Published online 2 June 2008 | Nature | doi:10.1038/news.2008.868

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Genetic analysis revives dispute about why some humans are quadrupeds.

Interest in quadrupedal humans was sparked by a 2006 report on this Turkish family. Jon Lane

A mutated gene may have a role in a rare condition in which humans walk on all fours, researchers say. But precisely how mutations in this gene might stop people from walking upright remains a matter of debate.

The existence of quadruped humans was first publicized by a 2006 British television documentary about a Turkish family in which several adults walk on all fours. Those with the condition also suffer from mental retardation and poor balance.

Since the broadcast, others with the condition have come to light, including one family in Brazil and another in Iraq. The affected individuals all move by what is called a ‘bear crawl’: resting their weight on their wrists and keeping their legs straight and their rears lifted in the air.

One researcher, Uner Tan of Çukurova University in Adana, Turkey, has controversially claimed that the quadrupeds have reverted back to an evolutionary stage before humans walked upright2. He referred to the condition as ‘devolution’ — that is, evolution run in reverse. By that reasoning, the Turkish family could harbour mutations in the genes that allow humans to walk upright, and finding those genes would allow researchers to pinpoint an important event in human evolution.

But others denounced that interpretation. “That was an outrageous claim,” says psychologist Nicholas Humphrey of the London School of Economics, who has also studied the condition. “It didn’t make any sense in genetic or evolutionary terms.” Instead, Humphrey argues that the families have more general problems with balance, and walk on all fours because they did not receive sufficient medical treatment. Give the afflicted a walker, he says, and they are able to stand up and walk.

Disrupted development

Today, at the European Society of Human Genetics meeting in Barcelona, Spain, researchers presented the isolation of a gene that is affected in some quadrupedal families. Tayfun Özçelik of Bilkent University in Ankara, Turkey, and his colleagues, who first published their findings in March, analysed four Turkish families. They found that quadruped individuals in two of the families carry a mutation in a gene called VLDLR1. The gene encodes a protein called very low-density lipoprotein receptor, which is required for proper neural development.

Özçelik does not support the ‘devolution’ concept, but does feel that the VLDLR protein must be specifically important for the ability to walk upright. However, not everyone agrees: the publication of his findings in the Proceedings of the National Academy of Sciences USA prompted two letters, published last week, disputing that claim3,4. Both argued that the mutations in VLDLR produce a more general effect on brain development, particularly in the region of the brain called the cerebellum, which is important in motor control.

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“We’ve found mutations in genes that are involved in development of the cerebellum, but what they’re doing is producing non-specific underdevelopment,” says Humphrey, who, with a team of collaborators, also pinpointed the VLDLR gene in some quadruped patients5. “It’s not necessarily a part of the cerebellum concerned with learning to walk. It could be just balance and the ability to stand upright."

Balancing act

But Özçelik counters that there are dozens of known syndromes that affect the sense of balance, yet none results in quadrupedal behaviour. He also notes that several of the families actively sought medical help, with one family travelling to visit more than ten different doctors. A walker, he says, sometimes helps but those with the syndrome quickly cast it aside and return to walking on all fours.

Meanwhile, genetic analysis suggests that the syndrome is not limited to VLDLR mutations. Quadrupedal walking is linked to a different chromosome in some families. And a member of one of the Turkish families carries a mutation in VLDLR but is able to walk upright, albeit with an off-balance, slightly drunken gait. This, says Özçelik, indicates that VLDLR is only one of a suite of genes that are important for bipedal walking.