A Human Parthenogenote

Turkeys do it; six families of lizards and one of snakes do it; flatworms and roundworms do it; and so do little-known pond dwellers called rotifers, gastrotrichs, and cladocerans. These creatures can all reproduce parthenogenetically.

In parthenogenesis [Greek for "virgin birth"], a mature egg cell becomes activated and goes on to divide and yield a viable offspringñwithout the input of sperm. Now, with the help of fluorescence microscopy, researchers from the University of Edinburgh report the first case of parthenogenesis, albeit it partial, in a human. The work of David Bonthron and co-workers was published in the October 1995 issue of Nature Genetics.

The first report of parthenogenesis is attributed to Swiss naturalist Charles Bonnet, who noticed that aphid eggs develop into aphids without benefit of sperm. Parthenogenesis is seen in some bee, wasp and ant societies, where drones (males) develop from unfertilized eggs.

This ultimate in feminist strategies is advantageous when an organism is well-adapted to its environment because it leads to a sudden population explosion. Parthenogenesis explains how a pond forming overnight from a puddle becomes rapidly overrun with little swimming creatures. In a changing environment, though, parthenogenesis becomes a liability. The organisms are genetically alike, and all perish if conditions become harsh. Because environments change, parthenogenesis is relatively rare.

Researchers have been able to study parthenogenesis, though, because it turns out to be relatively easy to induce in a laboratory setting. Take a mouse egg and shake it, shock it, prick it with a needle, or dunk it in a salt solution, and it just may double its DNA without splitting its cellular self, yielding an embryo of strictly maternal origin. These embryos grow and develop until about halfway through gestation, which is 10 to 11 days in mice. Then they shrivel and cease developing.

However, a normal fertilized mouse egg fused to a parthenogenetic one yields a mosaic embryo, with patches of each tissue type, that develops into an apparently unharmed rodent. This observation suggested to researchers that a human partial parthenogenote might be possible.

But no one has ever seen a human parthenogenote. One can arise, but it cannot survive for very long. If an egg happens to double itself, what develops is not an embryo, but a benign growth of disorganized tissues called a teratoma.

Could a parthenogenote derive from solely male tissue? Theoretically, yes. If an egg lacks a nucleus and is fertilized by a sperm whose nucleus subsequently doubles itself, a mass of placenta-like tissue develops instead of an embryo. The bottom line: it takes a set of chromosomes from each sex to make a baby. So the child described in the Nature Genetics article is truly exceptional.

At the center of the unusual study is a boy, called FD. Shortly after his birth 3 1/2 years ago, his parents noted a strange asymmetry to his head. The left side of his face seemed underdeveloped, with a jutting chin, sunken eye and oddly clenched jaw. An ear, nose and throat specialist discovered that the boy also had a cleft palate and a bifurcated uvula. Photographs of the boy from one side look completely normal, yet from the other perspective, not normal. The child is slightly developmentally delayed and has aggressive outbursts but is otherwise normal.

Because chromosome abnormalities are often associated with unusual facial structures, doctors took a blood sample to examine the boyís chromosomes. To their surprise, they found two X chromosomes, indicating a female. But the child was quite obviously a boy.

Could FD be a case of sex reversal, in which the gene on the Y chromosome determining maleness attaches to an X chromosome? Such "XX males" exist, looking and feeling quite male, but having the chromosome combination of a female. Physicians used fluorescent in situ hybridization (FISH) to search for the suspect Y region in blood cells, but it didnít turn up. So how could he be a he?

A look at chromosomes in the boyís other tissues deepened the mystery. Skin cells and those shed in urine were typical male cells, with one X and one Y chromosome. A FISH probe to the Y chromosome tagged with Texas red and an X probe tagged with fluorescein lit up the expected red and green in the XY cells, and just green in the XX cells.

To apply their knowledge of human development and deduce how FD arose, researchers needed to probe further and determine whether all three X chromosomesñthe two in the XX cells and the one in the XY cellsñwere identical or different. This analysis used the polymerase chain reaction to amplify and size certain repetitive DNA segments, called microsatellites. Comparing differing microsatellite patterns is a technique to distinguish chromosomes. The primers used to begin the PCR reactions were tagged with fluorescein so that the pieces of DNA could be tracked.

Again, results were surprising. Researchers had hypothesized that one of the Xs in the XX cells would differ from the other two. For this, they had an explanationña sperm indeed fertilized an egg, but another cellular product of egg cell formation, called a polar body, managed to double its DNA and persist. Polar bodies usually just decompose. But this neat explanation didnít hold up.

The microsatellite analysis revealed that all the X chromosomes in this most unusual boy were the same. In addition, the other chromosome pairs matched each other in the "female" cells. Normally, the genes on the two chromosomes of a pair contain different variants of many genes.

This genetic uniformity suggested parthenogenesisñthat these XX cells had somehow arisen from a developing egg cell that had doubled its chromosomes, instead of waiting for a sperm to restore the chromosome number of 46. But then where did the XY cells come from?

One explanation for FDís beginnings is that he was originally an activated immature egg cell that divided once, yielding one cell that doubled its chromosomes, and another that was fertilized, leading to two cell lines, one XX, one XY. Remarkably, FD is expected to be fertile and able to father normal children, because he has normal XY cells that presumably gave rise to his reproductive system.

The splitting and doubling egg scenario is just one plausible explanation for this small child whom they call a "human parthenogenetic chimaera," a hardly complimentary appellation. Chimaera was a firebreathing monster in Greek mythology with the head of a lion, body of a goat and tail of a serpent, who was killed by the hero Bellerophon riding Pegasus, the winged horse. But FD is also a little boy with a slightly askew face who in most respects is just a little boy.

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