The Genetics of Identity and Normalcy (2001-2015)

The Genetics of Identity and Normalcy (2001-2015) This chapter chronicles the fascinating history of discovery in the study of the genetics of identity and normalcy. Key concepts covered: Race assignment of individuals does not carry any general implication about genetic differentiation. Intelligence is heritable. Sex identity is physical; gender identity is psychological. There is strong evidence that sexual orientation and social behavior are hereditary. Epigenetics is the study of changes in organisms caused by modification of gene expression rather than alteration of the genetic code itself. Race and Intelligence The desire to categorize humans along racial lines, and the impulse to superpose attributes such as intelligence (or criminality, creatively, or violence) on those lines, illustrate the general theme concerning genetics and categorization. Race Polygenic trees based on the DNA sequencing of people throughout the world have shown that Africans represent the root of the trees. This is interpreted as evidence that humans evolved in Africa, and then migrated across the globe. As humans colonized and settled permanently in various parts of the world, they differentiated themselves into distinct groups called races. Undoubtedly, many of the features that distinguish races, such as skin color or body shape, were adaptive in the local setting. Nevertheless, genomic analysis has revealed that the vast proportion of genetic diversity (85 to 90 percent) occurs within races and only a minor proportion (7 percent) between racial groups. The differences between races are superficial, based on the alleles of a relatively small number of genes that affect external features. So race assignment of individuals does not carry any general implication about genetic differentiation. For race and genetics, the genome is a one-way street. You can use genome to predict where X or Y came from. But, knowing where A or B came from, you can predict little about the persons genome. Intelligence Intelligence has historically been conceptualized as a more or less trait. Is intelligence heritable? Studies of twins do in fact provide strong evidence for the heritability of intelligence. The scores of identical twins reared apart are highly correlated (0.74). In addition, adopted childrens scores are highly correlated with the scores of their birth parents and not with the scores of their adoptive parents. Also significant are findings that heritability can differ between ethnic and racial groups, as well as across time within a single group; that is, the extent to which genes vs environment matter in IQ depends on many factors, including socioeconomic status and education. Sex Identity v. Gender Identity In 1903, Nettie Stevens, a graduate study in Biology under Thomas Morgan, was the first to recognize that females have two large sex chromosomes in the shape of Xs and that males have one of full size X and another that is missing a portion, making it resemble a Y. Later, she corroborated with Edmund Wilson a cell biologist, to discover the XY Sex Determination System. The XY system works like this. During meiosis the male XY sex-chromosome pair separates and passes on an X or a Y to separate sperms; the result is that one-half of the sperm that are formed contains the X chromosome and the other half contains the Y chromosome. The female has two X chromosomes, and all female egg cells normally carry a single X. The eggs fertilized by X-bearing sperm become females (XX), whereas those fertilized by Y-bearing sperm become males (XY). Unlike other pairs of chromosomes in which each member normally carries alleles of the same genes, the paired sex chromosomes do not carry an identical complement of genetic information. The X chromosome, being larger, carries many more genes than does the Y. Sex Identity In the early 1980, a young geneticist in London named Peter Goodfellow (1951- ) began to hunt for the sex-determining gene on the Y chromosome. He intended to use the Botsteins gene mapping technique to narrow down the search to a small region of the Y chromosome. But how could a normal gene be mapped without the existence of a variant phenotype, or an associated disease? But how can you find such a variant? The answer came in 1955 when Gerald Swyer, an English endocrinologist investigating female infertility, discovered a rare syndrome that made humans biologically female but chromosomally male. Women born with Swyer dyndrome were anatomically and physiologically female throughout childhood, but did not achieve female sexual maturity in early adulthood. When their cells were examined, geneticists discovered that they had XY chromosomes in all their cells. The most likely scenario behind Swyer syndrome was that the master-regulatory gene that specifies maleness had been inactivated by mutation, leading to femaleness. In 1989, Goodfellow discovered that a gene called SRY, located in the Y chromosome, was the master-regulatory gene responsible for sex determination. If you turn SRY on, the animal becomes anatomically and physiologically male; turn if off, the animal becomes anatomically and physiologically female. A women with Swyer syndrome is in fact a genetic male, but with the SRY gene (in his Y chromosome) turned off due to mutation. Gender Identity Gender identity is ones innermost concept of self as male, female, a blend of both or neither how individuals perceive themselves and what they call themselves. Ones gender identity can be the same or different from their sex assigned at birth. In the 1970s and 1980s, there were several cases of sexual reassignment the conversion of chromosomal male children into females through physiological and social conditioning each troubled and troubling in its own right. Some of them suffered hanuting pangs of anxiety, anger, dysphoria, and disorientation well into adulthood. Others had trouble reconciling her sense of herself as fundamentally female. They might had been converted into women physiologically, but genetically they were still male and exhibiting male behavior in a female body. So they had never really acquired the female gender identity. But to enable more profound aspects of gender determination and gender identity, SRY must act on dozens of targets turning them on and off, activating some genes and repressing others. These genes, in turn, integrate inputs from the self and environment form hormones, behaviors, exposures, social performance, cultural role-playing, and memory to engender gender. This geno-development cascade specifies gender identity. The existence of a transgender identity provides powerful evidence for this geno-development cascade. In an anatomical and physiological sex, sex identity is quite binary: just one gene governs sex identity, resulting in the striking anatomical and physiological dimorphism that we observe between males and females. But gender and gender identity are far from binary. Image a gene call it TFY that determines how the brain responds to SRY. One child might inherit a TGY gene variant that is highly resistant to the action of SRY on the brain, resulting in a body that is antomically male, but a brain that does not read or interpret that male signal. Such a brain might recognize itself as psychologically female; it might consider itself neither male or female, or image itself belonging to a third gender together. Sexual Orientation Social Behavior Sexual Orientation Sexual Orientation, or sexual identity, is how one thinks of oneself in terms of to whom one is romantically or sexually attracted the choice and preference of sexual partners. For a while in the 1950s and 1960s, the dominant theory among psychiatrists was that sexual preference was acquired, not in born. In the 1980s, J. Michael Bailey (1957- ), a professor of psychology, conducted a study of sexual orientation using twins. When he looked for concordance of gayness among twins, the results were striking. Of the fifty-six pairs of identical twins, 52 percent were both gay. Of the fifty-four pairs of nonidentical twins, 22 percent were both gay, lower than the fraction for identical twins, but still significantly higher than the estimate of 10 percent gay in the overall population. This study provided strong evidence that homosexuality is hereditary. In 1991, Dean Hamer (1951- ), a researcher at the National Caner Institute, came across Bailys twin study, and began his search for the gay gene. His studies led to the first molecular evidence for genes that influence human sexual orientation. His research groups first paper, published in Science in 1993, reported that the maternal but not paternal male relatives of gay men had increased rates of same-sex orientation, suggesting the possibility of inheritance from the maternal side of the families. A genetic linkage analysis of DNA samples from these families showed that gay brothers had an increased probability of sharing polymorphic markers on a small stretch of the X chromosome, called Xq28, providing statistically significant evidence for linkage to the sexual orientation phenotype. This finding was replicated in two other studies in the United States whereas a study in Canada found contrary results. After nearly a decade of intensive hunting, what geneticists have found is not a gay gene but a few gay locations. But none of the genes in these locations were experimentally linked to homo- or heterosexuality. The long-sought gay gene on Xq28 remains unknown. Social Behavior In 1979, Thomas Bouchard, a scientist in Minnesota, came across an account of twins who had been separated from birth and were reunited at age 30. For these brothers, genes were identical, but they grew up in different environments. By comparing separated-at-birth twins against twins brought up in the same family, Bouchard could untwist the effects of genes and environment. Bouchard began recruiting such twins for this study in 1979. By the late 1980s, he have assembled the worlds largest cohort of reared-apart and reared-together twins. This work became the Minnesota Study of Identical Twins Reared Apart (MISTRA), better known as the Minnesota Twins Project. In this study, he found out that shyness, political conservatism, dedication to hard work, orderliness, intimacy, extroversion, conformity, and a host of other social traits were largely heritable. In the early 1990s, Richard Ebstein, a geneticist in Israel, read Bouchards paper on the separate-at-birth twins. He wanted to identify the actual genes that determined variant forms of behavior. To find such genes, he would have to begin with a rigorous definition of the subtypes of personality that he wished to link to genes. He split out personality into four dimensions: novelty seeking impulsive vs cautious reward dependent warm vs attached risk avoidant anxious vs calm Persistent loyal vs fickle Ebstein was particularly intrigued by one of the subtypes novelty seeker, or neophiles. He began to collect a cohort of extreme neophiles using surveys, advertisements, and questionnaires. He then used molecular and genetic techniques to determine the genotypes within his cohort with a limited panel of genes. The most extreme novelty seekers, he discovered, had a disproportionate representation of one genetic determinant: a variant of dopamine-receptor gene called D4DR. His study was also corroborated by several other groups. D4DR is a human gene, located on chromosome 11. It is (so far) one of the only genes proven to be directly linked to a human personality trait. When the D4DR gene is mutated or elongated, studies have shown that the individual may be more interested in danger, excitement and thrill seeking. Epigenetics In the 1950s, Conrad Waddington (1905-75), an English embryologist, was fascinated in the early development of the fetus and interested in the mystery of how cells can start so simply and then develop specialized functions. He realized that a cells identity must be recorded in some manner beyond its genome for this to happen. He termed the phenomenon epigenetics. The word epigenetics literally means in addition to genes. Epigenetics is the reason why a skin cell looks different from a brain cell or a muscle cell. All three cells contain the same DNA, but their genes are expressed differently (turned on or off), which creates the different cell types. Today, epigenetics is the study of changes in organisms caused by modification of gene expression rather than alteration of the genetic code itself. It also refers to external modifications to DNA that turn genes on or off. These modifications do not change the DNA sequence, but instead, they affect how cells read genes. In response to cues from the environment, chemical marks are selectively added to certain genes and erased from others, modulating the expression of the genes in that cell alone. These marks are layered above the genes, leaving a permanent imprint on genes. This genetic memory would ensure that gene expression is locked into place in each cell, enabling each cell to acquire and fix an identity. Hongerwinter The Dutch famine of 1944-45, known as the Hongerwinter (Hunger winter) in Dutch, was a famine that took place in the German-occupied part of the Netherlands during the winter of 1944-45, near the end of World War II. A German blockade cut off food and fuel shipments from farm areas. Tens of thousands of men, women, and children died of malnourishment; millions survived. People who survived suffered from malnourishment and growth retardation. Children who survived the Hongerwinter also suffered chronic health issues: depression, anxiety, heart disease, gum disease, osteoporosis, and diabetes. In the 1980s, when the children born to women who were pregnant during the famine grew up, they too had higher rates of obesity and heart disease. In the 1990s, when the grandchildren of men and women exposed to the famine were studied, they too had higher rates of obesity and heart disease. The acute period of starvation had somehow altered genes not just in those directly exposed to the event; the message had been transmitted to their grandchildren. Some heritable factor, or factors, must have been imprinted into the genomes of the starving men and women and crossed at least two generations. The factor responsible for the memory could not be an alteration of the gene sequence: the people in the Dutch cohort would not have mutated their genes over the span of three generations. Here, an interaction between the gene and the environment had changed a phenotype (ie, the propensity for developing an illness). Something must have been stamped into the genome by virtue of exposure to the famine some permanent, heritable mark that was now being transmitted across generations. Gurdons Frog Cloning Experiment Our lives begin when a fertilized egg divides and forms new cells that, in turn, also divide. These cells are identical in the beginning, but become increasingly varied over time. It was long thought that a mature or specialized cell could not return to an immature state, but this has now been proved incorrect. In 1962, John Gurdon (1933- ) removed the nucleus of a fertilized egg cell from a frog and replaced it with the nucleus of a cell taken from a tadpoles intestine. This modified egg cell grew into a clone of the adult frog. Gurdons experiment had proved that factors present in an egg proteins and RNA could erase the marks of an adult cells genome and thereby reverse the fate of a cell and produce a tadpole from a frog cell. The idea was controversial at the time, but it later led directly to the cloning of Dolly the Sheep by Ian Wilmut in 1996, and to the subsequent discovery by Shinya Yamanaka that adult cells can be reprogrammed into stem cells for use in medicine. Chromosome Silencing In 1961, Mary Lyon (1925-2004), a former student of Waddington, found a viable example of an epigenetic change in an animal cell. In her biological study of chromosomes on mice, she found out that every paired chromosomes stained with chromosomal dyes looked identical except the two X chromosomes in females. One of the two X chromosomes in female mice was inevitably shrunken and condensed. The actual sequence of DNA was identical between both chromosomes, but the genes in the shrunken chromosome did not generate RNA, and therefore the entire chromosome was silent or inactivated. As nearly all female mammals have two X chromosomes, X-inactivation prevents them from having twice as many X chromosome gene products as males, who only possess a single copy of the X chromosome. How can a cell silence an entire chromosome? In the late 1970s, scientists discovered the epigenetic marker a group of methyl molecules attached to the DNA. Methyl tags were not the only epigenetic marker on genes. In 1996, working at Rockefeller University in New York, a biochemist named David Allis found yet another system of markers. Rather than stamping the marks directly on genes, this system placed its marks on proteins, called histones, that act as the packaging material for genes. Yamanakas Cell-fate Reversal Experiment Shinya Yamanaka (1962- ), a Japanese stem-cell biologies, was intrigued by Gurdons frog cloning experiment the idea that chemical marks attached to genes in a cell might function as a record of its cellular identity. What if he could erase these marks? Would the adult cell revert to an original state and turn into the cell of an embryo? In 2006, Yamanaka succeeded in identifying four genes within the genome of mice that proved decisive in this process. The introduction of these four genes into a mature skin cell of a mouse caused a small fraction of the cells to transform into something resembling an embryonic stem cell. This means that cells from someones skin can be made into stem cells which in turn can turn into any type of tissue in the body, meaning they can replace diseased or damaged tissue in patients. The Origin of Genes At Harvard, a biochemist named Jack Szostak (1952- ) has spent over two decades trying to discover the origin of DNA. In his laboratory, starting with chemical from the early Earth, the planet before life began, he was able to synthesize lifes basic building blocks lipids, nucleotides and amino acids, and assembled them into larger structures such as membranes, RNA molecules and peptides. Szostak believes that genes emerged out of this soup through a fortuitous meeting between these partners.