History of Genes: History of Populations

Dr. Charles R. Scriver
Alva Professor of Human Genetics
McGill University
Montreal Children's Hospital

Delivered at the Community Health Events
Genetics of the Acadian People
9 August 1999
at McNeese State University in Lake Charles, LA
10 March 2001
at Nicholls State University in Thibodaux, LA

Who am I? Where is here? These are questions often asked. In seeking the answer to the second question, we will recognize that we reside at a particular place on planet Earth, in a universe that is constantly undergoing renewed understanding. Who am I? is a deep philosophical and spiritual question that has been of interest ever since humankind began to enquire. This question is even harder to answer …

The name Acadia appears in North America after 1605 to describe a permanent (over-winter) European settlement on the northern shore of what we now call Nova Scotia. The Acadian settlers came from France, spoke French, and were very successful colonists, reclaiming land from the sea and prospering in agriculture and fishing. By the year 1605, there were 79 surviving settlers in Acadia.

In 1621, trouble with Great Britain began. English-speaking Scots lay rival claim to the whole territory, which they called Nova Scotia. The European treaty of St. Germain-en-Laye, which was ratified in 1632, recognized the right of Acadians to keep their land. By 1670, the Acadian population had increased to 350 and by 1700 to 1400 people. The Acadians became a classic founder population, expanding by natural increase in relative geographic, cultural, and genetic isolation.

In 1713, following the Treaty of Utrecht in Europe, the North American colony of Acadia was ceded to Britain. The Acadians were treated with some respect at this time as politically neutral. However, as the descendants of the Puritan English colonists to the south of Acadia became increasingly unhappy with their political masters in London, the English in North America, especially those in what would become Lower Canada, became increasingly worried about the presence of a potentially disruptive French colony in Acadia.

Despite posing no actual threat to these North American colonies, the regional British government nonetheless sanctioned the destruction of Acadia.. Driven by land lust, the destruction of the Acadian homeland was an exercise in ethnic cleansing, with deportation of Acadians beginning in 1755. Flight and migration followed this strategic decision taken by Major Charles Lawrence in his neighboring colony of Nova Scotia.

By 1763, the population of 13,000 French-speaking Acadians had been widely dispersed: down the North American coast; into Quebec; to several island colonies along Atlantic coasts; back into France. Perhaps 50% of the Acadian refugees died during their exile and wandering. With each move, the exiles encountered pathogens unknown in pre-dispersal Acadia, and the resulting death toll averaged 25 to 30% each time any group of Acadians relocated. It took two generations before the Acadian population worldwide regained pre-dispersal numbers.

Ironically, following capture of Quebec in 1795, Britain had lost all but its Canadian colonies, and 7,000 immigrant New Englanders and 30,000 immigrant Loyalists will migrate in protest out of the new American nation (USA) to Canada. Meanwhile, surviving Acadians exiles are scattered: one third have resettled in Maritime Canada, one third in Lower Canada (eventually to become the province of Quebec after Canadian Confederation in 1867), and one third elsewhere . In due course, a new Acadian settlement is created in Louisiana. By 1785, over 1600 people have migrated to there from France, 1,000 from Caribbean Islands, and another 400 or so from the American colonies.

With each migration and resettlement, a founding population brings its genes, which are passed on to the next and succeeding generations. If the founding people are few, if they are isolated socially or geographically, and if a large natural increase in population follows, there can be a genetic founder effect. Founder effects can explain the clustering of certain genetics diseases (such as Usher syndrome), in particular human populations (such as Acadians) in particular places (such as Louisiana). Thus the history of the population can be the history of its genes.

Most human genetic diseases associated with a founder effect are inherited as recessives, meaning that the individual who is the carrier of the disease-causing mutation is silent (healthy). However, should such a carrier select a partner (such as a partner from the same isolated, founder population) who also carries a similar silent mutation, the chance that disease will appear in the offspring is significant: one chance in four at each pregnancy. A double dose of the mutation, one dose from each carrier parent, is necessary and sufficient to cause the disease. The double dose is more likely to occur in a founder population than in one that does not have a history of isolation.

The chance of inheriting a disease has poignant meaning when a particular population (your family or my family) experiences an event with serious consequences for health. We may well ask: Who am I?

The evolutionary origins of Homo sapiens (you and me) are identifiable in the milestones recording a very long journey of life on Earth (about 3.5 billion years). These milestones are recorded in our genome-the entire collection of our genetic material, including all our genes, found in each of our cells. The current series of genome projects, often lumped under the term The Human Genome Project, is among the biggest of the scientific projects in progress at the end of the twentieth century and continuing into the twenty-first. These genome projects attempt to understand the relationships of genes from different forms of life. The genome projects are telling us about the evolution of life as we know it today. What we learn from the genomes and genes of bacteria, yeast, worms, fruit flies and mice, for example, contributes to the knowledge of our own genetic makeup and what it means to be one of those particular organisms.

From both the philosophical and the biological perspective, there is "unity in diversity." There is unity in the collective organism Homo sapiens (you and me)-each of us has similar features. However, there is diversity among its individual members. Diversity in the genetic makeup is, in part, the explanation for human individuality. We each have our own biological self; our particular pair of parents scrambled our particular set of genes in particular ways when we began life. In their turn, our parents came from their particular communities and populations. Thus if we know our history, we begin to understand how we can have both individual and collective (biological) identities.

Two relevant points of view emerge. First, if our human individuality (Who am I?) is something we treasure, why should we want to clone a person? Cloning is a procedure that minimizes individuality. Cloning is impractical anyway, because the lifelong experience that shapes human individuality will occur in a different time and place from that which shaped the "parent" of the clone. Second, biological individuality is a significant feature of both our health and our diseases today. At the beginning of the twentieth century, life could be dangerous, nasty and short: Experiences of environmental accidents (such as infectious disease, epidemics, injuries, inadequate nutrition, etc.) were important explanations for individual human disease and for the high rates of illness and death. Subsequently, procedures such as vaccination, immunization, and better nutrition enhanced the quality of life and improved collective health and longevity. Nonetheless, disease continues. Biologists recognize that the manifestations of "modern" disease are likely to reflect the biological individuality of the persons affected rather than the experiences they encountered. Geneticists recognize that with human disease the genetic causes, compared to the environmental causes, are now relatively more important.

When the modern physician asks the question Why does this patient have this disease now?, it is likely that a genetic (biological) cause or susceptibility will be among the explanations. There has been a subtle change in the physician's approach. We used to ask: What is the disease the person has? Now we would ask: Who is the person who has the disease?

Stanley's story. Stanley lives in Montreal; his ancestors came from 
Poland; his and their religious affiliation is Jewish. Stanley carries a mild hereditary disease of the blood-an anemia called b-Thalassemia: b-Thalassemia is rare among Northern European Jews, but not so rare in populations from regions around the Mediterranean Sea in southern Europe. Stanley wonders about his Thalassemia mutation: Is it unusual and "new" or does he have a Mediterranean ancestor about whom he did not know?

Stanley's DNA is analyzed, and a mutation is found in a gene that encodes the blood protein b-globin. The mutation is an unconventional mutation, unlike any in the existing catalogue of hundreds of Thalassemia-causing mutations. However , a research group in Jerusalem has just identified the same mutation as Stanley's in a patient over there. Strangely, different persons in different parts of the world have an otherwise unique mutation. Moreover, it is two Jewish persons who have this (rare) mutation.

Stanley then asks a reasonable question: Am I related to the person in Israel? Two things are then done: Stanley visits the Jerusalem researchers and receives confirmation that the same mutation is transmitted through at least three generations in both the Montreal and the Jerusalem families. Furthermore, the background structure of the b-globin gene (the structure over a long length of the DNA molecule) is identical between Stanley and the Jerusalem patient; this indicates that the Montreal and Jerusalem mutations are probably identical by descent from a common ancestor. This means that Stanley and the Jerusalem patient are both descendants of a single couple many generations ago.

To understand this distant family relationship, Stanley next undertakes genealogical research to reconstruct the family histories. The Jerusalem family had immigrated recently from Russia. After much work in Polish and other archives, Stanley identifies ancestors for the two families in two towns close to each other in old Poland (within what was known as the Pale, where the Jews were settled in Eastern in Europe). Stanley realizes he has found living relatives. This is a great inspiration for Stanley, because most of his relatives died in the gas chambers of Europe in the Second World War. Stanley's wonderful story of discovery and reunion continues, but it began with a mutation in a DNA molecule.

Irene's story. Irene's wedding photo includes her older sister Gaby, the bridesmaid. Gaby has severely impaired cognitive development-she is mentally handicapped. Gaby's unfortunate development is the result of a disease called phenylketonuria (PKU). PKU is a recessive inborn error in the metabolism of the amino acid phenylalanine, an essential nutrient that must be provided in the diet because it cannot be made in the body. In PKU, a gene mutation prevents the change of phenylalanine into other chemicals; phenylalanine accumulates and high levels become toxic, destroying sensitive body tissues, like parts of the brain.

Because family and physicians understood Gaby's condition, Irene's PKU was diagnosed on the third day of her life some 40 years ago. Both sisters have inherited the same genetic defect, one PKU-causing mutation from each of their parents. However, Irene was placed on a low phenylalanine diet at three days of age. Irene then developed normally, she has a high IQ, and she holds a challenging job (where she met her husband).

PKU has great historical importance. It was the first genetic disease to benefit from a treatment. It made us realize that treatment is actually possible for some forms of genetic disease. (Treatment of PKU prevents the mental retardation). PKU was also the first genetic disease for which universal newborn screening became the norm. Early recognition of high blood phenylalanine levels through screening signals the need for follow-up diagnosis and treatment if necessary. To wait for signs of the disease (impaired mental development) is too late.

PKU affects about one in fifteen thousand persons. Because of screening and treatment, the PKU disease (mental retardation) is rarely seen now. The incidence of affected people in the population has not changed since universal screening began. The difference between then and now is that PKU is not a disease now. Conquering PKU is one of the triumphs of understanding human genetics.

Emily's story. It begins when she is inside her mother's womb. At birth, she will become the newest cousin of Jennifer, a young woman who had died earlier (in her twentieth year) of cystic fibrosis. The family fondly remembers Jennifer.

Cystic fibrosis (CF) is the most common genetic disease in North America. However, for many years, we had no reliable test to identify a carrier of the disease. Fortunately, the cystic fibrosis gene was isolated and characterized in 1989, and it then became possible to find mutations in the cystic fibrosis gene of suspected carriers by studying the nucleotide sequence of the DNA.

Emily's mother remembers that family members can be silent carriers of a CF mutation; knowing about the discovery of the CF gene, she seeks genetic counseling. In 1991, she and her husband have samples of DNA taken for testing; the tests do not reveal any of the common CF mutations known at the time. After additional tests, it is concluded that the risk to Emily for CF is very low. The pregnancy continues; Emily is born.

Meanwhile, genetic testing of other family members leads to the discovery of the mutations that caused cystic fibrosis in Jennifer. Members of the family who wish to know whether they are carriers of those mutations are tested. Now, armed with the knowledge that Jennifer's gene has given them, Jennifer's surviving family members can live a stronger life understanding the true risk of transmitting cystic fibrosis disease.

This particular story has personal significance for me. Emily is my granddaughter; she is visiting with me as I write this story.

Three different stories reveal how knowledge of DNA molecules, of heredity, of human histories, and of genetics (both the scientific discipline and its medical applications) can be helpful. There are many more stories worldwide, and many among your own families in Acadiana. Accordingly, I recognize five types of knowledge: the unknowable, the unknown, the known, the I-don't-want-to-know, and the forbidden. In relation to genetics, each of us harbors one or other of these forms of knowledge. Which do you recognize? You are free to choose. Your choice will bear on the answers to your questions: Who am I? Where is here?