In this issue
Issue #24 August 29, 2013 Aug 29, 2013 Aug 29
Issue #9 January 31, 2013 Jan 31, 2013 Jan 31
Issue #1 October 11, 2012 Oct 11, 2012 Oct 11
From Issue #24 August 29, 2013

Carry On

Why some devastating genetic conditions persist.

By Saul Hymes Twitter icon 

When my mother was pregnant with me, she and my father underwent screening for Tay-Sachs disease. She was an Ashkenazi Jew; he was not Jewish. Common in Eastern European Jewish populations, Tay-Sachs is a horrendous genetic neurodegenerative disease that kills most children before the age of 5. My father turned out to be a carrier for the mutation that causes it (an interesting story in its own right).1

My mother’s first test came back inconclusive. During the week that they waited for the results of a second test, my parents debated how to proceed if their unborn child were to have the disease. They were spared any tough decisions when my mother’s test came back negative. I was not at risk.

This mattered little until some 28 years later, when my wife and I decided to have children of our own. I had never previously had a reason to get tested for Tay-Sachs or any other genetic disease. But when two Ashkenazi Jews have a child together, it is suddenly very relevant — urgent, even. As with my own parents, the outcome of Tay-Sachs testing could affect our decision to proceed with a pregnancy already underway.

My wife’s obstetrician routinely tested mothers first, and thankfully, my wife’s test was negative for Tay-Sachs and every other testable genetic disease common in people of Eastern European Jewish descent. Because all of these diseases require both mother and father to be carriers, I was spared from testing, and I have continued to spare myself. I just never saw the point.

But over the years since then, my own ambivalence has raised questions. Is there any benefit to testing at all? After millions of years of evolution, why are these diseases still plaguing us? It turns out that answering these questions — especially in regard to how modern medicine addresses certain genetic diseases — involves a complicated interwoven set of traits and outcomes.

Bad genes, good people

Tay-Sachs disease is one of a number of fatal genetic diseases caused by inherited mutations or errors in our DNA. In earlier times, without an understanding of this, certain sick children would simply have been noted to be born to sickly families. Another common explanation was intrafamilial marriage like that between two siblings or first cousins.2

Of course, we now have names for many of these syndromes and diseases, including cystic fibrosis (CF), another familiar example present in my own ethnic group. While little can be done to cure these conditions, the medical community has become extremely good at prolonging quantity and quality of life by managing symptoms.3

Prior to the middle of this century, many genetic diseases were fatal early in life. A child afflicted with CF would have died of growth failure, malnutrition, and recurrent pneumonia in mid-childhood — and that would have been considered a long life.4 Similarly, a child born with Tay-Sachs in 1950 could expect to live no longer than six years. In those few years, neurologic deterioration results in blindness, seizures, and the inability to move, and life ends in agony.

But while half of those afflicted with CF are now expected to live into their 30s, a child with Tay-Sachs has the same prognosis as decades ago. Modern medicine still has little to offer these patients.

Based on the theory of natural selection, a disease that kills children prior to sexual maturity and reproductive age should have become a dead disease, with the mutated genes eventually vanishing from the population. However, in certain ethnic groups, these diseases and the mutations that cause them are quite common. Four percent of all people of European descent are carriers for the cystic fibrosis gene. According to the Center for Jewish Genetics, a similar percentage of Ashkenazi Jews are Tay-Sachs carriers.

So why, in 2013, after millennia of evolution, are these genetic diseases not only surviving but in fact common in certain populations?

Natural selection

The human genome contains 46 chromosomes, organized as two sets of 23 each; one version comes from the mother and one from the father. Some diseases are caused by only one defective dominant copy, in which its presence in either chromosome can result in its expression. But the majority are recessive diseases, mentioned above, in which two defective copies, one inherited from each parent, are needed for the disease.5

This is the case not only for classic genetic diseases like Tay-Sachs or cystic fibrosis, but also for non-disease recessive traits like blue eyes or blond hair. Possessing only one copy of a recessive gene typically results in no disease or no blue eyes; their owners are simply carriers, known as heterozygotes. But with a recessive gene contributed by each parents’ chromosomes, one out of four births from that couple, on average, results in a child with the disease or condition.6

In an early civilization in which there was no mitigating treatment that let an afflicted child survive to reproductive age, a set of parents with matched recessive genes should have had fewer of their children thrive and have their own offspring. Such couples should have been outcompeted by other pairs in which one or both partners lacked a recessive gene for one or more diseases. These other couples should have therefore had more children, and their children should have had more, and so on. Their descendants should eventually have dominated a population.

But what if having a mutant gene didn’t result just in being a carrier who never developed any symptoms of the disease? When there’s an evolutionary and reproductive upside to having a single copy of a recessive gene, it’s known as the heterozygote advantage. This holds true for at least one, and possibly both, of the diseases I’ve mentioned here so far: cystic fibrosis and Tay-Sachs.

As for what the advantages to being a carrier for horrible, historically untreatable diseases could be, one need look no further than the causes of death prior to modern medicine: the top three — for millennia and as recently as 1900 — were infectious diseases. If there were anything exerting selective pressure on a human population and its genes, one might suspect an infectious cause or two.

Something in the water

About 70,000 people worldwide have cystic fibrosis, and several hundred people die from its complications each year. Since 1989, scientists have known the mutated gene that causes it. It encodes a protein that transports chloride throughout the body. While individuals with two mutated copies of this gene will have the disease, people with only one copy — CF carriers — have no disease.

Instead, they have just enough of these proteins to confer protection against cholera, which is caused by the bacteria Vibrio cholerae and transmitted by contaminated water. Cholera results in a profuse watery diarrhea. Unlike other diarrheal illnesses, where the water you ingest fails to get absorbed and rushes out, cholera’s toxin actively hijacks the intestinal machinery of water and chloride metabolism. You secrete water, losing not just the stuff “passing through,” but water from the blood and tissues as well.7

Untreated, cholera can kill from dehydration in hours; it causes water loss as rapid as blood gushing from a stab or gunshot wound, and an epidemic of it — as the world recently saw in Haiti — can be a humanitarian disaster. But the cholera toxin acts on cystic fibrosis proteins. When cholera ran rampant in millennia past, CF carriers, with a mutated copy of the gene, had an advantage. They outlived and out-reproduced their compatriots who were too busy having the runs and dying of dehydration.

Tay-Sachs disease is historically a bit harder to puzzle out regarding a heterozygote (carrier) advantage. It had been observed anecdotally that Ashkenazi Jews were also relatively less likely to get infected with tuberculosis (TB).8 There was debate in the scientific literature about whether this was real or not, in part because until recently nobody could figure out exactly why this might be.

But in 2008, a paper was published showing that a relative of HEXA, the enzyme that is mutated in Tay-Sachs, helps defend against tuberculosis-type bacteria. The HEXA mutation causes those afflicted to accumulate the residue of certain molecules critical to the brain’s function. In both those with the disease and unaffected carriers, the related HEXB works overtime. The extra HEXB doesn’t harm carriers’ brains, but it may give Tay-Sachs carriers a better ability to fight off TB, based on mouse studies. Imagining the Europe of millennia ago, the advantage could have allowed Tay-Sachs carriers to outlive and out-reproduce their neighbors who were dying of TB, even while some of their siblings died in early childhood. (High rates of childhood mortality were always present before modern times even without genetic diseases.)

When there was no treatment for these infections and no treatment for the genetic diseases themselves, we had an explanation for the perpetuation of these genes.9 But with cures for these infections and treatment for some of these genetic disorders on the horizon, it’s worth considering whether these genes have, in a sense, rendered themselves evolutionarily obsolete.

Unnatural selection

Unlike Darwin’s finches or tortoises, or even early humans, modern humans can at least partially modify the outcomes of our genes and our environment. For example, we can treat and modify the course of CF enough to allow people to reach reproductive age. In resource-rich areas, we treat infections like cholera, which are quite rare anyway.

Without the deaths from these infectious diseases selecting for carrier protection from them, there is no longer any heterozygote advantage; people without a trait will reproduce at the same rates as those who are carriers. And with better management of the course of CF itself, those with the disease could, in theory, reproduce. (97 percent of men with CF are infertile, but not sterile; their sperm is viable.)

We could argue that human evolution has hit a sort of stalemate if not for two simple facts. Some genetic diseases are still rapidly fatal. And unlike animals, we have genetic testing and, ultimately, matchmakers. For those who think that matchmaking went out of style sometime after Tevye’s daughters got married, there is still a strong matchmaking profession in communities that are relatively more genetically isolated — such as Ashkenazi Jews.

Their work has changed since the days of the shtetl. Now, most matchmakers work closely with genetic counselors to perform a litany of tests on prospective partners before they are even married. If it’s determined that their potential offspring would be at risk for any known autosomal recessive diseases, the couple is broken up, and another match is found.

It’s a harsh but effective process. Through this testing and matchmaking, one can ensure that nobody marries or reproduces with anybody who could produce a child with a genetic disease (that we can test for).10 There is also the potential, taken to its extreme, to eliminate the gene and the disease from the gene pool altogether.

There’s obviously a slippery slope (and one rife with the potential for abuse) when it comes to anything that might be considered eugenics. But if a community decides that its members want to voluntarily breed out a disease for which they are collectively at risk, it’s hard to see why this would be considered such a bad idea.

For treatable diseases like CF, this may be wholly unnecessary. But for avoiding conditions like Tay-Sachs, which simply requires that you never pair up with the wrong person in the first place, having this kind of genetic matchmaking is key.11

Without plans to have more children, I’m an evolutionary dead end regarding Tay-Sachs. But the trait? That, I could have. That, I could have passed on. For the sake of my children and my children’s children, I think I’ll go out and get tested.

  1. While I had thought, growing up, that my father was not Jewish, I learned the full details of his history when I was a teenager, and was fascinated to discover that his great-grandfather (my great-great-grandfather) was a German Jew. Despite the religious and cultural side of the Jewish heritage being lost before and during the war years through this ancestor’s marriage to a Catholic woman, the genes never lie. 

  2. The classic example of a consanguineous union leading to a greater likelihood of a genetic disease is the presence of Hemophilia B in the Victorian-era British royal family and its descendants, which then included numerous other royal houses of Europe. 

  3. In recent years, correction of the underlying genetic mutation has become possible through lung transplants (in the case of CF) or bone-marrow transplants (in the case of another genetic disorder, sickle-cell disease). If the patient survives the grueling transplant regimen, they can sometimes become considered cured. In lieu of this, symptomatic management and treatment of the sequelae of the diseases has prolonged lifespan for CF, for example, into the 40s. There is no cure or symptomatic management for Tay-Sachs, unfortunately. 

  4. In the era around 1938, when CF was discovered, many patients died as young as 1 year of age. The disease was, in fact, partially identified on the basis of autopsies of infants. 

  5. For parents who each have a copy of the mutated gene, the odds are 25% for each combination appearing in their children: two mutated copies, two non-mutated copies, one copy from the father, and one copy from the mother. 

  6. Unlike in the case of NASA’s Mars Rovers, where the strategy has been to “follow the water,” the water in the human body usually follows the salt — sodium chloride. We excrete or absorb chloride or sodium and water goes with it. No wonder spilling salt is considered such bad luck! 

  7. During World War II, TB ran rampant in Eastern-European Jewish settlements, but despite this, healthy relatives of children with Tay-Sachs disease did not seem to contract TB, even when repeatedly exposed. 

  8. Other genetic diseases common in certain populations, such as sickle-cell disease, glucose-6-phosphate dehydrogenase deficiency, and phenylketonuria, are also associated with a heterozygote advantage in protection from certain infections. 

  9. Mount Sinai Hospital, where I trained, has a very well-known Ashkenazi Jewish genetic disease testing program that works closely with matchmakers in the community. In Israel, testing for cystic fibrosis has a 100 percent utilization in ultra-Orthodox communities before marriage. These groups are more insular and thus have a higher risk for inbreeding and transmission of this disease. And we are already seeing that increased screening reduces the disease’s prevalence

  10. Having an abortion is off the table for observant Jewish groups, as well as for many other religious and ethnic communities. 

Saul Hymes is an Assistant Professor of Pediatric Infectious Disease at Stony Brook Long Island Children's Hospital, not far outside New York City. When he is not caring for children with infections, doing clinical research on antibiotics, or teaching the next generation of doctors, he greatly enjoys writing, and would have been a journalist or computer programmer in another life. He posts infrequent medical musings.

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