Child fossil shows molecular complexity of bone disease

In 2003, a skeleton was discovered in the Atacama Desert in Chile. This skeleton, which has since been named “Ata” was tiny, about six inches long, with strange and dramatic deformities: a long skull pointed at the top, deep angular eye sockets and fewer ribs than normal. Some observers thought it looked alien. 

Ata eventually ended up in a private collection in Spain and came to the attention of Garry Nolan, an immunologist at Stanford University. 

With the permission of Ata’s owner, samples of bone marrow were taken from the skeleton’s ribs and humerus, and Nolan and his collaborators extracted fragments of DNA from the bone marrow cells. 

The process was unexpectedly successful, as the DNA was more abundant and less degraded than predicted, suggesting that the skeleton was mere decades, rather than centuries, old. 

Nolan and his colleagues were able to determine the majority of Ata’s DNA sequence, and after comparisons with human and primate genomes, they concluded in 2013 that the skeleton was that of a human. 

Although eight percent of the DNA could not be confirmed as human during initial whole-genome sequencing efforts, this was determined to be a result of degradation, and subsequent analyses returned a match of around 98 percent. 

Since there was no evidence of a Y chromosome, Ata was determined to be female. The presence of the mitochondrial B2 haplotype suggested that Ata had indigenous Chilean ancestry and other analyses indicated European ancestry as well. 

After this information about Ata’s origins emerged, there was still the mystery of the skeleton’s deformations. Misshapen bones, though the most visible, were not the only intriguing characteristics. 

Ata was around the size of a 20-week-old fetus. However, when Ralph Lachman, a pediatric radiologist at Stanford, examined X-rays of the skeleton, he noted some features as characteristic of a six- to eight-year-old child. 

A study published on March 22 in the journal Genome Research reported findings gathered over five years of extensive analysis of Ata’s genome. Over 3 million single nucleotide variations, over 500,000 insertions or deletions, and over 1000 structural variations were found, as compared with a reference human genome. 

The authors reported the presence of mutations in seven genes associated with bone abnormalities, including short stature, scoliosis, Ehlers-Danlos syndrome and cranioectodermal dysplasia. In addition, researchers identified several novel missense single nucleotide variations, which computer algorithms predicted could have damaging effects.

Some of these variations were in genes associated with collagen, an important structural protein that makes up most of the organic content of bone. The authors theorized that this combination of known and novel mutations could explain Ata’s various abnormalities, including the skeleton’s small size, inconsistent apparent age and misshapen skull. 

The authors also noted that the area in Chile where Ata was found was once a nitrate mining town, suggesting that the mutations may have been a result of DNA damage from nitrate exposure while Ata was still in the womb. Nolan theorized that Ata may have been stillborn or died soon after birth. 

In addition to being an intriguing scientific mystery, Ata may have implications for how scientists and doctors examine genetic diseases. 

“To me, it seems that when doctors perform analyses for patients and their families, we’re often searching for one cause,” Atul Butte, director of the Institute for Computational Health Sciences at the University of California, San Francisco, said in a press release. 

However, the large variety of mutations found in Ata’s genome might indicate the value of looking at multiple genetic causes for a disorder. 

“We’re going to want to make sure that if there’s one mutation, we know that — but if there’s more than one, we know that too,” Butte said.