On Genetics and Genealogy, Part I
by James D. Shoemaker, M.D., Ph.D
As some of you may know, I am a physician working in the field of genetic diseases at St. Louis University. As I have become more familiar with the methods of family history, I have been struck by the many overlapping issues between the fields of genetics and genealogy. I would like to use this column to begin to describe some of them. First, just how related are we? Can modern molecular biology distinguish the fact that many of us are 8th , 9th or 10th cousins? Are two of us who might be Brewster cousins, for example, really any more related than any other two ethnically similar people? The answer is complicated, but an estimate may be made from the frequency of genetic diseases in our population. Among American Caucasians, the rate of diseases which result from inheriting the same mutated gene from both of your parents (a monogenic disease) has been estimated to be about 1% of all births1. This means that there is a fairly high background of inbreeding in our population. To illustrate this, we all know that most states forbid, for public health reasons, the marriage of first cousins. The risk of having a child with a monogenic disease for first cousins can be calculated and is about 6%, for second cousins 1.6%, and third cousins 0.8%2. Thus the general population, marrying at random, has about the same "inbreeding" risk as second- to-third cousins. Another way to think of this, more familiar to genealogists, is to estimate how many ancestors we all have in common. If you have 4 grandparents, 8 great-grandparents, etc., back x generations you have 2x grandparents. How many generations back do you have to go before you have a number of grandparents equal to the total population at the time? The population of the world 1000 years ago has been estimated at 250,000,000, and the population of Western Europe about one-tenth of that, 225 equals over 33 million, so if a generation is 20-40 years, only 25 generations ago, if there were no inbreeding, your ancestors would be every single Caucasian who has descendants. It is no exaggeration to say that it is likely that every person of Northern European descent is a descendant of Charlemagne, and assuming they had descendants who survive to this day, Joe the Baker and his wife, Kitty. Likewise, if Joe and Kitty lived 1000 years ago, and had only two kids, who each had two kids, who in turn over the centuries have had only two kids in orderly 30-year generations, the entire population today would be their descendants (actually over 8.5 billion descendants). When you average out all these effects, we all turn out to be about as similar as third cousins. This is not to say we are not all unique. We all have two copies each of about 80,000 genes, and for each one of us, probably about 20% of those genes have one copy that is "mutant" 3. Another way of looking at this is that one letter out of about 500 in our genetic code is probably a mutation, for a total of about 160,000 mutations per person4. Most of these mutations make no difference at all, but are useful for DNA identification techniques. Current molecular biological methods can follow patterns of these mutations through families and determine descent with a high degree of certainty. Incidently, according to experts in the field, paternity does not match what would be surmised from civil records in about 10% of cases. Yet for all their power, no DNA identification scheme today can deduce the most common physical traits of the person whose DNA is being analyzed--not their height, weight, skin color, hair or eye color. In the next Missouri Compact: how your maternal (mitochondrial) or paternal (Y chromosome) ancestry could be proven, once and for all.
1. Scriver, CR, et al, The Metabolic and Molecular Basis of Inherited Disease, 7th Edition, p.66.
2. Hartl, D, A Primer of Population Genetics, 2nd Ed, p. 58
3. #1, above, p.64
4. #1, above, p. 65
On Genetics and Genealogy, Part II
I am sure everyone has heard something about tracing genealogical lines through the study of mitochondria [might-oh-con'-dree-ah] or Y chromosomes. The infamous cases of Jesse James and Thomas Jefferson, respectively, depended on studies of these biological materials. The study of mitochondria for lineage analysis rests on the principle that we receive these only from our mothers whereas the Y chromosome is carried only by males and passed only to their sons.
Mitochondria are "organelles": that is, they are to each cell of the body what an organ is to the body as a whole. The functions of the mitochondria are many and include the production of energy, the burning of fats, and the disposal of nitrogen. Mitochondria have their own genes, distinct from the genes of the cell found in the cell's nucleus. This plus other factors leads us to believe that the mitochondria are remnants of bacteria that developed a live-in relationship with early one-celled creatures. Each human egg contains up to 1000 mitochondria and these can include several different sets of mitochondrial genes. Since each of us develops from a single egg, and we get no mitochondria from the father's sperm cell, the mother's mitochondrial get distributed throughout our various body organs as we grow in the womb. This makes the study of mitochondrial genetic mutations especially difficult--each person may have normal mitochondria in some tissues and mutations in others--but one thing is certain, they all came from your mother.
To a genealogist, the significance of this is that your mitochondrial genes are a "shortcut" back through your all-maternal line to the origin of that line. The Armed Forces Institute of Pathology, which has the grim task of identifying the remains of US soldiers, has exploited this fact by classifying mitochondrial genetic patterns according to their region or ethnic group of origin. Thus, from a small sample of tissue such as bone or teeth the mitochondrial genes can tell whether the source was Native American, African-American, Northern European or whatever. By studying the variations in the mitochondrial DNA from around the world, and by knowing or estimating the rate of variation (how often mutations are introduced), it has been possible to estimate the age of the human species. This is the so-called "Eve" hypothesis that places the origin of our species in Sub-Saharan Africa about 200,000 years ago.
The Y chromosome's burden of mutations seems to be much lighter. Similar regional and ethnic studies of the Y chromosome have shown virtually no mutations in the functioning parts of the genes, and only a relatively small amount of variation in the nonsense or space-filling parts of the genes. In the case of Thomas Jefferson's male descendants, it was the discovery of a rare and unusual mutation in the Y chromosome that made it possible to compare candidate descendants to known ones. Of course, these genes may have been carried through Jefferson's male cousins or nephews.
The implications of recent knowledge about the distribution of mitochondrial and Y chromosome variations has led to the somewhat self-evident historical hypothesis that whereas women tended to stay at home, men tended to roam. So the picture derived from study of those alive today shows remarkable homogeneity of the Y chromosome, as if we are all descended from a few aggressive males who roamed the pre-historic world in search of conquest. Actually, this is probably not true1. The reasons that all ethnic groups have very similar Y chromosomes may actually have to do with properties intrinsic to the functions of the proteins encoded by the genes on the chromosome. The best mathematical estimates of the age and heritage of our species based on Y chromosome analysis suggests an age around 188,000 years, roughly similar to the age based on mitochondrial studies, and also seems most compatible and an effective ancient human population size of 10,000 with equal numbers of males and females contributing to the genetic diversity1. There have been many recent scientific publications detailing evidence on the origins of the Native Americans based on Y chromosome analysis, with the most definitive placing the ethnic group of origin in central Siberia about 40,000 years ago.2
All of these conclusions are based on the simple idea that mutations happen in the course of the reproductive process and that if the mutations don't render the offspring sterile, they are passed down through the generations unchanged. So the mutations in genes that all animals have, like the mitochondrial ones, carry the record of every mutation that ever happened in the descent of the creature being studied. Some of you may have seen the billboards along Highway 40 in St. Louis offering a prize of $250,000 to anyone who can "prove" the theory of evolution. Certainly there has been much in the press about limiting the teaching of evolution in Kansas and elsewhere. This sort of debate would not need to occur if more people were aware that each of us carries in every cell of our bodies the written evidence, in our own genetic codes, of the origins of our traits, our ethnic group and our species and our exact temporal relationship to those species who were our progenitors. It would make a great deal more sense and be a more interesting proposition to offer $250,000 to anyone who could find a genetic sequence in anything now alive or that ever lived that contradicts the general evolutionary scheme hypothesized by Darwin and his intellectual descendants. Of course, the way science is funded in this country, it would have to be paid in advance. In the next article, we will examine how familial traits can be passed on without the involvement of genes due to maternal or paternal "imprinting".
1. Hammer MF A recent common ancestry for human Y chromosomes. Nature, Nov 23, 1995, 378(6555) p.376-8.
2. Santos FR The central Siberian origin for native American Y chromosomes. Am J. Hum Genet 1999, Feb, 64(2) p. 619-28.
On Genetics and Genealogy, Part III
Everybody has probably wondered at some time how family resemblances are passed from one generation to the next. This is one of the "payoffs" of genealogical research, especially for adoptees, when the researcher finally meets relatives who, one way or another, just look like family. There are many imponderable surprises in raising your own family, and one of them has to be the recognition in one's children of impossibly obscure traits you are sure you have completely hidden all your adult life. People report that their offspring have exactly the same taste in clothes they had as children, or the same habit of doodling pictures of the sun during class, or the same attitude towards playing tag--traits you would assume are not due to "genes" but cannot plausibly be due to teaching or role-modeling either, since we are never children in front of our children. Of course, when we speak of family resemblances, there is always the recognition of Uncle Bob's nose or Aunt Minnie's telephone voice in someone in the next generation. How are these traits transmitted? Probably not always through the "genes" as we normally think of them.
The central dogma of current biology is that genes are segments of DNA made up of 4 "letters" (adenine, guanine, cytosine and thymine) arrayed in sets of three that specify the order of the 20 amino acids in proteins; that the order of amino acids specifies, in a way that is so complex no current computer can completely calculate it, the shape and chemical function and of the proteins; that the shape and chemical properties of proteins, along with the order in which they are made, somehow determines the life and death of cells, the cellular structure of the organs and everything about us.
But do scientists really believe there is a bulbous-nose gene? Or a squeaky voice gene? Or a set of genes that makes you smirk or snort in a certain recognizable way after a joke even if you were raised apart from your biological family who recognizes it? Recent discoveries of genes governing the propensity for alcoholism, risk-taking, shyness, obesity and other complex behaviors reveal they are not simple Mendelian traits, but only genes that, if you have them, increase your likelihood of developing the traits involved. They are not as simple as Gene A makes you rude and Gene B makes you polite. Even traits like eye-color and height and risk for diabetes, cancer and heart disease are usually inherited in a complex way, and not an all-or-nothing way. This is due to the fact that the protein product of every gene must interact with all the other gene products and that essential life functions are ensured by redundancy, back-up plans and compensatory mechanisms, just like the Space Shuttle.
But there is now the realization that everything in genetics is not due to the simple A-G-C-T alphabet of the genetic code. The first proof of this was in the area of genetic imprinting. It has now been shown that inheritance of some traits depends on which parent you got the gene from. Classical genetics always assumed that maternal and paternal genes had the same chance of influencing body type. Indeed, this was the whole biological point of sexual reproduction, that the "superior" copy of a gene from either parent would dominate in the offspring, yielding an offspring potentially stronger than either parent. However, there are now several genes known that are suppressed when inherited from the father or mother by a process involving a chemical change called methylation to the letter "C" in the genetic code. This results in full expression of the copy of the gene derived from the other parent, with no chance of compensation or correction. In short, some genetic traits are not due to the lack of the gene itself, but due to lack of translation of that gene into protein.
It has been hypothesized that physical traits such as facial features may not be the result solely of genes themselves, but from the way the chromosomes unfold during the developmental process. Imagine cells of the face as having facets like a diamond or a geodesic dome. From which facet will a cell bleb off its daughter cells? The ultimate shape of the face will be determined by the direction in which cell division proceeds. This is probably neither completely random nor controlled by genes or gene products, but rather by the way in which the chromosomes are coiled up and oriented as cells divide, then uncoiled as the genes are transcribed into proteins. In other words, the exact shape of an eyelid or nostril may be due to a very complex dance choreographed not by the genetic code but by the coiling architecture of the DNA and the way it is packed into the nucleus of cells. Since chromosomes must make exact copies of themselves using themselves as templates, you can imagine how this shape might be passed from one generation to the next without the involvement of the genetic alphabet itself.
This helps to explain why so little of the total DNA is actually comprised of genes that have protein products. The rest has been regarded as "spacers" or "deadwood", but may actually be crucial to the passing on of the shape of the chromosomes that ultimately determine some aspects of our own shapes.
On Genetics and Genealogy, Part IV
This is the fourth in a series of articles for Missouri Compact on some of the issues that overlap between the modern field of genetics and genealogy. The methods of genealogy have been changing rapidly over the last several years with each new technology, the microfiche, the CD-ROM, the Internet, the GEDCOM file and personal computer-based genealogical software. Similarly, even since this column began, when I first became Governor of the Missouri Society two years ago, there has been a dramatic change in the impact of genetics upon genealogy. The most impressive change is that the type of genetic testing mentioned in the second article in the series, mitochondrial DNA analysis for tracing the maternal line, is now commercially available from of a service of Oxford University in England, the Oxford Ancestor Project. Here are their instructions taken from their Internet WebSite: http://www.oxfordancestors.com/
Step 1. Send an email to [email protected] with your full return postal address and the number of tests required. SEND NO MONEY AT THIS STAGE. We mail you a DNA sampling kit with full instructions. This contains the small brush used to collect cells from your inner cheek easily and painlessly.
Step 2. Return the DNA brush with your payment cheque. We confirm receipt by email. Your cheque will not be banked until your results have been mailed back to you. Expect delivery within 28 days of our receipt of your sample.
So what do you get for the $180 you send along with brushings from your inner cheek? You get to find out which of the "Seven Daughters of Eve" you descended from. The Oxford group has determined that 99% of people of European descent can be classified as having come from one of seven original "founder" females of Europe: Ursula, Tara, Helena, Katrine, Velda, Jasmine or Xenia. These 7 are among 18 worldwide mitochodrial DNA types so far identified. These are fictional names assigned to each of 7 areas of Europe:
The geographic distribution of Ursula appears to follow the use of stone tools, Ursula's clan members drifted across all of Europe. The clan of Tara settled in Tuscany 17,000 years ago. Descendants moved across northern Europe and crossed the English Channel. Helena's clan lived in the Pyrenees. As the climate warmed 12,000 years ago, Helena's descendants traveled northward to what is now England. Members of this group are now present in all European countries. Katrine originated in Venice 10,000 years ago. Most of Katrine's descendants now live in the Alps. Velda was originally from Spain 17,000 years ago. Velda is now associated with northern Finland and Norway. Jasmine's people were from Syria, where they farmed wheat and raised domestic animals. Jasmine's descendants traveled throughout Europe, spreading their agricultural innovations with them. Less is known about the most remote matriarch, Xenia, but it is believed that her people lived in the Caucasus Mountains 25,000 years ago. Just before the Ice Age, this clan spread across Europe, and even reached the Americas. In a few months, the Oxford Ancestor Project promises to have a commercial version of its Y chromosome (male lineage) analysis available as well.
I raise the next topic with trepidation, but with confidence that today's Mayflower Descendants are sophisticated enough to accept it. It is the concept of "good breeding". I have confidence in the tolerance of our members to the idea that "good breeding" may not promise everything our grandparents might have hoped, because in the Missouri Society, just a few years ago, we changed our Constitution and Bylaws to say that anyone who can prove lineal descent from a Mayflower Passenger may become a member regardless of their "acceptability", social, or otherwise. This reflects modern thinking that just because one's parents and grandparents were good people, it is no guarantee of one's character, and conversely, if your ancestors were lowlife red-necks, you might have the social graces of royalty. The observation of history confirms that greatness is rarely transmitted intact to succeeding generations, whereas great talent can arise, seemingly out of nowhere, in families of the most undistinguished sort. What are the genetic facts behind these unsettling realities?
First, each of us carries within us a "shadow person": a complete set of human genes that are, to an extent, suppressed or dominated by a "superior" set of genes. We have two copies of each of our 23 chromosomes, and most of the time, even potentially fatal mutations in one copy can be masked by the other copy. However, the biological process of creating our children separates these two copies from each other, and since the time of Mendel it has been apparent that the "shadow" traits have just as good a chance of being passed on as the dominant ones seen in the parents, although if the traits go unseen in the parents, they will probably go unseen in the offspring unless the chosen spouse has the same hidden traits. Unfortunately, if you choose a spouse from within your historically exclusive social class and geographic area, you are just increasing the chances of revealing the weak, suppressed genes of your "breeding group".
Another biological fact restricts the likelihood of seeing your own finer qualities in your children: the chromosomes we pass on are those of our parents and not our own. Of course, we carry the genes of our parents, but these genes are arrayed in linked sets called chromosomes. The 23 chromosomes in our eggs or sperm are in place while we are still embryos, and the viability of those chromosomes, including the "shadow traits" they may possess, are as yet untested in life. Through the process of meiosis, the egg or sperm that creates your child recombines the genes of your two parents into single chromosome copies. This is the first time that the best (or worst) traits of your mother and father have the chance to be physically linked and potentially amplify each other's weaknesses or play to each other's strengths in the formation of an individual. For better or worse, these recombined traits will have to compete with those of your in-laws for expression. This is nature's way of ensuring an element of surprise in the most carefully arranged marriages. Talents such as verbal or musical ability, or personal mannerisms may be due to the action of many genes acting together, including genes from many different chromosomes. The ultimate result is: the endearing traits of one of your parents that appeared in you by the mechanism of gene dominance may re-appear in your children by the mechanism of meiotic recombination, but may be broken up again in succeeding generations, never to reappear.
On a final topic, every genealogist has had to endure the tiresome jokes of the form, "Well, there is a perfectly good reason why my kids are like they are, half their ancestors were men/women!" (Choose your own gender to blame). This statistical estimate that exactly half your ancestors are of one sex and half are the other may not be precisely true, as known to most family researchers. It is possible to have an excess of one gender or the other if you are descended from two or more children of an ancestor through two or more spouses. For example, if you have Francis Eaton as an ancestor through both his wives, Sarah and Christian Penn, you have a male ancestor deficit and an excess of females. If, however, you are descended from Christian Penn (the second wife above) through both her husbands, Francis Billington and Francis Eaton, you have a deficit of female ancestors and an excess of males. I will leave it to the reader to decide which is preferable.
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