[This is part 2 of Stephen Meyer's response to Francisco Ayala's critique of Signature in the Cell. Read part 1 here, or download the entire response as a PDF.]
The closest that Ayala comes in his review to recognizing the central affirmative argument in the book is his rather clumsy attempt to refute the idea of intelligent design by insisting that existence of "nonsensical" or junk sequences in the human genome demonstrates that it did not arise by intelligent design. As he claims explicitly, "according to Meyer, ID provides a more satisfactory explanation of the human genome than evolution does."
Again, I have to wonder whether Professor Ayala even cracked the pages of the book. My book is not about the origin of the human genome, nor about human evolution nor even biological evolution generally. It's about chemical evolution, the origin of the first life and the genetic information necessary to produce it. In fact, I explicitly acknowledge in the epilogue that someone could in principle accept my argument for the intelligent design of the first life and also accept the standard neo-Darwinian account of how subsequent forms of life evolved. I don't hold this "front-end loaded" view of design, but my book makes no attempt to refute it or standard accounts of biological evolution. For this reason, it's hard to see how Ayala's attempt to defend biological evolution and refute the particular hypothesis that intelligent design played a discernable role in the origin of the human genome in any way challenges the argument of Signature in the Cell.
Even so, it is worth noting that the argument that Ayala makes against intelligent design of the human genome based upon on the presence of "nonsensical" or so-called junk DNA is predicated upon two factually flawed and out-of-date premises. Ayala suggests that no designer worthy of the modifier "intelligent" would have allowed the human genome to be liberally sprinkled with a preponderance of nonsense DNA sequences and that the presence and apparently random distribution of such sequences is more adequately explained as a by-product of the trial and error process of undirected mutation and selection. According to Ayala, the distribution of a particular sequence (the Alu sequence), which he asserts contains genetic nonsense, suggests a sloppy, unintelligent editor, not an intelligent designer. As he argues:
It is as if the editor of Signature of the Cell would have inserted between every two pages of Meyer's book, forty additional pages, each containing the same three hundred letters. Likely, Meyer would not think of his editor as being "intelligent." Would a function ever be found for these one million nearly identical Alu sequences? It seems most unlikely.
Thus, in essence, Ayala claims that (1) a preponderance of nonsense DNA sequences and (2) the random distribution of these sequences shows that the human genome could not have been intelligently designed. But both of the factual claims upon which Ayala bases this argument are wrong.
First, neither the human genome nor the genomes of other organisms are predominantly populated with junk DNA. As I document in Signature in the Cell, the non-protein-coding regions of the genomes (of various organisms) that were long thought to be "junk" or "nonsense" are now known to perform numerous mission-critical functions. Non-protein-coding DNA is neither nonsense nor junk. On page 407 of Signature in the Cell, I enumerate ten separate functions that non-protein-coding regions of the genome are now known to play. (References to peer-reviewed scientific publications documenting my claims are there provided). Overall the non-coding regions of the genome function much like an operating system in a computer in that they direct and regulate the timing and expression of the other protein-coding genetic modules.
Further, the Alu sequences that Ayala specifically cites as prime examples of widely and randomly distributed nonsense sequences in the human genome are NOT non-functional or "nonsense." Short Interspersed Nuclear Element (SINE) sequences of which Alu is one member, perform numerous formatting and regulatory functions in the genomes of all organisms in which they have been found. It is simply factually incorrect for Ayala to claim otherwise.
In general, SINEs (and thus Alus) allow genetic information to be retrieved in multiple different ways from the same DNA data files depending on the specific needs of different cell types or tissues (in different species-specific contexts). In particular, Alu sequences perform many taxon-specific lower-level genomic formatting functions such as: (1) providing alternative start sites for promoter modules in gene expression--somewhat like sectoring on a hard drive (Faulkner et al., 2009; Faulkner and Carninci, 2009); (2) suppressing or "silencing" RNA transcription (Trujillo et al., 2006); (3) dynamically partitioning one gene file from another on the chromosome (Lunyak et al., 2007); (4) providing DNA nodes for signal transduction pathways or binding sites for hormone receptors (Jacobsen et al., 2009; Laperriere et al., 2004); (5) encoding RNAs that modulate transcription (Allen et al., 2004; Espinoza et al., 2004; Walters et al., 2009); and (6) encoding or regulating microRNAs (Gu et al., 2009; Lehnert et al., 2009).
In addition to these lower-level genomic formatting functions, SINEs (including Alus) also perform species-specific higher-level genomic formatting functions such as: (1) modulating the chromatin of classes of GC-rich housekeeping and signal transduction genes (Grover et al., 2003, 2004; Oei et al., 2004; see also Eller et al., 2007); (2) "bar coding" particular segments for chromatin looping between promoter and enhancer elements (Ford and Thanos, 2010); (3) augmenting recombination in sequences where Alus occur (Witherspoon et al., 2009); and (4) assisting in the formation of three-dimensional chromosome territories or "compartments" in the nucleus (Kaplan et al., 1993; see also Pai and Engelke, 2010).
Moreover, Alu sequences also specify many species-specific RNA codes. In particular, they provide: (1) signals for alternative RNA splicing (i.e., they generate multiple messenger RNAs from the same type of precursor transcript) (Gal-Mark et al., 2008; Lei and Vorechovsky, 2005; Lev-Maor et al., 2008) and (2) alternative open-reading frames (exons) (Lev-Maor et al., 2007; Lin et al., 2008; Schwartz et al., 2009). Alu sequences also (3) specify the retention of select RNAs in the nucleus to silence expression (Chen et al., 2008; Walters et al., 2009); (4) regulate the RNA polymerase II machinery during transcription (Mariner et al., 2008; Yakovchuk et al., 2009; Walters et al., 2009); and (5) provide sites for Adenine-to-Inosine RNA editing, a function that is essential for both human development and species-specific brain development (Walters et al., 2009).
Contrary to Ayala's claim, Alu sequences (and other mammalian SINEs) are not distributed randomly but instead manifest a similar "bar-code" distribution pattern along their chromosomes (Chen and Manuelidis, 1989; Gibbs et al., 2004; Korenberg and Rykowski, 1988). Rather like the distribution of the backslashes, semi-colons and spaces involved in the formatting of software code, the "bar-code" distribution of Alu sequences (and other SINEs) reflects a clear functional logic, not sloppy editing or random mutational insertions. For example, Alu sequences are preferentially located in and around protein-coding genes as befits their role in regulating gene expression (Tsirigos and Rigoutsos, 2009). They occur mainly in promoter regions--the start sites for RNA production--and in introns, the segments that break up the protein-coding stretches. Outside of these areas, the numbers of Alu sequences sharply decline. Further, we now know that Alu sequences are directed to (or spliced into) certain preferential hotspots in the genome by the protein complexes or the "integrative machinery" of the cell's information processing system (Levy et al., 2010). This directed distribution of Alu sequences enhances the semantic and syntactical organization of human DNA. It appears to have little to do with the occurrence of random insertional mutations, contrary to the implication of Ayala's "sloppy editor" illustration and argument.
Critics repeatedly claim that the theory of intelligent design is based on religion, not science. But in his response to my book, it is Ayala who relies on a theological argument and who repeatedly misrepresents the scientific literature in a vain attempt to support it. The human genome manifests nonsense sequences and sloppy editing ill-befitting of a deity or any truly intelligent designer, he argues. He also sees other aspects of the natural world that he thinks are inconsistent with the existence of a Deity. I'll leave it to theologians to grapple with Ayala's arguments about whether backaches in old age and other forms of generalized human suffering make the existence of God logically untenable. But on the specific scientific question of the organization of the human genome, I think the evidence is clear. It is Ayala who has been sloppy, and not only in his assessment of the human genome, but also, I must add, in his critique of my book. * * * * * * *
Allen TA, Von Kaenel S, Goodrich JA, Kugel JF. 2004. The SINE-encoded mouse B2 RNA represses mRNA transcription in response to heat shock. Nature Structural and Molecular Biology 11(9): 816-821.
Chen LL, DeCerbo JN, Carmichael GG. 2008. Alu element-mediated gene silencing. EMBO Journal 27(12): 1694-1705.
Chen TL, Manuelidis L. 1989. SINEs and LINEs cluster in distinct DNA fragments of Giemsa band size. Chromosoma 98(5): 309-316.
Eller CD, Regelson M, Merriman B, Nelson S, Horvath S, Marahrens Y. 2007. Repetitive sequence environment distinguishes housekeeping genes. Gene 390(1-2): 153-165.
Espinoza CA, Allen TA, Hieb AR, Kugel JF, Goodrich JA. 2004. B2 RNA binds directly to RNA polymerase II to repress transcript synthesis. Nature Structural and Molecular Biology 11(9): 822-829.
Faulkner GJ, Carninci P. 2009. Altruistic functions for selfish DNA. Cell Cycle 8(18): 2895-2900.
Faulkner GJ, Kimura Y, Daub CO, Wani S, Plessy C, Irvine KM, Schroder K, Cloonan N, Steptoe AL, Lassmann T, Waki K, Hornig N, Arakawa T, Takahashi H, Kawai J, Forrest AR, Suzuki H, Hayashizaki Y, Hume DA, Orlando V, Grimmond SM, Carninci P. 2009. The regulated retrotransposon transcriptome of mammalian cells. Nature Genetics 41(5): 563-571.
Ford E, Thanos D. 2010 (In Press). The transcriptional code of human IFN-beta gene expression. Biochimica et Biophysica Acta.
Gal-Mark N, Schwartz S, Ast G. 2008. Alternative splicing of Alu exons--two arms are better than one. Nucleic Acids Research 36(6): 2012-2023.
Gibbs RA, Weinstock GM, Metzker ML, Muzny DM, et al. 2004. Genome sequence of the Brown Norway rat yields insights into mammalian evolution. Nature 428(6982): 493-521.
Grover D, Majumder PP, B Rao C, Brahmachari SK, Mukerji M. 2003. Nonrandom distribution of alu elements in genes of various functional categories: insight from analysis of human chromosomes 21 and 22. Molecular Biology and Evolution 20(9): 1420-1424.
Grover D, Mukerji M, Bhatnagar P, Kannan K, Brahmachari SK. 2004. Alu repeat analysis in the complete human genome: trends and variations with respect to genomic composition. Bioinformatics 20(6): 813-817.
Gu TJ, Yi X, Zhao XW, Zhao Y, Yin JQ. 2009. Alu-directed transcriptional regulation of some novel miRNAs. BMC Genomics 10: 563.
Jacobsen BM, Jambal P, Schittone SA, Horwitz KB. 2009. ALU repeats in promoters are position-dependent co-response elements (coRE) that enhance or repress transcription by dimeric and monomeric progesterone receptors. Molecular Endocrinology 23(7): 989-1000.
Kaplan FS, Murray J, Sylvester JE, Gonzalez IL, O'Connor JP, Doering JL, Muenke M, Emanuel BS, Zasloff MA. 1993. The topographic organization of repetitive DNA in the human nucleolus. Genomics 15(1): 123-132.
Korenberg JR, Rykowski MC. 1988. Human genome organization: Alu, lines, and the molecular structure of metaphase chromosome bands. Cell 53(3): 391-400.
Laperriere D, Wang TT, White JH, Mader S. 2004. Widespread Alu repeat-driven expansion of consensus DR2 retinoic acid response elements during primate evolution. BMC Genomics 8: 23.
Lehnert S, Van Loo P, Thilakarathne PJ, Marynen P, Verbeke G, Schuit FC. 2009. Evidence for co-evolution between human microRNAs and Alu-repeats. PLoS One 4(2): e4456.
Lei H, Vorechovsky I. 2005. Identification of splicing silencers and enhancers in sense Alus: a role for pseudoacceptors in splice site repression. Molecular Cell Biology 25(16): 6912-6920.
Lev-Maor G, Ram O, Kim E, Sela N, Goren A, Levanon EY, Ast G. 2008. Intronic Alus influence alternative splicing. PLoS Genet. 4(9): e1000204.
Lev-Maor G, Sorek R, Levanon EY, Paz N, Eisenberg E, Ast G. 2007. RNA-editing-mediated exon evolution. Genome Biology 8(2): R29.
Levy A, Schwartz S, Ast G. 2010 (In press). Large-scale discovery of insertion hotspots and preferential integration sites of human transposed elements. Nucleic Acids Research.
Lin L, Shen S, Tye A, Cai JJ, Jiang P, Davidson BL, Xing Y. 2008. Diverse splicing patterns of exonized Alu elements in human tissues. PLoS Genetics 4(10): e1000225.
Lunyak VV, Prefontaine GG, Núñez E, Cramer T, Ju BG, Ohgi KA, Hutt K, Roy R, García-Díaz A, Zhu X, Yung Y, Montoliu L, Glass CK, Rosenfeld MG. 2007. Developmentally regulated activation of a SINE B2 repeat as a domain boundary in organogenesis. Science 317(5835): 248-251.
Mariner PD, Walters RD, Espinoza CA, Drullinger LF, Wagner SD, Kugel JF, Goodrich JA. 2008. Human Alu RNA is a modular transacting repressor of mRNA transcription during heat shock. Molecular Cell 29(4): 499-509.
Oei SL, Babich VS, Kazakov VI, Usmanova NM, Kropotov AV, Tomilin NV. 2004. Clusters of regulatory signals for RNA polymerase II transcription associated with Alu family repeats and CpG islands in human promoters. Genomics 83(5): 873-882.
Pai DA, Engelke DR. 2010. Spatial organization of genes as a component of regulated expression. Chromosoma 119(1): 13-25.
Schwartz S, Gal-Mark N, Kfir N, Oren R, Kim E, Ast G. 2009. Alu exonization events reveal features required for precise recognition of exons by the splicing machinery. PLoS Computional Biology 5(3): e1000300.
Trujillo MA, Sakagashira M, Eberhardt NL. 2006. The human growth hormone gene contains a silencer embedded within an Alu repeat in the 3'-flanking region. Molecular Endocrinology 20(10):2559-2575.
Tsirigos A, Rigoutsos I. 2009. Alu and b1 repeats have been selectively retained in the upstream and intronic regions of genes of specific functional classes. PLoS Computational Biology 5(12): e1000610.
Walters RD, Kugel JF, Goodrich JA. 2009. InvAluable junk: the cellular impact and function of Alu and B2 RNAs. IUBMB Life 61(8): 831-837.
Witherspoon DJ, Watkins WS, Zhang Y, Xing J, Tolpinrud WL, Hedges DJ, Batzer MA, Jorde LB. 2009. Alu repeats increase local recombination rates. BMC Genomics 10: 530.
Yakovchuk P, Goodrich JA, Kugel JF. 2009. B2 RNA and Alu RNA repress transcription by disrupting contacts between RNA polymerase II and promoter DNA within assembled complexes. Proceedings National Academy of Science U S A 106(14): 5569-5574.