Introduction
In 2005, Uner Tan described a never-before-seen syndrome that he observed in a Turkish family of 19 (Tan 2005). The disorder, labeled Unertan Syndrome, causes severe mental retardation, primitive language capabilities, and, most notably, quadrupedality (the use of four limbs to walk). Tan observed that 5 out of the 19 family members were affected by this autosomal, recessive disease, which was likely the result of inbreeding. Affected individuals were between the ages of 15 and 32 and walked exclusively on their hands and their feet.
The discovery of this unusual trait was of great interest to scientists around the world. Many hoped that the cause of Unertan Syndrome could be traced to a specific genetic mutation that would shed light on the evolution of bipedalism in humans. The story of the Turkish "handwalkers" also caught a great deal of attention in the popular press. In 2006, NOVA ran a documentary on the Turkish family, looking at the potential scientific impact of genetic analysis on the quadruped family (NOVA 2006). Below is the trailer for the NOVA documentary.
Journal Article
In March of 2008, a paper was published in PNAS that investigated the genetic cause of Unertan Syndrome by performing genome-wide linkage analysis on individuals from 4 families (A-D) affected by the disorder (Ozcelik 2008). All affected individuals had similar phenotypes: significant underdevelopment of the cerebellum (cerebellar and verminal hypoplasia), severe mental retardation, and quadrupedal locomotion (Figure 1). Genetic causes were suspected to account for both the underdevelopment of the cerebellum and the inability to walk on two feet. It is important to note that many of the individuals sought medical attention to rid themselves quadrpedal movement, with little to no success. Thus, environmental factors were likely not the sole cause of the disease in general and quadrupedal locomotion specifically. Based on the inheritance pattern of the disease, it appeared to be autosomal, recessive in nature.
Figure 1: Phenotypic (A) and cranial radiologic (B) presentation of quadrupedal gait.
Affected individuals suffered from severe underdevelopment of the cerebellum,
including in some cases the lack of the inferior vermis (Figure extracted from Ozcelik 2008).
Linkage analysis showed that the disorder was genetically heterogeneous, as it mapped to the 9p24 region in families A and D, while mapping to the 17p13 region in families B and C. In this paper, only the 9p24 mutations were investigated, making families A and D the primary focus of the paper. However, the author makes it clear that future studies will investigate the 17p13 region to try to piece together the molecular cause of Unertan Syndrome.
The 9p24 chromosomal region contains the VLDLR (very low density lipoprotein receptor) gene, known to be involved in brain development and cerebellar maturation. This gene was, therefore, a likely candidate for mutations in individuals from families A and D that could be the cause of Unertan Syndrome. Sequencing of the VLDLR gene was done for all individuals from both families, and two distinct mutations were discovered (Figure 2). In family A, a nonsense mutation (C to T) was found at base pair 769. In family D, a one base deletion was found at base pair 2339. Both of these mutations resulted in premature stop codons in the VLDLR gene, causing truncation of the lipoprotein receptor. For individuals in families A and D, truncation of the very low-density lipoprotein receptor (VLDLR) seems to be the cause of Unertan Syndrome. Linkage analysis showed that the disease was recessive. The pedigree of family A (Figure 3) demonstrates the recessive nature of the disease.
Figure 2: Identification of VLDLR mutations in families A and D. (A)
Sequencing results for a homozygous recessive individual from family A with the
VLDLR c769C->T nonsense mutation (left, top) compared with a homozygous
dominant individual (left, bottom). (B) Affected individuals in family D (right, top)
were homozygous for a one nucleotide deletion (c2339delT) that resulted in a
premature stop codon. (Figure extracted from Ozcelik 2008)
Figure 3: Pedigree of family A. Black symbols represent affected individuals.
Squares indicate males, and circles indicate females. Black bars represent the
haplotype carrying the VLDLR mutation. The high frequency of disease haplotypes
in the pedigree is likely the result of significant inbreeding (Figure extracted from
Ozcelik 2008).
After demonstrating that mutations in VLDLR were the likely cause of Unertan Syndrome in families A and D, the paper then briefly discusses the molecular role of the lipoprotein. VLDLR is a transmembrane protein that has been shown to be important for brain development. As a component on the reelin pathway, VLDLR helps with the migration of neurons along glial fibers during the development on brain tissues. In the cerebellum specifically, the reelin pathway regulates Purkinje cell alignment.
VLDLR contains 19 exons. The mutation seen in family A occurs in exon 5, while the mutation in family D occurs in exon 17 (Figure 4). Both of these mutations would prevent the translation of the transmembrane domain of the protein (Figure 4), and it is hypothesized that the protein cannot be inserted into the cell membrane as a result. Without VLDLR in the membrane of the cell, the paper suggests that brain development is greatly hindered, especially in the cerebellum.
Figure 4: Structure and Molecular Mechanism of VLDLR. (A) VLDLR contains 19 exons. Mutations in families A (R257X) and D
(17OTfsX3) are indicated with arrows. Both mutations cause truncation of the protein. (B) Because VLDLR is truncated by each mutation,
neither mutated protein has a transmembrane domain. It is hypothesized that VLDLR can, therefore, not localize to the membrane to assist
in brain development via the reelin pathway (Figure extracted from Ozcelik 2008).
Based on the data presented in this paper, it is safe to say that VLDLR is one of the causes of Unertan Syndrome. However, there is at least one other genetic cause of the disease, most likely located on chromosome 17p13. The exact molecular mechanism of VLDLR is also not fully understood. The author makes it clear that much more work remains to be done. It is likely that this breakthrough will give us a better understanding of the evolution of bipedalism in the future, but for now, those types of claims are merely speculation. This paper was a first step towards a much larger goal.
Popular Press
The popular press found the story of the "handwalkers" to be of great public interest. Aside from being a strange and mysterious condition, Unertan Syndrome may hold the key to understanding how humans came to walk upright. This press attention makes the topic a good candidate for comparing scientific literature with scientific journalism. I will look specifically at two articles and analyze them in the context of the scientific publication that was previously discussed.
Science Daily: Genetic mutation linked to walking on all fours.This BBC article does a fairly good job of explaining the science of the PNAS article in simpler terms, but it changes the focus of the PNAS article slightly. The author correctly points out that the researchers "found that the affected individuals in two families had mutations in the gene responsible for the expression of very low density lipoprotein receptor (VLDLR), a protein which is known to be critical to the proper functioning of the cerebellum during development." These claims are supported by the data presented in the paper.
However, the link to quadrupedalism is less obvious. From the title of the article, it is suggested that the findings of the PNAS paper indicate a direct link between bipedalism and VLDLR. This is untrue and not supported by the data. While the title is somewhat overstated, the body of the article does point out that "it has been suggested in the past that lack of access to medical care exacerbated the effects of an under-developed cerebellum, and that this led to quadrupedality." The author is also quick to point out that the "Hutterites, a group of Anabaptists who line in colonies of North America," have been found to be deficient in VLDLR, but "most of the affected individuals cannot walk at all." While these points definitely question the link between VLDLR and bipedalism, it is the author himself, and not the PNAS article, who suggested this direct link in the first place.
BBC News: Quadruped families evolution clueOnce again, while the text of this article is accurate, the title overstates the findings described in the PNAS paper. The author makes a fairly large jump in claiming that the discovery of a single genetic cause of Unertan Syndrome is a clue to the evolution of bipedalism in humans. Before that claim can be made, researchers must demonstrate that the quadruped locomotion of the handwalkers is not just a side-effect of other symptoms that result from cerebellar hypoplasia. Still, the body of the article is surprisingly accurate. The author includes a quote from scientist Nicholas Humphrey, who says, "I do not believe for a moment that what we have here is a gene for walking on all four legs." I think that the author of the PNAS paper would agree with this claim. The fact that VLDLR is linked to quadrupedalism certainly does not in itself convey any evolutionary significance, as I'm sure the author of the PNAS paper would agree. However, it does hold potential for directing future research on the topic which may shed light on the evolution of bipedalism in humans.
Conclusion
In comparing the primary source journal article from PNAS with popular press articles from BBC and Science Daily, I was surprised at the accuracy of the reporting. Within the body of the text, no untrue claims were made. Additionally, the authors of the articles did a good job of presenting views that opposed the conclusion that VLDLR was directly associated with quadrupedalism. However, I also found that the titles of the articles were much more overstated than the articles themselves. This is understandable, as it is no doubt important to have a title that will catch someone's attention quickly. It is, therefore, important that the reader of scientific journalism read the text for what it says and not for what the title of the article may imply.
As for the story of the handwalkers and the evolution of bipedalism, much more research on the topic is necessary before significant conclusions can be drawn. The research in this study has shown that more than one gene is responsible for the onset of Unertan Syndrome. Likewise, it is highly unlikely that a single gene would be responsible for walking on two feet. Gene's involved in the development of balance (such as VLDLR), morphology, and other factors are all likely to contribute to this very human trait. Regardless, using genomic approaches to analyze the cause of Unertan Syndrome will doubtlessly help in the understanding of why humans walk on two feet instead of four.
References
European Society of Human Genetics. 2008, June 4. Genetic Mutation Linked To Walking On All Fours. ScienceDaily. <http://www.sciencedaily.com/releases/2008/06/080602075844.htm>. Accessed 2008, September 14.
Family that Walks on All Fours. 2006, November 14. NOVA. <http://www.pbs.org/wgbh/nova/allfours/about.html>. Accessed 2008, August 31.
Ozcelik, Tayfun et al. 2008, March 18. Mutations in the very low-density lipoprotein receptor VLDLR cause cerebellar hypoplasia and quadrupedal locomotion in humans. Proceedings of the National Academy of Sciences. <http://www.pnas.org/content/105/11/4232.abstract?etoc>. Accessed 2008, August 31.
Quadruped families evolution clue. 2008, June 1. BBC News. <http://news.bbc.co.uk/2/hi/health/7427525.stm>. Accessed 2008, September 16.
Tan, Uner. 2005. A new syndrome with quadrupedal gait, primitive speech, and severe mental retardation as a live model for human evolution. International Journal of Neuroscience. <http://cogprints.org/4941/1/UNERTAN_SYNDROME_(IJN).pdf>. Accessed 2008, September 16.