Well, even Newton had his Einstein, and now genetics revolutionaries are showing that Mendel’s laws can be broken. Genes, it turns out, act so perversely they would have shocked the monk into a vow of perpetual silence. Mutant genes grow from one generation to the next like a sci-fi escapee, so that Grandma’s tiny and innocuous mutation becomes Grandson’s tragic birth defect. Genes costume themselves so that one inherited from Mom has a markedly different effect from the exact same gene inherited from Dad. “It’s the sort of stuff that’s just not supposed to happen,” says geneticist and pediatrician Judith Hall of the University of British Columbia. “But it does.”
The violations of Mendel’s laws represent a true paradigm shift for genetics. They also have sobering clinical implications. Prenatal testing and genetic counseling both rely on Mendel’s rules. Because Mendel wasn’t 100 percent right, neither are they. Scientists don’t know how often the rules fail “because we pick it up only when it leads to disease,” says Hall. But the rules being violated are many:
A gene is a gene is a gene, says Mendelian genetics. But that was before researchers stumbled over “imprinted” genes a couple of years ago. It seems that some bits of DNA-genes strung along the chromosomes like beads on a string-can be marked, with the molecular equivalent of a pink or blue ribbon, as having come from a particular parent (diagram). For these genes, says Hall, “it makes a difference whether they are inherited from the mother or the father.” (New molecular techniques can trace any gene in an individual to one or the other parent.) If the father’s chromosome 15 is missing some DNA, for instance, his child will have the rare Prader-Willi syndrome, which is marked by mental retardation and growth abnormalities; if the mother is missing the same bit, the child will have Angelman syndrome, marked by more severe retardation, excess laughing and unusual movement. In other cases a paternal gene leaves the child healthy, but the identical maternal gene produces a birth defect. Psoriasis, diabetes and some forms of mental retardation all manifest themselves differently depending which parent they are inherited from. “It isn’t nice and clean like it used to be,” says Hall.
Even cancer may have a “parent of origin” effect. In some cases of a neck tumor called paraganglioma, patients inherited a bit of DNA on the chromosome 11 inherited from the father. Inheriting the identical bit from the mother doesn’t cause tumors. Say a boy and girl, call them Dick and Jane, inherit the defective gene on chromosome 11 from their father; both develop the neck tumor. Jane passes the same gene she inherited from her father to her own children, but they don’t develop the tumor: the gene came from a mother. But when Dick passes the DNA to his daughters, they do develop the tumor-the gene came from Dad. His daughters’ children don’t get the tumor.
How the sperm or egg gets tagged with these pink or blue bows remains a mystery. For eggs, at least, it happens when the child’s mother is in the womb. That’s when eggs form. A grandmother’s exposure to chemicals, radiation or disease during her pregnancy, which affects her fetus’s eggs, can affect her grandchildren’s health.
Genes can mutate. But mutations are not supposed to grow like a loaf of bread with too much yeast. Yet consider Martha (not her real name), who has 50 copies of a particular snippet of DNA on her X chromosome (two X’s make a girl a girl). Her daughter, Zoe, has 100 copies but is still healthy. Zoe’s child has 1,000 copies-and is mentally retarded. Somehow, when the X was passing down through the generations, the dangerous bit grew like Topsy. In growing, it knocked out healthy genes; the more it grew the more healthy genes it toppled. “The same mutation, depending what gene it knocks out, can cause very different problems,” says Dr. Haig Kazazian of Johns Hopkins medical school. “They could include manic depression, schizophrenia, coronary-artery disease and learning disabilities.” So much for the conclusion of classical genetics that one mutation causes one specific defect.
A cell supposedly has a strong central government. Its seat is the cell nucleus, and the laws are writ in the chromosomes within. But now geneticists find a rogue government in the hinterlands. The rebels are mitochondria little bodies inside cells that generate energy to make muscles move, heart tissue contract, lungs expand. Each cell has hundreds of mitochondria. Each mitochondrion contains its own genes, which sometimes mutate. Mitochondria with mutant genes do not generate as much energy as normal mitochondria.
The trouble starts when the mutation hits a cell that is dividing to form, say, eggs. By chance, one egg may get the lion’s share of mutant mitochondria. If it goes on to develop into a fetus, the child could grow up to have a disease of the heart, brain, muscle or other energy-guzzling organ. But that baby’s sister, if born of an egg that happened to get very few mutant mitochondria, would be perfectly healthy. “Mendel’s rules say that a single mutation should cause a single change and thus a single medical effect,” says Douglas Wallace of Emory University. “But a mutation in mitochondria can have many different clinical effects, depending on what [percentage] of mutant mitochondria an individual inherits.”
The effect also depends on what organs the mutants wind up in. When a fertilized egg divides and multiplies, the mutant mitochondria randomly go into one or another embryonic organ-to-be. If the nascent heart cells get a lot of mutants, for instance, the child will get heart disease. But if, in that child’s brother the mutants happen to go to the brain, the brother would have epilepsy. “Mitochondrial genetics defies everything you’ve ever learned about genetics,” says Wallace. Among the diseases traced to mitochondrial mutations: adult-onset diabetes and blindness.
According to the rules, children get their 23 pairs of chromosomes equally from Mom and Dad: one of each pair comes from Mom, the other from Dad. Now it turns out that both chromosomes of a pair can come from the same parent (diagram). Eggs and sperm are supposed to have just half of a human’s requisite DNA per cell; when they fuse, the fetus has the right allotment. But sometimes an egg, or a sperm, has all the needed DNA; when it meets its mate, the embryo has too much DNA. Usually such an embryo aborts. But sometimes it survives, by shedding the extra DNA. If it’s the DNA from the sperm that gets jettisoned, then the fetus grows with a double dose of maternal DNA.
And that can make genetic counselors look no wiser than palm readers. Say a couple is tested for cystic fibrosis. Joe doesn’t have the gene; Carol has one CF gene and one normal gene. Since the normal gene masks the CF gene, she doesn’t have CF. (As Mendel found, someone can show a recessive trait only if she has two of the recessive genes.) The counselor tells the couple that their child cannot inherit CF. But say the child inherits both chromosomes from Carol and, by chance, two copies of her disease gene. There is no healthy gene from Joe to defeat the CF gene. The child will have cystic fibrosis. At least five babies who “couldn’t” inherit CF have recently been born with it.
Exceptions to Mendel’s rules, and the heartbreak they cause, are probably rare. But then it took scientists more than a century after Mendel harvested his bumper crop of genetic laws to see that people are more complicated than peas. So far this genetics revolution has hit the lab more than the doctor’s or counselor’s office; researchers say practitioners hardly know what to make of it all. They should figure it out quickly.
PHOTO: New twists on the double helix: Computer-generated image of DNA (HOWARD SOCHUREK–MEDICHROME)
PHOTOS (2): Harvest of chromosomes: Some of the 23 human pairs, Mendel (ALFRED PASIEKA–BRUCE COLEMAN, CULVER PICTURES)
DIAGRAM: Mendel’s Mistakes: The Sexual Equality Rule: Textbooks say each parent gives us one of each member of a pair of chromosomes. Turns out you can get two from mom and none from dad, and thus inherit a recessive disease like cystic fibrosis. (ROHR– NEWSWEEK)
DIAGRAM: The Gertrude Stein Rule: A gene is a gene is a gene, goes dogma. But for some genes, which parent it came from makes a big difference. Inheriting the gene from father causes a rare disorder; inheriting the identical gene from mother doesn’t.
