In 2007, Eugenie Scott, a leading anti-ID activist, gave a lecture at the American Museum of Natural History titled “What Do Creationists Believe about Human Evolution?” The talk, which I’ve been responding to here, was sponsored by the Leakey Foundation, a human origins research and education group, and it was recently posted on their YouTube channel where it’s attracting some attention. In the first part of this response we saw how Dr. Scott conflated ID with creationism, and in the second part we saw how she misunderstood ID’s challenge to evolution and glossed over problems with unguided Darwinian explanations of the origin of Homo based on the non-gradual increase in hominid skull sizes. After covering fossils, in her lecture Dr. Scott presents two genetic arguments for common ancestry between humans and apes.
“Perhaps the best rebuttal to the design argument is the existence of something called pseudogenes,” Scott states. “Pseudogenes are screwed-up genes,” she says in her first argument. She then proceeds to cite the beta-globin pseudogene — the example used by leading theistic evolutionist biologist Kenneth Miller in the Kitzmiller v. Dover trial.
Just Sitting There, Not Doing Diddly
Scott confidently asserts that because of mutations the beta-globin pseudogene “isn’t going to do diddly. It’s just going to sit there” and “not do a thing.” She goes on to say this pseudogene is “not going to function. It’s not going to do anything” because it is an “inert gene.” Her slide, which she borrowed (with permission, she notes) from Ken Miller’s slide deck at the 2005 Kitzmiller v. Dover trial, calls the beta-globin pseudogene “non-functional.” During the trial, Miller likewise testified that the human beta-globin pseudogene is “broken” because “it has a series of molecular errors that render the gene non-functional.” Since humans, chimpanzees, and gorillas share “matching mistakes” in the pseudogene, he told the court, this “leads us to just one conclusion … that these three species share a common ancestor.” In her lecture, Scott wraps a bow on the story as evidence for evolution:
What is the explanation for this? Well, an evolutionary explanation is that all of these organisms inherited this pseudogene from a common ancestor. The creationist explanation for this would have to be God separately created a dysfunctional gene in humans, in monkeys, in apes, and in lemurs. Maybe he did. But it’s not the most parsimonious explanations. It makes much more sense, as Dobzhansky said, why are things like they are instead of some other way? Common ancestry makes biology makes sense.
It’s a nice tidy story. But a 2013 study in Genome Biology and Evolution showed it is false. Titled, “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,” the paper reported the beta-globin pseudogene is functional. And as we’ll see below, a 2021 paper in Developmental Cell found that this pseudogene—which Dr. Scott claimed does “diddly”—has “essentiality” and “indispensability” for human red blood cell formation.
A Functional Pseudogene
Humans have six copies of the beta-globin gene. Five produce beta-globin proteins, but the sixth, the pseudogene copy, has a premature stop codon (and other mutations) that prevent translation into a protein. In Scott’s telling this means that the pseudogene cannot have any function whatsoever. But molecular biology now knows that pseudogenes can produce transcripts which can regulate protein-coding versions of the same gene—and that’s exactly what the researchers propose is going on here.
They compared all six genes across humans and chimpanzees, and found the beta-globin pseudogene exhibits fewer differences than would be expected if it were non-functional and accumulating random mutations at a constant rate. This “conserved” sequence suggests the beta-globin pseudogene has a selectable function, making it less tolerant of mutations — what is often called “purifying selection.” The beta-globin pseudogene’s inability to produce a translatable RNA transcript does not preclude it from being functional. The researchers argue the pseudogene HBBP1 works something like an on/off switch, regulating expression of protein-coding beta-globin genes. Here’s a lengthy quote from the paper:
[I]n 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. … Over the past years, the β-globin cluster has been regarded as a complex genetic system and a paradigm of gene expression regulation. More recently, a boost of studies on the β-globin cluster have contributed to a better understanding of the mechanisms underlying the regulation of each gene in the cluster. Remarkably, chromosome conformation (3C and 5C) analyses for the β-globin locus disclosed strong interactions between the LCR and the region encompassing both HBD and HBBP1. Furthermore, distinct spatial interactions of the LCR in fetal and adult stages were uncovered by another study based only in 3C assay in which HBD sequence was proposed to be enrolled in the maintenance of a transcriptionally competent structure at the adult stage. 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. Importantly, one SNP (rs10128556) in HBBP1 has been also identified as a modulator of HbF levels reinforcing the idea that this genomic region is indeed involved in the Hb fetal-to-adult switch. … We hypothesize that the clear signature of purifying selection at HBD and HBBP1 may reflect constraints on local chromatin conformation and the maintenance of a nucleosome free region available for frequent interactions with the LCR. … [P]urifying selection is driving not only HBD evolution but also its neighbor pseudogene, HBBP1. In the light of recent advances in the characterization of the β-globin cluster, 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. [Internal citations removed.]
But there’s a lot more to this story. You’ll note that they “hypothesize” function based upon clear genetic evidence and knowledge of how gene regulation operates. The precise function of the HBBP1 pseudogene was confirmed and identified in a 2021 paper published in Developmental Cell titled “Genome-wide analysis of pseudogenes reveals HBBP1’s human-specific essentiality in erythropoiesis and implication in b-thalassemia.”
HBBP1 “Indispensability” Confirmed by Empirical Study
The 2021 paper was unmistakable in reporting the important function of this pseudogene, stating: “Pseudogenic HBBP1 confers human-specific essentiality in erythropoiesis.” Erythropoiesis is the process of producing red blood cells, and they report “human-specific indispensability of the HBBP1 transcript” in erythropoiesis and find “HBBP1 is essential for erythroid development and differentiation.”
Because it’s difficult to do studies on living humans, most studies finding functions for human pseudogenes are forced to infer function based upon the presence of a naturally occurring disease where some genetic element isn’t working properly. But this study is innovative in that it sought to understand a pseudogene that is functional and even essential in healthy humans. The paper explains:
In this study, we aimed to generate an overview of the function of pseudogenes under normal conditions by implementing an integrative strategy in humans, thereby prioritizing candidates for in-depth studies of their function, mechanism, clinical relevance, and evolution. We found that one duplicated pseudogene, hemoglobin subunit beta pseudogene 1 (HBBP1), is essential for human erythropoiesis by competitively binding RNA-heterogeneous nuclear ribonucleoprotein A1 (HNRNPA1) and upregulating T cell acute lymphocytic leukemia 1 (TAL1), a key regulator of erythropoiesis. Moreover, the essentiality of HBBP1 and its interaction with TAL1 is human-specific. … Overall, our analyses demonstrate pseudogenes’ tissue-specific expression and suggest their functions in both normal and pathological bone marrow.
… The impact on early erythroid differentiation (day 11) suggests that HBBP1 mediates early erythroid-lineage development. … Collectively, deletion of the HBBP1 locus or impairment of its transcription leads to defective erythroid-lineage commitment. … Given HBBP1’s high expression at birth and in adulthood, we predicted that HBBP1 functions similarly during adult erythropoiesis. Thus, we introduced a third system by extracting HSPCs from adult bone marrow (BM) and conducting loss-of-function studies through knockdown of HBBP1. Analogously, there were fewer erythroblasts and lower expression of hemoglobin. Note that HBBP1 depletion appears to be correlated with globin switching from fetal to adult ß-globin… In summary, our loss-of-function studies supported the importance of HBBP1 transcripts for erythroid-lineage commitment and maturation. [Internal citations omitted.]
As a functional pseudogene, they found that HBBP1 is not an “outlier” but could represent a common mode of gene regulation among a particular class of pseudogenes:
Finally, we ask whether HBBP1 represents an outlier or indicates a pattern in duplicated pseudogenes acting as RBP [RNA-binding protein] decoys. To approach this question, we analyzed the transcriptome and interactome features of duplicated pseudogenes relative to retropseudogenes. … The 104 RBP-binding duplicated pseudogenes share two features similar to HBBP1: (1) stronger co-regulation with their coding paralogs as revealed by higher correlation compared with pseudogenes without RBP-binding (0.31 versus 0.15), (2) pseudogene-specific binding for the majority (62%) of cases. Together with pseudogenes’ low conservation, a proportion of duplicated pseudogenes may shape human evolution by interacting with RBPs. (internal citations omitted)
Who Is Stopping Science?
The authors of the 2021 study conclude that their research findings have “far-reaching implications regarding the functions of pseudogenes, their underlying mechanisms, and species-specific phenotypes.” Citing some of the same studies I reviewed in my recent commentary on pseudogene functionality, they note that, “Possibly due to the traditional view that pseudogenes are functionless evolutionary relics, only dozens of human pseudogenes have been functionally characterized.”
That traditional view of pseudogenes as “functionless evolutionary relics” is exactly what Eugenie Scott promotes in her lecture (following Ken Miller’s Dover testimony). Yet the paper finds this traditional view is wrong: “these analyses emphasize the significance of functional pseudogenes and echo the emerging opinion that pseudogenes should not be excluded from functional analyses.” The study’s authors continue:
In conclusion, pseudogenes represent a new layer in the flow of genetic information. The highly integrative framework implemented in this study provides a prototype for determining the function of pseudogenes under normal and pathological conditions. Exploration of species-specific regulatory functions of pseudogenes or even studies of population-specific pseudogenes are expected to blossom in future.
In other words, the “traditional view” that pseudogenes are “functionless evolutionary relics” has hindered research into understanding the true nature of pseudogenes. But now that we’re overcoming that old view, they expect studies elucidating specific functions of pseudogenes to “blossom” in the future.
The implication of this story is that in their rush to oppose intelligent design, Darwin defenders like Eugenie Scott and Ken Miller not only made an argument that has turned out to be completely wrong. It may also have slowed the progress of science.
Next and final post, “Chromosomal Fusion and Correcting Mistakes: Retrospective on an Old Debate.”