by Katherine J. Wu
figures by Daniel Utter
Let’s talk about sex.
Seriously. Not intercourse, though – more about how genetic sex is programmed during development. Sexual identity has been in the news often lately, and unsurprisingly so: the past few years have yielded sweeping reforms in civil rights, spurring new conflicts surrounding everything from age-old battles in gender equality to legislation enforcing anti-transgender bathrooms. It’s a complicated subject, to say the least. With regards to science, we don’t know enough about gender identity to draw any conclusions about its biological underpinnings, and certainly not about what is “right” or “wrong.” We are only now beginning to fully understand how mammalian sexual identity has evolved, and its dependence on the sex determination systems that allow biological development of sexual characteristics in different organisms.
The sex determination we’ll discuss today is (unfortunately?) not the dogged resolve to copulate. Most multicellular organisms, humans included, use sexual reproduction to reproduce. Compared to asexual reproduction, in which cells can simply create carbon copies of themselves, sexual reproduction allows for the introduction of genetic diversity into a population. In most sexually reproducing organisms, there are two sexes – but the ways in which these sexes are determined and the ways in which they manifest vary greatly. What are the ways in which sexual characteristics are encoded? Why are there so many systems for one seemingly common result?
SRY not SRY
We were all taught the classic recipe in grade school: an X chromosome from mom and an X chromosome from dad will yield a genetic female, while an X chromosome from mom and a Y chromosome from dad will yield a genetic male. The XY sex determination system (Figure 1A) is certainly what’s most familiar to us, and it’s used in most other mammals, as well as a few select insects and plants. Briefly, human cells all carry chromosomes, which carry our genes. When egg meets sperm, each parent contributes 22 non-sex chromosomes and one sex chromosome – always an X from the mother, and either an X or Y from the father. Thus, the contribution from the father determines the sex of the baby.
Following fertilization, a fetus begins to develop. At first, its sexual organs manifest as a genderless gonad, or sex gland – basically a small, thick ridge of tissue near what will become the abdomen. The “default” sex (i.e., without any other further input) is actually female – however, the presence of a gene called SRY on the Y chromosome initiates the release of testosterone and the formation of male sex organs. SRY is a transcription factor – a genetic element that can turn on the expression of other genes. In this way, SRY is like the master switch to turn on the suite of “male” genes in a developing organism. Thus, the presence of a single Y chromosome switches on the male pathway, something that is clear in what’s called Klinefelter Syndrome, in which individuals carry two X chromosomes and one Y chromosome, but develop testes and appear generally “male.” Without the presence of a Y chromosome, and thus without SRY, cells secrete estrogen instead of testosterone, and an XX baby develops female sexual organs.
It seems like a pretty clear system – but it wouldn’t be biology without exceptions and extra rules muddying the waters. When it comes to sex chromosomes, X’s and Y’s are not the only ingredients available. Many other sex determination systems exist, and the concept of “male” vs. “female” isn’t quite as simple as humans once thought.
The Birds and the Bees (and Some Other Things Too)
Unsurprisingly, with the immense variation observed in our natural world, more than one sex determination system exists. Ours, XY, is not even predominant. A few key examples tend to predominate: the ZW system in birds, XO in insects, haplodiploidy, and environmental sex determination systems.
The ZW system (Figure 1B) exists in birds and some reptiles, and operates opposite of XY: females get the mixed set of sex chromosomes (ZW), while males are ZZ. Thus, unlike in humans, the mother’s contribution determines the sex of the progeny. Just as the mammalian Y chromosome carries the male-determining SRY, the avian W chromosome carries similar master switches FET1 and ASW, which are necessary for female development of the offspring, which will otherwise “default” to male.
In the XO sex determination system (Figure 1C), which is found in several insects, females are still XX, but instead of carrying a Y chromosome, males simply carry a single X – the “O” in “XO” indicates the absence of a second sex chromosome. Each sperm carries either an X chromosome or no sex chromosome at all – but once again, as in XY, the father’s contribution determines the sex of the offspring.
After this, things start to get a little weirder. Honeybees utilize the system of haplodiploidy (Figure 1D), in which unfertilized eggs (which carry only one set of chromosomes and are thus haploid) develop into males and fertilized eggs (which carry two sets of chromosomes and are thus diploid) develop into females. Importantly, this is distinct from the XO system, where progeny inherit two copies of all non-sex chromosomes, regardless of sex; in haplodiploidy, males inherit only one copy of all chromosomes, sex and non-sex (Figure 2A).
Honeybee colonies typically center around a single fertile queen, serviced by an army of male drones and female workers. The queen lays a vast number of eggs, some of which are fertilized and develop into females. Those that remain unfertilized develop into males. Thus, in this system, males have no fathers and can produce no sons. Furthermore, if a queen chooses only one drone to mate with, all her daughters will share 75% of their genes with each other (unlike in humans, where siblings share 50% of their genes) because they each inherit the full set of their father’s genes, rather than just half. While this system seems vastly overcomplicated, it is believed to have been evolved to promote the social nature of honeybees: as a female worker, it turns out to be more evolutionarily advantageous to protect your sisters (with whom you share 75% of your genes) than it is to produce daughters of your own (with whom you share only 50% of your genes) (Figure 2B). Thus, the community structure revolves around the queen. This is an interesting case where the genetically determined sex of individuals shapes their role within the larger community.
Finally, there exist systems in which sex determination isn’t dependent on chromosomes at all. In alligators and some turtles, the temperature at which the egg is incubated during a sensitive period determines sex: lower temperatures produce females, higher temperatures produce males (the phenomenon of “cool chicks” and “hot dudes”) (Figure 1E). However, this rule does not hold true in every species – sometimes the opposite rule is in effect, or temperatures at either extreme produce one sex, while an intermediate temperature produces the other. Some snails and fish are actually able to reverse sex midway through life, depending on environmental conditions, in a process called sex reversal. Thus, genetic sex is a far more fluid process than one might assume.
The fact that genetic sex can be directed by the flip of a single switch may be surprising. Sex is complex – but then again, there are a lot of other factors at play and, clearly, environment can have a big influence on how sex expresses itself. Additionally, there are many documented cases of humans with a genetic sex that appears “contrary” to their physical appearance. For instance, we know of genetically XX persons who have developed testes and external characteristics of men, and genetic XYs who develop as females. An example of the latter case occurs in Swyer Syndrome, often when there is a mutation in the SRY gene. While the rest of the Y chromosome is left intact, a malfunctioning SRY means that the male “switch” is never flipped, and the indifferent gonads do not get signals to become testes. Swyer Syndrome patients develop externally as female, but do not have ovaries and are infertile.
Finally, inheriting extra or too few chromosomes can considerably alter how sex manifests. Klinefelter is a common example, as well as Turner Syndrome (XO), where a sex chromosome is missing, often leading to developmental defects. Thus, all it takes is a small genetic change to turn SRY, or any of the genes it targets, on (or off).
We know very little about how sexual reproduction and sex determination systems evolved – the theories are, of course, difficult to test. But another important question is, once sexual reproduction did evolve, why did it branch off in so many ways? And, perhaps more pressingly, is it still evolving in ways that could affect us?
The answers are still mostly elusive. There has been some indication that the XY and ZW systems are still connected to a common ancestor, even though they manifested a complete reversal somewhere down the line. One small but interesting line of evidence lies in the platypus, which encodes a whopping 10 sex chromosomes (males are XYXYXYXYXY instead of XY – apparently, size matters to platypodes) that bear great similarity to the bird Z chromosome, but technically operate under XY sex determination rules. Interestingly, though, the platypus Y lacks SRY. Thus, platypodes may end up being the “missing link” between these two systems.
Furthermore, analysis of the Y chromosome has indicated that it probably evolved from the X chromosome, acquiring some literal “man power” along the way. This “differentiation” event solidly distinguished the roles of the two chromosomes, and they began to evolve away from each other over time. In its current state, the Y chromosome is much smaller than the X chromosome, and appears to have lost the unnecessary X genes along the way. Y continues to exhibit signs of this (very, very slow) Y degeneration as time progresses. In fact, the XO sex determination system is believed to have arisen from complete loss of an effective Y chromosome that was ultimately discarded for its relative inefficiency. There’s no need for panic, though, XY readers – your Y chromosome is unlikely to be going anywhere anytime soon, or maybe ever. Complete loss of Y is a pretty extreme event, and much evidence has accumulated that the loss of genes from the Y chromosome will ultimately plateau.
Plenty of Fish (Sexes) in the Sea
Sex determination in humans is fairly well established. But our system is neither the dominant mode of sex determination, nor a more “correct” version of it. A final lesson comes in with the fairly new discovery of polygenic sex determination (PSD), wherein multiple genes and chromosomes contribute to the ultimate sex of offspring. This can take the form of XY and ZW systems being combined into the same species, for instance. Domesticated cantaloupes (yes, the fruit) produce four sexes, and there is some evidence that several species of fish rely on PSD). This system is still poorly understood, but importantly, the added variation on each side of the equation indicates that even genetic sex is often not a binary trait. Perhaps it’s time to rethink our preconceptions about the divides between “male” and “female.”
Katherine Wu is a third-year graduate student in the Biological and Biomedical Sciences Program at Harvard University and is, as far as she knows, XX and not XY.
 … Making King Henry VIII’s decision to behead a bunch of his wives for failing to bear him sons a little misinformed. Oops. Not that he could have known at the time – no one did. So, moot point.
 If only Anne Boleyn had been a pigeon.
 For the most part, the genes on the X chromosome only need to be present in one copy, hence the favoring of “loss” of duplicates on the Y chromosome. In fact, in women, who have two X chromosomes, one X chromosome in each cell is packaged into a dormant state called a Barr body. This actually happens at random in each cell (that is, it’s not always the X from mom or the X from dad that’s turned off – it can be one or the other), resulting in “mosaicism.” This is actually how the coats of calico cats are patterned, and why the vast majority of calicos are female! Cool fact: if you stumble upon a male calico cat, it is almost certainly XXY.
- To learn more about why honeybees can’t produce males from fertilized eggs, check out this brief article: http://mbe.oxfordjournals.org/content/early/2013/12/06/molbev.mst232.full
- An excellent review on the evolution of sex determination: http://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.1001899
Featured image from Wikimedia Commons.