By Carolyn Y. Johnson
Washington Post
When couples have trouble conceiving a baby or lose a pregnancy, they often undergo routine tests, which can turn up a shock: One of the prospective parents may be missing a chromosome.
The most common chromosomal abnormality – carried by about 1 in 800 people – is a “Robertsonian translocation,” when two chromosomes get fused together. People are often healthy, but one short of the typical 46 chromosomes for a human. Most don’t learn they carry this genetic anomaly unless they experience reproductive problems and seek testing.
Robertsonians – commonly abbreviated as ROBs – are the stuff of genetics textbooks. First discovered in grasshoppers in 1916 by W.R.B. Robertson, a zoologist and geneticist, they have been observed in mice, catfish, cattle, plants, butterflies, bats and people.
Last week in the journal Nature, a team led by scientists at Stowers Institute for Medical Research in Missouri pieced together for the first time the precise mechanics of how these rearrangements occur in humans by using new genome sequencing technologies to study the fused ROBs of three people. The research reveals that swaths of DNA previously overlooked as junk are playing a key role in how chromosomes end up fused together and how they evolve.
Unraveling how ROBs form is basic science, unlikely to have an immediate impact on anyone’s health or fertility, but it shows how new technologies continue to open doors, solving decades-old mysteries. Researchers are already beginning to use what they’ve learned to mine existing genetic databases to see if they can find people who unwittingly carry ROB chromosomes, to see if they’re at elevated risk for cancers, infertility or rare diseases. This type of research could also pave the way to better understanding genetic diseases or one day lead to new tools to help people understand their reproductive risks.
“In my genetics classes, it was taught. People talked about how this could lead to … functional consequences – infertility and perhaps cancer. The conversation always stopped there: We don’t know how it happens,” said Glennis Logsdon, a genome scientist at the University of Pennsylvania Perelman School of Medicine who was not involved in the study. “That’s where this paper picks up.”
The first draft of the human genome was famously unveiled in 2001 at an estimated cost of $3 billion. But the work wasn’t done. About 8% of the human genome was still missing – swaths of the 3 billion letters of DNA that eluded scientists. By examining what is sometimes called “junk DNA” or the “dark matter” of the genome, scientists were able to fill in the blanks in 2022 with the most complete human genome yet, made possible by new sequencing technologies.
“Even in my institute, when I give a talk, people say, ‘I had no idea there were things we didn’t know about the human genome,’ ” said Jennifer Gerton, a chromosome biologist at Stowers, who teamed up with researchers at University of Tennessee Health Science Center and the National Institutes of Health to untangle a long-standing genetic mystery lying in plain sight.
Typically, humans have 46 chromosomes that carry genetic information. Chromosomes are threadlike structures of DNA, spooled around proteins. When cells are about to divide, chromosomes condense into a characteristic X-shape. A handful of human chromosomes – the “acrocentric” ones that have a short and long arm – sometimes break up and get jumbled into a chimera in which the long arm of one chromosome attaches to another.
Unlike other chromosomal abnormalities, which can cause severe health problems or developmental challenges from the dawn of life, ROBs are carried by many people who never realize it. The diagnosis tends to surface during reproduction, when carriers are at greater risk of losing pregnancies or having children with other chromosomal abnormalities. A fraction of people with Down syndrome can trace it to a ROB.
In probing why these rearrangements happen, scientists were aided by genome sequencing techniques that have brought into focus short, repetitive bits of DNA found on the short arms of several chromosomes that had been previously overlooked as genetic garble.
“Until recent … sequencing technologies and strategies, it was not possible to sequence through the highly repetitive regions of the acrocentric short arms, so this work and finding could not have been done,” David Ledbetter, a human geneticist at Florida State University College of Medicine not involved in the work, said in an email.
These repeating sequences had been impossible to decipher with previous versions of genome sequencing technology. That’s because traditionally human genomes have been sequenced by chopping its 3 billion letters up into lots of short pieces and then stitching them together. When there were long stretches of genomes with repetitions, it was often hard to figure out how they fit together or when they started and ended.
Adam Phillippy, director of the Center for Genomics and Data Science research at the National Human Genome Research Institute, compared the older techniques to assembling a jigsaw puzzle with extremely tiny pieces, where large areas of sky or grass are challenging to assemble. Newer technologies provide bigger puzzle pieces, making it easier to put them together.
The new study revealed that among translocations studied in three people, these short repeating segments contain the break point where ROBs form. They called these shared, repetitive regions a “recombination hotspot” where the chromosomes line up next to each other and sometimes break and exchange genetic information. They also found a clue as to why one particular chromosome, number 14, is prone to these translocations. It has the repetitive segments, but spelled backward, so when it lines up with another chromosome and a break occurs, the long arms can fuse together.
Now, Phillippy’s team at the NIH is using data banks to identify people who carry Robertsonian chromosomes, to see if they are more prone to certain diseases or health risks.
“I think this is a very important study,” said André Marques, a group leader at the Max Planck Institute for Plant Breeding Research. “The study really shows how a human chromosome can fuse together, a long-standing mystery that helps a lot to explain both genetic disease and also the engine of chromosomal evolution.”