that parts many times repeated are eminently liable to vary in number and structure; consequently it is quite probable that natural selection, during the long-continued course of modification, should have seized on a certain number of the primordially similar elements, many times repeated, and have adapted them to the most diverse purposes. Charles Darwin, 1859 (The Origin of Species, page 477)

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