Blogging the Human Genome: Why do we have two fewer chromosomes than our closest primate relatives?

The chromosomal evidence that mankind nearly went extinct.

Blogging the human Genome Entry 10

Illustration by Andrew Morgan

Humans have 46 chromosomes. Our closest primate relatives have 48. So where did those extra two disappear to?

Counting chromosomes was surprisingly tricky for most of the 20th century. Except for certain moments—when cells are dividing, for instance—chromosomes don’t form compact, countable bodies inside cells. Instead, they unravel and flop about, which makes counting chromosomes a bit like counting strands of Ramen in a bowl. Chromosomes also start to deteriorate after cells die, which makes counting harder still. Counting is therefore easiest in recently living samples of cells that divide often, like the sperm-making cells in male gonads.

Finding fresh primate testes wasn’t too onerous even in the early 1900s, and biologists soon nailed down the chromosome count for chimps, orangutans, and gorillas at 48. But lingering taboos made obtaining human testes difficult. People didn’t habitually donate their bodies to science back then, and some desperate biologists took to lurking near town gallows to harvest the manhood of condemned criminals.

Given the difficult circumstances, work on the human chromosome number remained unsettled for decades—guesses ranged from 15 to 50-some. (And despite the consistent counts in other species, some European scientists beholden to racial theories proclaimed that Asian, black, and white people had different numbers of chromosomes. No points for guessing who they thought had most.) A Texas biologist named Theophilus Painter finally narrowed the range with some definitive work in 1923. Rather than depend on the criminal-justice system for raw material, Painter relied on a former student who worked at a lunatic asylum and had access to the discards of castrated inmates. But even Painter’s best slides showed human cells with either 46 or 48 chromosomes, and after going round and round, and counting and recounting from every possible angle, Painter still couldn’t decide. Perhaps worried his scientific paper would be rejected if he didn’t at least pretend to have a definitive answer, Painter took a breath and guessed—wrongly. He said that humans have 48, and that became the standard figure.

By the mid-1950s, the invention of better microscopes and an easing of restrictions on human tissues allowed scientists to correct Painter’s mistake. But as so often happens, solving one mystery just opened up another, because now scientists had to figure out how humans ended up two chromosomes down. The answer is surprising, and involves the uncomfortable fact that the human race probably almost went extinct at one point.

Around a million years ago, in some fateful man or woman in Africa, what were the 12th and 13th human chromosomes (and still are the 12th and 13th chromosomes in many primates) got entangled at their tips. Instead of separating cleanly, 12 and 13 fused together, like one belt buckled onto another. This amalgam eventually became human chromosome 2.

Fusions like this are not uncommon—one in every 1,000 babies has some sort of chromosomal fusion—and most go unnoticed because they don’t upset anyone’s health. (The ends of chromosomes contain few genes, so often nothing gets disrupted.) However, a fusion by itself can’t explain the drop from 48 to 46. A fusion leaves a person with 47 chromosomes, not 46, and the odds of two identical fusions in the same cell are remote. And even after the drop to 47, the person still has to reproduce to pass on the trait, a serious barrier.

To see why that’s so unlikely, let’s go back a million years, when most proto-humans had 48 chromosomes, and follow a hypothetical Guy who has 47. Again, a chromosome fused at the tips won’t affect Guy’s day-to-day health. But having an odd number of chromosomes will cripple the viability of his sperm. (If you prefer to think of a female, the same is true of her eggs.)

Say the fusion left Guy with a normal chromosome 12, a normal 13, and a 12-13 hybrid in each cell. During sperm production his body has to divide those three chromosomes into two cells, and there are only a few possible ways to divvy them. There’s {12} & {13, 12-13}, or {13} & {12, 12-13}, or {12, 13} & {12-13}. The first four sperms are either missing a chromosome or have a duplicate, practically a cyanide capsule for an embryo. The last two cases have the proper amount of DNA for a normal child. But only in the sixth case does Guy pass the fusion on. Overall, then, two-thirds of Guy’s children die in the womb, and just one-sixth inherit the fusion. And any Junior with the fusion would then face the same terrible odds trying to reproduce. Not a good recipe for spreading the fusion—and again, that’s still only 47 chromosomes, not 46.

What Guy needs is a Doll with the same two fused chromosomes. Now, the odds of two people with the same fusion meeting might seem infinitesimal. And they would be—except in inbred families, where the chances of finding a cousin or half-sibling with the same fusion don’t round down to zero so easily. What’s more, while the odds of Guy and Doll having a healthy child remain low, every 36th spin of the genetic roulette wheel (because 1/6 x 1/6 = 1/36), the child would inherit both fused chromosomes—giving him 46 total.

And here’s the payoff: Junior and his 46 chromosomes would likely have an easier time having children than his 47-chromosomed parents. Remember that the fusion itself doesn’t ruin you—lots of healthy people have fusions. It’s only reproduction that gets tricky, since fusions can lead to an excess or deficit of DNA in embryos. But because he has an even number of chromosomes, little Junior wouldn’t have any unbalanced sperm cells: Each would have the right amount of DNA to run a human, just packaged differently. As a result, all of his children have a good chance of being healthy. And if his children start having their own children—especially with other relatives with 46 or 47 chromosomes—the fusion could start to spread.

Scientists know this scenario isn’t just hypothetical. In 2010, a doctor in rural China discovered a family with a history of consanguineous (“similar blood”) marriages. Among the various overlapping branches of the family tree, he discovered a male with 44 chromosomes. In this family’s case, chromosome 14 and chromosome 15 had fused, and, consistent with the outline above, they had a brutal record of miscarriages in their past. But from that wreckage a perfectly healthy man with two fewer chromosomes emerged—exactly like that unknown Guy who started down the path to 46 chromosomes a million years ago.

But that solves only part of the mystery: How did having 46 chromosomes then spread worldwide? It’s possible that having two fewer chromosomes than everyone else gave Guy and Doll’s family a whopping evolutionary advantage, allowing them to out-compete the 48-chromosome sluggards. But probably not. More likely, they happened to be living at a point when the human race nearly got wiped out.

Take your pick for the cause of our near-extinction—ice ages, plagues, Indonesian gigavolcanoes. But humans have far less genetic diversity than most other species, and the most reasonable explanation for this is a genetic bottleneck: a severe reduction in the population of humans in the past, perhaps multiple times. One study suggested that our population, worldwide, might have dropped as low as 40 adults. (The world record for fitting people in a phone booth is 25.) That’s an outlandishly pessimistic guess even among disaster scientists, but it’s common to find estimates of a few thousand adults, below what some minor league baseball teams draw. Consider that these humans might not have been united in one place, but scattered into small, isolated pockets around Africa, and things look even shakier for our future. Had the Endangered Species Act existed way back when, human beings might have been the equivalent of pandas and condors.

But however alarming, bottlenecks and near-extinctions aren’t necessarily all bad. With less competition around, a beneficial brain-boosting gene, say, could have an easier time spreading. And those who slip through the bottleneck become big Darwinian winners, because whatever genes those dumb-lucky survivors have can spread far and wide. Guy and Doll were likely two of those survivors, and they bequeathed to the rest of us our unique arrangement of 46 chromosomes.