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NHGRI uses new sequencing strategies to rapidly pinpoint causes of rare inherited illnesses
by Jeffrey Bouley  |  Email the author


BETHESDA, Md.—A team of researchers from the National Human Genome Research Institute (NHGRI) has demonstrated a new technical strategy that promises to rapidly determine the genetic cause for very rare inherited illnesses. In addition, the theory is that the knowledge gained from this work might lead to insights on more common illnesses and ways to diagnose or treat them.  
Relying on inexpensive, high-speed sequencing and a newly developed ability to capture pieces of the genome that encode genes, the team diagnosed an extremely rare X chromosome-linked cleft palate syndrome known to affect just two families. The disorder, called TARP (talipes equinovarus, atrial septal defect, robin sequence, persistent left superior vena cava), is caused by a mutation in a gene called RBM10.  
This is the first example of uncovering a gene defect on the X chromosome by analyzing DNA samples from unaffected carriers. In this case, the DNA came from the mothers of the two affected families. DNA was unavailable from any of the affected male infants because they died before, or soon after, birth. TARP syndrome is 100 percent lethal in males.  
The findings were published in the May 14 issue of the American Journal of Human Genetics.   
"This study demonstrates the feasibility of using new sequencing technologies to uncover causative genes for thousands of rare diseases, an effort that historically has been costly and arduous," says the paper's senior author Dr. Leslie G. Biesecker, chief of NHGRI's Genetic Disease Research Branch. "It is also gratifying to know that the two families known to be affected by TARP syndrome finally have answers about what causes the devastating disorder that has afflicted their families for decades."  
"Studying the function of genes in rare diseases—both those we already know something about and the one-third of genes in the human genome we don't yet—can lead to a better understanding of their larger biological function and role in other human diseases," notes Dr. James C. Mullikin, a co-author of the study and acting director of the NIH Sequencing Center in Rockville, Md., where the sequencing work was done. "For instance, further studies of the RBM10 gene may give researchers further insight into more common forms of cleft palate."  
TARP syndrome was originally described in 1970. It affected a single family. Subsequently, it was mapped to the X chromosome by a group that included NHGRI researchers in 2003. However, the mapping work only narrowed the search to a region containing 28 million base pairs, or letters of DNA sequence, on the X chromosome that contained more than 200 genes.  
At the time, sequencing all of those genes to identify and validate variants was a daunting and costly task. So the samples were returned to the refrigerator until recently, when NHGRI researchers identified a second family with TARP syndrome. Meanwhile, new sequencing technologies drove down the cost of sequencing DNA, and another technique was developed for capturing exons. Until recently, it was not possible to sequence the exome on a single chromosome.  
Several months ago, a kit specifically designed to capture and sequence only the exons along the X chromosome prompted the researchers to try again. NHGRI's researchers used the kit to sequence all of the exons on the X chromosomes of the mothers from the two families. Similar kits are currently available or being developed to target the exons on each of the other 22 chromosomes, as well as the Y sex chromosome.
In the original family, the researchers found an insertion of single base pair, a mutation called a single frame-shift mutation, and in the second family the substitution of a single base pair, a mutation called a single nonsense mutation, both within the RBM10 gene, or the RNA binding motif 10 gene. This gene is a member of the larger RBM gene family, but only mutations in a few of its family member genes are known to cause human disorders.  
"There are about 2,500 of these rare, inherited disorders, and the cause of the great majority of them is unknown," says Biesecker. "With the help of these new technologies, biomedical researchers can potentially start making major inroads into finding the genes that cause such diseases."

Complete Neanderthal Genome Sequenced  
So, if use of sequencing technologies for startling rare genetically inherited diseases doesn't seem esoteric enough, guess what else the NHGRI has been up to? Well, a few days before the above story was released, the institute reported that researchers have produced the first whole genome sequence of the 3 billion letters in the Neanderthal genome, and the initial analysis suggests that up to 2 percent of the DNA in the genome of present-day humans outside of Africa originated in Neanderthals or in Neanderthals' ancestors.  
"This sequencing project is a technological tour de force," says Dr. Eric D. Green, director of NHGRI. "You must appreciate that this international team has produced a draft sequence of a genome that existed 400 centuries ago. Their analysis shows the power of comparative genomics and brings new insights to our understanding of human evolution."
The Neanderthal DNA was removed from bones discovered at Vindija Cave in Croatia and prepared in the clean room facility of the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany, to prevent contamination with contemporary DNA.   To understand the genomic differences between present-day humans and Neanderthals, the researchers compared subtle differences in the Neanderthal genome to the genomes found in DNA from the five people, as well as to chimpanzee DNA. An analysis of the genetic variation showed that Neanderthal DNA is 99.7 percent identical to present-day human DNA, and 98.8 percent identical to chimpanzee DNA. Present-day human DNA is also 98.8 percent identical to chimpanzee.  
The comparison between Neanderthal and present-day human genomes has produced a catalog of genetic differences that allow the researchers to identify features that are unique to present-day humans. For example, the catalog includes differences in genes that code for functional elements, such as proteins, in which the Neanderthal versions are more like those of the chimpanzee than present-day humans. Some evolutionary changes were found in known genes involved in cognitive development, skull structure, energy metabolism, skin morphology and wound healing.

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