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Remember in 2005-06 when there was a whole lot of buzz about the quadrupedal siblings in Turkey? There first was this paper, “Cerebellar hypoplasia and quadrupedal locomotion in humans as a recessive trait mapping to chromosome 17p,” and then there was this paper, “A new syndrome with quadrupedal gait, primitive speech, and severe mental retardation as a live model for human evolution,” which made a big splash… enough of a splash that a NOVA special was made.

John Hawks criticized this all, especially on the merit if this ‘behavior’ is due to genetic mutations, but he also had beef with how the press was handling the implications of these people. I too didn’t like how everyone was calling these modern humans with a syndrome as primitive cavemen, but what can you do?

Of course, as physical anthropologists, we can’t ignore these quadrupeds because they walk on all fours, and some of our closest evolutionary cousins (chimpanzees and gorillas) also walk on all fours. But you can’t say these people reverted back to a more ancestral primate locomotion technique. Chimps and gorillas walk on their knuckles, whereas these people walk plantigrade. Also, they look more strained walking on fours than do our more furry primate brethren, and that makes sense because limb proportions and overall body size of these people still are bipedal in pattern.

Walking on All Fours

Well, it has been pretty quiet since then. We haven’t heard much from the two families in Turkey who walk on all fours, have speech deficiencies, and exhibit hypoplasia of the brain. I think that will all change with this new awesome PNAS paper that just came out recently. The paper, “Mutations in the very low-density lipoprotein receptor VLDLR cause cerebellar hypoplasia and quadrupedal locomotion in humans,” identifies two mutations in the VLDLR gene from members of the family who have this syndrome.

The last author of this new paper, Uner Tan, was actually the guy who published that 2006 paper which got Hawks to say Tan is incorrect in thinking that the language and locomotion disabilities of these quadrupeds in Turkey are genetically linked. Hawks said,

“Human bipedality and human cognition are both highly complex traits involving anatomical, developmental, and behavioral specializations. Each of them involved hundreds, and for cognition I would say thousands, of different genetic changes. There was no small set of macromutations that caused these traits to arise…

….I think it’s really unlikely that a gene that causes cerebellar ataxia was a critical bipedality gene. It may be necessary to walking normally, but it probably (indeed, evidently from the nature of the disorder) is very important to a lot of other things as well. A gene that breaks early brain development is no more likely than other genes to have a specific function role in the development or practice of bipedalism in humans…

…The main point is this: the fact that a gene breaks something doesn’t mean that it was the key gene necessary to create something. Suppose that you want to figure out how a car works. So you look at cars that aren’t working right, and you see what is broken. Now, you will notice that cars run sort of poorly with flat tires, they run with depleted batteries but won’t start, they will run for a bit without motor oil, but then seize up, and so on.

Cerebellar ataxia breaks a whole lot of things. It’s like breaking the crankshaft — the engine might run, but it is going to make a whole lot of noise, and the car isn’t going to move. We may conclude that the crankshaft is necessary for the wheels to move. But does that mean that the crankshaft is the key component of the wheel? Clearly not.

The analogy between cars and organismal development is useful because both systems depend on hierarchical functions. Early things must all work right for later things to develop. When an upstream gene (or part) breaks, it doesn’t mean that downstream things affected by the broken gene were caused by the broken gene.”

Now it seems like Tan et al. have found a gene that affects the development of bipedality and language, as well as a lot of other things. Actually the authors used genome-wide analytic tools to genetically map regions on three different chromosomes that are shared and are responsible for the condition seen in the two different families. Most the most interesting genetic similarity is a homozygoitic 1.3 megabase region of chromosome 9. Within this region, lies the gene VLDLR.

VLDLR is a gene that encodes a low density lipoprotein receptor. Its widely found in heart, skeletal muscle, and adipose tissue and thought to function in fatty acid metabolism, bringing in different molecules like enzymes and transporters into the cell. VLDLR has been actually identified as a critical component of the reelin signaling pathway, a cascade of events that develop the central nervous system. So it is not exclusively expressed in heart, muscle, and fat. Any deleterious mutation in VLDLR would ultimately effect how the nervous system is made and how it functions. Since locomotion and language are controlled by the central nervous system, you can begin to see how important VLDLR is. Aside from neural development, the authors hypothesize that VLDLR functions in positioning cells in the brain, and maturing the cerebellum so that bipedalism can function.

The authors decided to hone in on VLDLR. They made a pedigree chart that shows the affected individuals, and sequenced the VLDLR gene from affected individuals in both families. They were able to identify two mutant alleles, specific to each family, that deviated with the wild type VLDLR gene. Affected individuals in the first family carried a swap of a cytosine to a thymine in position 769 of the gene. This is a single nucleotide polymorphism (SNP) that caused a nonsense mutation, resulting in a premature stop codon. The second family actually had a deletion of a thymine in position 2339. This is also a single nucleotide SNP. Had this deletion been in 3 bases, carriers of this allele may have had a functioning VLDLR receptor, but since it involved a single base, a frame shift occurred and basically messed up everything downstream. I’ve taken out the chormatogram from the sequencing to show you what the mutations look like:

VLDLR sequence comparison of two quadrupedal families from Turkey

The authors confirmed the extent of these mutations using qPCR. They were able to show how the early stop and frameshift mutations are both in the part of resultant protein that binds reelin, and ultimately are not able to begin the reelin signal transduction.

This paper is really elegant! It is very simple and powerful. They were able to correlate a phenotype to a mutation in a important gene that affects how the nervous system is developed, and how it functions. Since these people affected by Unertan syndrome have serious neurological disorders, it is a pretty clear genotype-phenotype association. I feel Tan and crew are vindicated from Hawks criticisms.

    Ozcelik, T., Akarsu, N., Uz, E., Caglayan, S., Gulsuner, S., Onat, O.E., Tan, M., Tan, U. (2008). Mutations in the very low-density lipoprotein receptor VLDLR cause cerebellar hypoplasia and quadrupedal locomotion in humans. Proceedings of the National Academy of Sciences DOI: 10.1073/pnas.0710010105
    TAN, U. (2006). A NEW SYNDROME WITH QUADRUPEDAL GAIT, PRIMITIVE SPEECH, AND SEVERE MENTAL RETARDATION AS A LIVE MODEL FOR HUMAN EVOLUTION. International Journal of Neuroscience, 116(3), 361-369. DOI: 10.1080/00207450500455330
    Turkmen, S. (2005). Cerebellar hypoplasia and quadrupedal locomotion in humans as a recessive trait mapping to chromosome 17p. Journal of Medical Genetics, 43(5), 461-464. DOI: 10.1136/jmg.2005.040030
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