genetic changes--9/23/26
Today's selection -- from Beyond Inheritance by Roxanne Khamsi. There are constant genetic changes happening within our testes and ovaries during our own lives:
“Like astronomers who use telescopes to peer into the sky for clues about the dawn of the universe, and geologists who dig deep into the ground for hints about how the Earth formed, geneticists are not immune to the pull of origin stories. They pore over sequence data from present-day humans and re-create theoretical lineages that posit when different ailments crept into our species. Through these methods, some have calculated, for example, that fifty-two thousand years ago or so, midway through the Stone Age in Europe, one of our human ancestors was born with a mutation that causes cystic fibrosis. Nowadays, it's the most common life-threatening inherited genetic disease in the United States. Other teams have suggested that sickle cell disease, one of the most frequent heritable blood disorders in the world, dates back to between twenty-two thousand and seven thousand years ago–perhaps to an individual living in northern Africa or the rainforests of what is now known as Cameroon. Meanwhile, some researchers reckon that the most recent common ancestor carrying a prevalent mutation for Tay-Sachs disease–which progressively destroys the nerves of the brain and spinal cord-lived around twelve hundred years ago.
“Scientists have generally viewed mutation in reproductive cells–which transmit traits to future generations–as something that happens, but happens seldom. They have thought broadly about the chance of advantageous DNA changes that occasionally help spur the evolution of new species, for example. And likewise, the emergence of disadvantageous mutations for devastating conditions such as cystic fibrosis, sickle cell, and Tay-Sachs seemed for so long to be like huge but infrequent earthquakes in the genome. In other words, they seemed rare. To this day, many researchers still view reproductive cells-which form the ‘germ line’ that passes genetic material from generation to generation–as relatively impervious to new DNA changes. ‘I think that this is the stereotype that many people have,’ explains Kateryna Makova, a scientist at Penn State University. ‘They think that the germ line is very fixed.’
“And, in fact, even when new mutations do occur in our reproductive sperm and egg cells, the vast majority likely have zero impact. They usually land in the extensive unimportant tracts of the genome. ‘One important thing to realize is that most mutations are just neutral,’ Makova says. This understanding was introduced in the late 1960s by the Japanese biologist Motoo Kimura. He argued that a lot of evolutionary change is simply the result of random genetic drift, and that many of the tiny changes in the genome don't affect what our DNA actually produces.
But consequential DNA errors do sometimes crop up in an individual's reproductive cells during their lifetime. And in recent years, many scientists have gained a greater appreciation of the importance of this phenomenon. Much like those astronomers who now, equipped with high-tech telescopes, can spot the birth of numerous new stars in distant galaxies, geneticists are better than ever at detecting new sequence changes in reproductive cells. The technical name for these errors is ‘de novo germline mutations.’ (The Latin phrase de novo is roughly translated as ‘from the new.’)
 |
| X-chromosomes (red) and Y-chromosomes (green) in embryonic stem cells of male (X/Y) and female (X/X) mice. |
“Earlier in this book, we met patients with health conditions caused by new mutations–people like Ascrea, who had a heart condition that almost claimed her life, or the pregnant woman with the blood disorder called paroxysmal nocturnal hemoglobinuria who passed away. But in each of these cases, the new mutation happened during development and affected only some of their cells. The acquired genetic conditions described in the preceding chapters have affected parts of the brain, lymph nodes, and skin, just to name a few. Mutations that strike only in those tissues can disrupt the life of the affected individual but are not transmitted to their children. In contrast, when the reproductive cells that go on to form an individual are struck with a new genetic error, it can get endlessly passed down to subsequent generations. In this way, a noninherited mutation becomes an inherited one. And since the genomes of the sperm and egg are recapitulated in every cell of a developing embryo, all the child's cells will carry that mutation. The stakes are extremely high.
“There's a scientific awakening among geneticists that there are more genetic changes happening within our testes and ovaries while we live than previously thought, and that these might have implications beyond our own health to affect the genetic well-being of our children.
“Part of the reason that de novo germline mutations have been overlooked is that finding them used to be an insurmountable technical challenge. Detecting how often these tiny changes within the three billion letters (or subunits) of DNA occur in each generation has been likened to measuring the frequency of needles in haystacks. But that has slowly begun to change. New sequencing tools and computational methods have made it easier and cheaper to pick up small typos and structural variations in the genome, beyond the major chromosomal abnormalities that can be detected with a microscope. One analysis of genetic data from twenty-eight people across four generations of a Utah family revealed around 150 de novo genetic changes per generation detectable by modern technology. That number was about 50 percent higher than previous estimates.
“It's not unheard-of now to encounter people whose illnesses are linked to a de novo germline mutation. New research has linked such mutations to aggressive cancers such as retinoblastoma, which originates in the eyes, and osteosarcoma, which starts in the bones. Akiva Zablocki, the head of the Hyper IgM Foundation, whom we met briefly in chapter 3, knows about de novo mutations and their health impact. His wife, who is the youngest of seven siblings, was the only one in her family to have the hyper IgM mutation, which means it was most likely a de novo change in either the sperm or egg that formed her. Because she was a carrier for the trait, she passed it on to their son (who, thankfully, received a successful bone marrow transplant for the immune disorder).
“Of the tens of thousands of de novo germline mutations identified in disease so far, almost half have been linked to autism (which might be a reflection of the robust research funding allocated to study this neurodevelopmental condition). A survey of forty-six thousand mutations found that 45 percent had been associated with autism. This strong signal correlating genetic changes in reproductive cells with autism is notable because prior research has suggested that children born to older fathers, whose sperm is more likely to contain new mutations, are at heightened risk of this disease.
“There's a hope that knowing more about de novo germline genetic errors will help scientists better understand the molecular machinery that breaks down in certain diseases–and that this, in turn, will point drug developers toward the cellular functions to target and resuscitate with new medications. Sometimes, discovering a de novo mutation can even provide long-sought answers about tragedies that seem to strike out of the blue: In recent years, doctors have identified cases in which these genetic aberrations were likely the cause of some previously unexplained sudden infant deaths. The reality is that congenital genetic diseases do not always go back millennia. Sometimes they creep in and cause unthinkable heartbreak within the time span of our lives.”
COMMENTS (0)
Notice: Trying to access array offset on value of type bool in /home/customer/www/delanceyplace.com/public_html/cmsAdmin/plugins/websiteComments/websiteComments.php on line 279