Using newly affordable technology, researchers at the University of Utah and other institutions have sequenced for the first time the entire genome of a family.
The study revealed that parents pass fewer genetic mutations to their children than previously thought, which is of interest mostly to evolutionary biologists. But of broader importance to modern medicine -- and to one Utah family -- researchers also zeroed in on the genetic causes of two rare diseases, trailblazing the quest to identify more complex and common genetic disorders.
"Just a few years ago if you had asked me, or other geneticists, we wouldn't have been so sanguine about being able to identify these rare diseases," said physician Jared Roach, senior research scientist at the Seattle-based Institute for Systems Biology, which led the study. "But I anticipate we'll see more of these types of studies over the next 12 months as this technology rolls out."
The study, published Thursday in Science Express, was co-authored by Lynn B. Jorde and Chad D. Huff in the Department of Human Genetics at the U.'s medical school.
No one could be more pleased to be riding the next wave of human genetic research than Debbie Jorde, Lynn Jorde's wife and the woman whose DNA was scrutinized -- along with the DNA of her two adult children, Logan and Heather Madsen, and their biological father.
"It's nice to have answers, though we haven't dwelled on why this happened," Debbie Jorde said of her children's illnesses. "We focused more on handling our challenges. The possibility that we can be of help to other people, human kind, really makes us feel like living with all of these challenges hasn't been a waste; that it was for a reason."
The Madsen children are among only 30 people worldwide who have been diagnosed with Miller's syndrome, a condition characterized by facial and limb malformations. Theirs was the first reported family to have two children affected by the syndrome.
They also inherited Primary Ciliary Dyskinesia (PCD), a rare condition in which the tiny hair-like structures that are supposed to remove mucus from the lungs don't work.
Bound by a strict confidentiality agreement, researchers did not disclose the family's identity. But Debbie Jorde and her children have been the focus of clinical papers and medical school lectures over the years. Logan's paintings have been featured in newspaper articles, and the family consented to be interviewed by The Salt Lake Tribune.
The odds of having both PCD and Miller's syndrome are less than one in 10 billion, which made the family the perfect test case for new family sequencing technology.
David J. Galas at the Institute for Systems Biology wanted to use the new technology to determine the average rate of human genetic mutation, Lynn Jorde explained.
"It's one of those basic constants we as geneticists need to know, sort of like how physicists need to know the speed of light," he said. But until very recently, the technology wasn't readily available or affordable, he added.
Even with the latest technology, pinpointing a mutation among 3 billion "base pairs" of DNA is like finding a needle in a haystack. So the research team needed to find children who had inherited a recessive disorder from parents who showed no genetic abnormalities -- the rarer the better.
"Galas asked, 'Do you know a family like that?' " recalls Lynn Jorde. "I said, 'As a matter of fact, I do.'"
Long before the Jordes met at a social function, and later married, Lynn Jorde had read about the Madsen children. Before agreeing to have their genes sequenced, Debbie Jorde and her adult children underwent counseling and talked to medical ethicists.
Lynn Jorde agreed to certain constraints to avoid any appearance of coercion or conflict-of-interest. Debbie, Logan and Heather agreed that the benefits of narrowing the cause of their disorders outweighed any risk of public exposure.
"Until now we didn't know what caused [Miller's syndrome]. We didn't even know if it was genetic," said Lynn Jorde. "Now we have the causal gene and we understand how it was transmitted."
By comparing the children's DNA sequences to their parents, researchers identified the genes responsible for their disorders. The one tied to Miller's syndrome, "DHOHD," is a metabolic building block, which means it's possible the disease could be treated nutritionally, said Roach. "There's no guarantee, but there's hopeful speculation."
Logan Madsen endures chronic back pain. Together, the siblings have logged 50 reconstructive and life-saving surgeries. They deal with attention deficit disorder and are considered to have autism spectrum disorders. Heather Madsen is plagued by fatigue and undergoes daily therapy for her lungs.
"Life is full in ways I wish it wasn't and not full enough in ways I wish it was," said the 33-year-old. She writes poetry and finds peace in sharing her story and her medical history as it makes her feel less isolated.
Logan, 29, relieved to learn from researchers that it's unlikely he would pass along either PCD or Miller's syndrome to children.
Researchers also were able to estimate that each parent passes 30 mutations to offpsring, far less than previous estimates of 75, a calculation based on evolutionary comparisons of humans to chimps.
"The mutation rate was less than half of what we'd thought," said Lynn Jorde. "That's the kind of power you get from looking at the whole genome."
The rate will need to be replicated with other families before it's considered conclusive. "But it's in line with other estimates, so we think we're on track," said Lynn Jorde.
By the numbers
22,000 » Each person's number of genes, which make up their DNA, the genetic blueprint for human life.
More than 3 billion » The number of "base pairs" that determine genetic makeup.
$3 billion » Cost of the Human Genome Project, begun in 1990 and completed in 2003
$5,000 to $10,000 » Cost today to have a person's genome sequenced