Keep denying the facts and they'll deny you right back.

Denying ENCODE Data Won't Change the Emerging Facts of Biology

Casey Luskin July 15, 2015 3:20 AM 

Editor's note: This is Part 2 of a 4-part series on ENCODE that Casey Luskin has been publishing this year in Salvo Magazine. Parts 1, 2, and 3 have already been published. Part 4 will be published later this year. Part 1 can be found here atENV.

As we've already seen, the ENCODE project found that 80 percent of the human genome is biochemically functional -- with 100 percent functionality in sight -- overturning the concept of junk DNA. Fearing the demise of a cherished argument, evolutionists immediately retaliated in their customary style -- by becoming emotional and attacking the messengers. Even top journals like Science and Nature recognized the "anger," "rudeness," "intemperate griping,"¹ and "vitriolic . . . hyperbole and mockery"² of ENCODE's critics.

But what were the substantive responses to ENCODE from hard-line evolution-defenders, and do their arguments hold up? Let's examine their top objection.

Arguing That It's Still Junk

The most common counterpoint has been that the ENCODE consortium may have detected "biochemical activity" for most of our genome, but that's very different from demonstrating that the activity has some necessary or important biochemical "function."

According to the central dogma of biology, DNA is transcribed into RNA, and then RNA is translated into protein. ENCODE found that the vast majority of our DNA is making RNA. But what if the process stops there and the RNA isn't doing anything useful? What if it's not junk DNA, but junk RNA?

Under this view, "all this extra transcription may simply be noise, irrelevant to function."³ Or, as outspoken ENCODE critic Dan Graur argues, "transcription is fundamentally a stochastic [random] process," and ENCODE researchers are falling prey to the "human propensity to see meaningful patterns in random data."⁴

Aside from the fact that, even from an evolutionary viewpoint, it would seem colossally wasteful to expend cellular resources creating enormous amounts of RNA from over two-thirds of our genome if that RNA wasn't doing something beneficial, this rejoinder is factually false.

Transcription Isn't Random

ENCODE didn't merely study the genome to determine which DNA elements are biochemically active and making RNA. It also studied patterns of biochemical activity, uncovering highly non-random patterns of RNA production--patterns which indicate that these vast quantities of RNA transcripts aren't junk.

"By studying the trans-cellular patterning of biochemical signatures," writes John Stamatoyannopoulos, a leading ENCODE researcher at the University of Washington, "we gain telling insights into elements responsible for cell-selective regulation of transcript expression, the combinatorial patterns of transcription factors (TFs) that occupy them, and their likely genic targets." ⁵

In other words, we find meaningful patterns of RNA production throughout the genome, creating an orchestrated army of bio-molecules that correlate with the activity of transcription factors--proteins that turn genes on and off. This suggests that our genome's biochemical activity is not just doing something, but doing something very important. And it's not hard to speculate what sort of tasks these RNAs might be doing, for RNA molecules can have all kinds of biochemical functions--including enzymatic properties and gene regulatory functions--whether or not they are translated into proteins.

The fact that DNA transcription is immense--and nonrandom--was confirmed in a 2013 paper that studied RNA transcripts in yeast. It found that while the yeast genome contains only about 6,000 genes, there were over 1.8 million unique RNA transcripts, which were "arranged in a remarkably complex, overlapping pattern across the genome."⁶

RNA Transcripts Specify Development

Clearly RNAs in yeast are encoding many protein sequences. Yeast, however, is only a single-celled organism; in multicellular organisms like animals, RNAs can have additional important functions. They can regulate gene expression and participate in RNA editing and RNA splicing--processes in which different pieces of RNA are stitched together and modified to create new RNA transcripts that in turn can yield additional types of proteins. Such RNA functions have been understood for some time. But a new revelation from ENCODE is that RNAs help specify how cells develop into a particular type.

Animals are composed of many different types of cells. Humans, for example, have nerve cells, blood cells, bone cells, skin cells, and so on. Different kinds of cells combine to form tissues, tissues interact to form organs, and organs coordinate to form an animal's body plan. The distribution of different types of cells is thus foundational to an organism's body plan. But what determines the specific type into which a given cell will develop?

ENCODE's results suggest that a cell's type and functional role in an organism are critically influenced by complex and carefully orchestrated patterns of expression of RNAs inside that cell. As Stamatoyannopoulos observes, ENCODE found that "the majority of regulatory DNA regions are highly cell type-selective," and "the genomic landscape rapidly becomes crowded with regulatory DNA as the number of cell types" studied increases.⁷ Thus, as two pro-ENCODE biochemists explain, "Assertions that the observed transcription represents random noise . . . is more opinion than fact and difficult to reconcile with the exquisite precision of differential cell- and tissue--specific transcription in human cells."⁸

Stamatoyannopoulos further finds that repetitive DNA (often called "transposable elements"), which comprises over 50 percent of our genome, is active only in specific cell types. This non-random transcription of repetitive DNA into RNA suggests that transposable elements have functions whose importance are on par with other gene regulation mechanisms:

In marked contrast to the prevailing wisdom, ENCODE chromatin and transcription studies now suggest that a large number of transposable elements encode highly cell type-selective regulatory DNA that controls not only their own cell-selective transcription, but also those of neighboring genes. Far from an evolutionary dustbin, transposable elements appear to be active and lively members of the genomic regulatory community, deserving of the same level of scrutiny applied to other genic or regulatory features.⁹

Opponents of ENCODE further assert that "there is currently no evidence that the majority of highly repetitive elements are functional."¹⁰ But the vast majority of our genome--including repetitive DNA--is transcribed into RNA in nonrandom, cell-type-specific ways. That is evidence of some important function.

Individual RNA molecules then form networks in a cell, interacting with DNA, proteins, and other RNAs to control which genes are turned on and off, and which genes are expressed as proteins, thereby playing a crucial role in determining the cell's type. As Stamatoyannopoulos puts it, this complex system exudes function:

More of the human genome sequence appears to be used for some reproducible, biochemically defined activity than was previously imagined. Contrary to the initial expectations of many, the overwhelming majority of these activities appear to be state-specific--either restricted to specific cell types or lineages, or evokable in response to a stimulus. . . . [B]iochemical signatures of many ENCODE-defined elements exhibit complex trans-cellular patterns of activity. . . . Together, these observations suggest that the genome may, in fact, be extensively multiply encoded--i.e., that the same DNA element gives rise to different activities in different cell types.¹¹

These consistent and predictable cell-type-specific patterns of RNA expression show that mass genomic transcription of DNA into RNA is not random, but has important functional purposes.

No Accident

Finally, transcription doesn't just happen by accident. It can't start without special stretches of DNA, called promoter sequences, which bind to special enzymes called transcription factors (TFs). And just any enzyme won't do--TFs must be able to recognize the specific DNA promoter sequence that they're keyed to unlock for transcription. Without that precise biochemical correspondence, transcription can't occur.

Once the right TFs bind to a promoter sequence, a molecular machine called RNA polymerase can then find the right place on the DNA to start converting the genomic message into a strand of RNA. The fact that the vast majority of the genome is transcribed suggests that these specified molecules--DNA promoter sequences and TFs--exist and are carefully matched throughout the genome.

If all that RNA is junk, why do these innumerable specified molecules exist throughout our cells?

Faulty Default Assumptions

For ENCODE-critics, however, none of this is enough. Their evolutionary mindset is wedded to the notion that organisms are poorly cobbled, junk-filled kluges. "If you don't know a function," Dan Graur argues, "assume as a null hypothesis that it doesn't have function."¹² His default assumption was dubious to begin with, but ENCODE provides empirical evidence that it is false. As a Nature summary puts it:

Results from the ENCODE project show that most of these [non-coding] stretches of DNA harbour regions that bind proteins and RNA molecules, bringing these into positions from which they cooperate with each other to regulate the function and level of expression of protein-coding genes.¹³

Despite their bluster, critics have been unable to disprove what a leading ENCODE researcher stated in 2014: "There is not a single place in the genome that doesn't have something that you might think could be controlling something else."¹⁴ If we're willing to follow ENCODE's experimental evidence where it leads, unhindered by evolutionary assumptions, evidence of important genomic function is everywhere.

References:

[1.] Yudhijit Bhattacharjee, "The Vigilante," Science, 343:1306-1309 (March 21, 2014).

[2.] "ENCODE debate revived online," Nature, 509:137 (May 8, 2014).

[3.] Philip Ball, "Celebrate the Unknowns," Nature, 496:419-420 (April 25, 2013). See also Alexander Palazzo and T. Ryan Gregory, "The Case for Junk DNA," PLOS Genetics, 10(5):e1004351 (May 2014); W. Ford Doolittle, "Is junk DNA bunk? A critique of ENCODE," Proceedings of the National Academy of Sciences, 110(14):5294-5300 (April 2, 2013); Graur et al., "On the Immortality of Television Sets: 'Function' in the human genome according to the evolution-free gospel of ENCODE," Genome Biology and Evolution, 5(3):578-590 (2013); and Deng-Ke Niu and Li Jiang, "Can ENCODE tell us how much junk DNA we carry in our genome?" Biochemical and Biophysical Research Communications, 430:1340-1343 (2013).

[4.] Graur et al., "On the Immortality of Television Sets."

[5.] John Stamatoyannopoulos, "What does our genome encode?" Genome Research, 22:1602-1611 (2012).

[6.] Pelechano et al., "Extensive transcriptional heterogeneity revealed by isoform profiling," Nature, 497:127-131 (May 2, 2013).

[7.] Stamatoyannopoulos, "What does our genome encode?"

[8.] John Mattick and Marcel Dinger, "The extent of functionality in the human genome," The HUGO Journal, 7:2 (2013).

[9.] Stamatoyannopoulos, "What does our genome encode?"

[10.] Palazzo and Gregory, "The Case for Junk DNA."

[11.] Stamatoyannopoulos, "What does our genome encode?"

[12.] Bhattacharjee, "The Vigilante."

[13.] Ines Barroso, "Non-coding but functional," Nature, 489:54 (Sept. 6, 2012).

[14.] Bhattacharjee, "The Vigilante."