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Dover Revisited: With Beta-Globin Pseudogene Now Found to Be Functional, an Icon of the "Junk DNA" Argument Bites the Dust


A new paper in Genome Biology and Evolution argues that the famous beta-globin pseudogene is functional. Why is this pseudogene famous?

Well, it's been Exhibit A -- literally, offered as evidence in a court case -- for critics of intelligent design who argue that our genome is full of useless, functionless junk, and therefore can't be a product of design. Near the beginning of his testimony on the very first day of the 2005 Kitzmiller v. Dover trial, Brown University biology professor Kenneth Miller testified to the court that the beta-globin pseudogene is "broken, and it has a series of molecular errors that render the gene non-functional." (Day 1 AM, p. 79.) He further told the court:

And the fact that all three of these species have matching mistakes leads us to just one conclusion, and that's the same conclusion that Charles Darwin predicted almost a century and a half ago, and that is that these three species share a common ancestor. Matching mistakes are evidence of common ancestry. (Day 1 AM, p. 81)
In his 2008 book Only a Theory, Miller is even more explicit in asserting that this pseudogene refutes intelligent design. He writes that "A detailed analysis of the beta-globin pseudogene shows a series of mutations have rendered it nonfunctional" (p. 102). In Miller's view, that takes care of ID:
The gorilla and chimpanzee pseudogenes have exactly the same set of molecular errors [in their beta-globin pseudogene] ... There's no escaping the implication of these matching mistakes, and there's no point in arguing that six identical mistakes could have turned up independently in three unrelated species. The only sensible interpretation is that the original errors developed at random in a single common ancestor of these three species. In a court of genetic copyright law, any motion that a designer could claim originality for the human genome would be tossed out in a flash. (pp. 102-103)
Now a new paper in Genome Biology and Evolution, "Evolutionary Constraints in the β-Globin Cluster: The Signature of Purifying Selection at the δ-Globin (HBD) Locus and Its Role in Developmental Gene Regulation," argues that the beta-globin pseudogene is not broken, but in fact performs an important function in regulating gene expression. From the abstract:
HBD encodes the d-globin chain of the minor adult hemoglobin (HbA2), which is assumed to be physiologically irrelevant. Paradoxically, reduced diversity levels have been reported for this gene. In this study, we sought a detailed portrait of the genetic variation within the β-globin cluster in a large human population panel from different geographic backgrounds. We resequenced the coding and noncoding regions of the two adult β-globin genes (HBD and HBB) in European and African populations, and analyzed the data from the β-globin cluster (HBE, HBG2, HBG1, HBBP1, HBD, and HBB) in 1,092 individuals representing 14 populations sequenced as part of the 1000 Genomes Project. Additionally, we assessed the diversity levels in nonhuman primates using chimpanzee sequence data provided by the PanMap Project. Comprehensive analyses, based on classic neutrality tests, empirical and haplotype-based studies, revealed that HBD and its neighbor pseudogene HBBP1 have mainly evolved under purifying selection, suggesting that their roles are essential and nonredundant. Moreover, in the light of recent studies on the chromatin conformation of the β-globin cluster, we present evidence sustaining that the strong functional constraints underlying the decreased contemporary diversity at these two regions were not driven by protein function but instead are likely due to a regulatory role in ontogenic switches of gene expression.

(Ana Moleirinho, Susana Seixas, Alexandra M. Lopes, Celeste Bento, Maria J. Prata, and Antonio Amorim, "Evolutionary Constraints in the β-Globin Cluster: The Signature of Purifying Selection at the δ-Globin (HBD) Locus and Its Role in Developmental Gene Regulation," Genome Biology and Evolution, Vol. 5(3): 559-571 (2013) (emphasis added).)

Allow me to help translate.

Humans have six genes related to producing beta-globin, a protein that is one of the two types of globin-molecules that combine to form hemoglobin. Of those six genes, five encode the beta-globin protein, but the sixth, the famous beta-globin pseudogene, has a premature stop codon that prevents it from producing a complete RNA transcript for beta-globin. Darwinian presuppositions have led many scientists, including Ken Miller, to assume this "pseudogene" was "non-functional" genetic junk. However, some researchers were willing to think independently and dig a little deeper.

The researchers in this study looked at copies of the beta-globin genes (including the pseudogene copy, named HBBP1) from 1,092 humans, and from 14 populations around the world. They also looked at chimpanzee copies of the same genes. When they compared all these copies of the genes from different populations and species, they found that the genes, including HBBP1, the pseudogene copy, had less variation (i.e., fewer differences) than would be expected if they were non-functional and, accordingly, accumulating neutral mutations at a constant rate. This suggests that the beta-globin pseudogene is not "non-functional," and has a function.

Of course we know that the beta-globin pseudogene doesn't create a complete RNA transcript for a beta-globin protein. But that doesn't mean it can't play roles in gene expression. That's exactly what the investigators think this protein does, and thus they write: "the strong functional constraints underlying the decreased contemporary diversity at these two regions were not driven by protein function but instead are likely due to a regulatory role in ontogenic switches of gene expression."

Interestingly, they found that regions adjoining the genes exhibit high levels of variation, suggesting that the pseudogene is under "purifying selection" -- i.e., it performs a function and thus natural selection selects against mutations that would change the sequence of the pseudogene:

Taken together, the results obtained for the β-globin cluster cannot be reconciled with other explanatory hypotheses rather than purifying selection: the low values of nucleotide diversity are confined to HBD and HBBP1 and do not extend into the flanking regions which display contrastingly high levels of variation; the haplotype structure of HBD and HBBP1 are similar across worldwide populations
So what is the function? They write: "These recent findings suggest that HBD and HBBP1 might be involved in chromatin looping in the human β-globin cluster, a crucial mechanism for temporal coordination of gene expression." Specifically, they think HBD and HBBP1 play a crucial role in regulating gene expression during development: "we propose that the complex patterns of diversity observed in this genomic region arose from distinct functional constraints related with the intricate process of chromatin and protein interactions coordinating the differential expression of genes at the β-globin cluster during development" (emphasis added).

Of course more work will have to be done to identify the details of exactly how this pseudogene works to regulate gene expression, but given that other studies have already found that chromatin looping is involved in regulating expression of globin genes, the proposal in this paper appears sound. Indeed another recent paper in Genome Research found that the HBBP1 beta-globin pseudogene is associated with DNase I hypersensitivity, which means it is transcribed, and potentially functional. The bottom line is that whatever the exact mechanism turns out to be, it seems strongly supported now to say that this "pseudogene" has genuine function.

But Ken Miller's argument for Darwinian evolution, and against ID, depends on the beta-globin pseudogene being "non-functional," implying as he does that the genetic differences between it and protein-coding beta-globin genes are errors. In light of this new evidence for the functionality of the beta-globin pseudogene, it seems that those genetic differences may not be errors at all. If so, then Miller's argument, his Exhibit A, collapses.

Image: Ronald Reagan Federal Building and Courthouse, Harrisburg, PA/Wikicommons.