Thomas Jefferson declared that all men are created equal, and he was mostly correct.

All males are about 99.9 percent identical when it comes to their genomes, the biological entities that carry the codes for traits passed down through generations of parents and their children. That means that any two males differ by only 0.1 percent at the genetic level, and these differences account for all of the variety preset in males before they begin to develop in their mothers and then the outside world.

Of course, despite the lofty language and democratic philosophy, the country’s Founding Fathers made some notable exemptions in their conception of equality and inalienable rights for the new nation’s citizens. And even as women continue to fight for equality in many aspects of society today, they are less like men than even Jefferson knew, sharing only 98.5 percent of their genetic makeup with men. That’s 15 times greater than the difference between any two human males, who are about as genetically similar to a male chimpanzee as to a human female.

“Maybe our genome is evolved to be read in fundamentally two different ways,” said Dr. David C. Page, Director of the Whitehead Institute and a Professor of Biology at the Massachusetts Institute of Technology, referring to the way in which the genetic code is translated by the body when creating proteins, the building blocks of cells. “We really can’t think about sex difference in health and disease without putting sex and gender in an evolutionary context.”

At a Grand Rounds presentation in May sponsored by the Women’s Behavioral Health Division of Yale School of Medicine’s Department of Psychiatry, Page traced the origin of the human X and Y chromosomes that determine each individual’s sex and argued that researchers and health care practitioners need to fundamentally change how they approach the study and treatments of disease to reflect differences between males and females that exist within every cell of their bodies.

“Until and unless we arrive at an appreciation of how males and females read their genomes differently — we will continue to be surprised every time we encounter a sex difference in disease incidence, severity, or response to therapy,” Page said. “And I think we have to do something about that.”



A Long Time Ago, in a Gamete Far, Far Away...



Life on our planet began with single-cell organisms such as bacteria that reproduce asexually. There isn’t a mother and a father. A cell simply reproduces its genetic material and divides into two or more cells that are genetically identical to the parent cell.

About three or four billion years ago, these single-cell organisms without a distinct nucleus (prokaryotes, or bacteria) began exchanging genetic information in a limited fashion. Then about two billion years ago, organisms such as yeast, with distinct cellular nuclei and specialized structures called organelles (eukaryotes), put their genes in pairs so that they could be divided into two structurally identical gametes (one-cell reproductive units called spores in the case of yeast) and reassembled to create a new organism. This special kind of cell division is called meiosis.

Around 600 million years ago, animals began to evolve specialized gametes — structurally different single-cell units for females (eggs) and males (sperm). Sperm cells fertilize an egg, which then combines the genes of both parents. But such animals, including modern-day turtles, had no specialized sex chromosomes that determine the sex of the offspring. Males and females were genetically identical, and the sex was determined by the temperature at which the egg is incubated.

And finally, starting about 300 million years ago, our ancestors began to evolve sex chromosomes.

In humans, there are 23 pairs of chromosomes, which are structures found within the nucleus of every cell containing the tightly packed molecules known as deoxyribonucleic acid (DNA), the material that carries the genetic code.

One pair of the 23 chromosomes, known as sex chromosomes, determines at conception whether a fertilized egg will develop into a male or female. Today, human females have one pair of identical X chromosomes. Human males, instead of a matched pair, have one X and one smaller Y chromosome.

A human egg contains only an X chromosome. A human sperm contains either an X or a Y chromosome, thereby determining the sex of the offspring after fertilization. XX = female. XY = male.

Dr. Page and his colleagues have spent the better part of the last two decades reconstructing the evolutionary origins of the human X and Y chromosomes. They have traced the origins of these sex chromosomes to ordinary chromosomes called autosomes in evolutionary ancestors that humans share with birds.

“We have been distracted and deceived for the last 50 years by the existence of our sex chromosomes,” Page said. “Most genes that are actually involved in making the different anatomies of human males and females are not on the sex chromosomes. Most of them are on the autosomes. They are exactly the same in males and females. It’s just that the autosomes are read differently in males and females because of the sex chromosomes, just as the entirety of the genome is read differently in males and females.”



Y Marks the Spot

According to Page, about 300 million years ago, humanity’s reptile ancestors had only ordinary chromosomes that, as in today’s turtles, did not determine a newly conceived organism’s sex. Eventually a mutation arose on a member of one of these ordinary pairs of chromosomes that became what lives on today as the sex-determining gene on the Y chromosome known as SRY.

Then, Page said, first in the immediate vicinity of SRY and then over a larger region, what were slowly becoming the X and Y chromosomes stopped swapping information. The X chromosome continued to trade genetic information with other X chromosomes through female meiosis. But during male meiosis, the Y became isolated. And damaging mutations that would have ordinarily been purged through the natural sharing process began to accumulate, leaving the Y chromosome smaller and with fewer surviving genes from that earlier ancestor.

Using computer simulations, Page’s team has identified 639 genes that existed on the autosomal ancestor of the X and Y chromosomes humans shared with birds 300 million years ago. Today, the human X chromosome retains 629 of these ancestral genes. The Y chromosome only has 17 survivors, all of which also continue to survive on the X.

And these genes did not just survive all that time in species that eventually evolved into humans. In at least one of eight mammalian species that Page’s team studied, 36 of the 639 genes survive today.

Additional research revealed that the surviving human genes had special qualities, Page said. Those that survived on the Y chromosome are broadly expressed (active in many tissues and organs throughout the body) in both adult tissues and in embryos prior to implantation. Of the 17 surviving genes on the Y chromosome, 12 are expressed widely across the body, not just in the testes, where sperm are produced, Page said. Many play central roles in the execution of gene regulation and expression.

“So what I’m saying is the genes that survived were a very, very nonrandom sample,” Page said. “They are involved in the central execution of molecular biology.”



Going Beyond the Gonads

Dr. Page called for medical schools to study the differences between XX and XY cells at a more fundamental level.

For the last 50 years, students have been taught that outside the gonads — reproductive organs where sperm and eggs are produced — cells with XX and XY pairs are functionally equivalent because there is nothing on the Y chromosome that acts outside the testes. They’ve been taught that hormones secreted by the testes and the ovaries, where eggs are produced, are entirely responsible for making the body more masculine or feminine.

But Page argued that there are intrinsic biochemical differences between XX and XY cells that affect tissues and organs across the entire body and have a significant impact independent of sex hormones. And medical practitioners must understand these differences to properly treat their patients.

“Imagine if you’re going to surgery and your surgeon has never been instructed in the anatomical differences between men and women,” he said. “Would you sign the consent form?”

The same concept holds for understanding the biology of disease.

Page points to dilated cardiomyopathy, a genetic defect in which the heart balloons dangerously and kills men an average of 10 years earlier than women. Or how there are about three times as many women than men with rheumatoid arthritis and as many as five times the number of boys diagnosed with autism as there are girls. Of those who suffer from the autoimmune disorder lupus, 90 percent are women.

Because there are no obvious anatomical distinctions accounting for these and many other differences, Page urges researchers to examine how XX and XY cells work differently throughout the body.

“Those cells know at a fundamental level whether they are XX or XY,” he said, arguing the state of our current molecular knowledge of sex differences is the equivalent of the knowledge of anatomy in the 16th century.

But he remained optimistic, even as he proposed the restructuring of medical science to finally grapple with overlooking for too long the most fundamental difference between men and women.

“I feel like science is about tearing things apart,” Page said. “There’s a new building that needs to be built after we tear down this old one. A new opportunity to better understand the nature of what it means to be male and female.”



For more news from Women's Health Research at Yale, sign up for our e-blasts, connect with us on Facebook and Twitter, or visit our website.



For questions, please contact Rick Harrison, Communications Officer, at 203-764-6610 or rick.harrison@yale.edu.