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  • Dealing With New Developments

    Edwin M. Knights Jr., M.D.

    When the New England Historic Genealogical Society conducted its survey of genealogists’ experiences with DNA analysis in October, 2005, the majority of responses were positive, although there was considerable concern about the need for help from independent consultants both for genealogists contemplating DNA studies for their families and for assistance in the interpretation of confusing results. Those who pioneered using DNA analysis were the most frustrated, because only limited numbers of markers were available and these varied from laboratory to laboratory, along with the technology. DNA laboratories emerged, submerged and merged. It was very difficult to predict the cost of a significant family study. Turn-around times were unpredictable and could be lengthy. Prices could be very high.

    DNA analysis has become increasingly important -- almost essential, in fighting crime. The FBI established the Combined DNA Index System (CODIS) based upon FBI-developed software for analyzing and tracking DNA profiles. CODIS is obviously very important and is used in the vast majority of states. One would expect the technology for these analyses would have to be uniform, but this is far from true. Advances in DNA testing have sped up the results but have created incompatibilities in data. For 10 years restriction fragment length polymorphism (RFLP) was the usual method for analysis -- slow, but reliable. Polymerase chain reaction (PCR) has many advantages, but can generate DNA profiles which don’t match those created by RFLP. Next, short tandem repeat (STR) appeared, combining the speed and sensitivity of PCR with features that are compatible with the RFLP results. The FBI has designated 13 STR loci that must be included in convicted felon DNA profiles.

    The result has been a log-jam of data which has failed to be incorporated in CODIS or become accepted by the National DNA Index System. Laboratories are forced to retrain personnel in methodology and validation, using reagent kits that produce similar data but by slightly different ways. This is a huge problem for forensic laboratories, and for the legal prosecution of criminals.

    This brief glimpse of the chaos in the forensic world gives a little more insight into what to expect from your genealogical DNA analysis, especially as some of these laboratories also offer genetic testing for genealogists. New Y-STR loci (markers) are continually being discovered. According to John Butler, over 200 Y-STR markers had been identified by 2003, and 150 more by the middle of 2004. Over 200 population studies have been done, using thousands of Y-STR haplotypes. Multiple Y-STR kits are now commercially available. Who is checking, and comparing the results obtained? What methodology is your lab using?

    Medical DNA testing has alread left the genetic level and moved on to genomics and protenomics. They are also finding valuable information in RNA, the messenger DNA. The complexity of DNA mutations is shown by just a single disease -- cystic fibrosis. There are hundreds of different genetic variations; a committee finally recommended using 150 of these for CF screening.

    Genealogical DNA testing is based upon examination of nucleotides at specific sites on your DNA. While they are not designed to disclose useful medical information, or to identify genetic disorders, we will see how they can reveal heritable medical disorders, especially if accompanied by carefully documented family history data.

    Y-DNA testing of the male’s chromosome has been particularly useful, especially in recognizing paternal ancestry, as the DNA data follows the tradition of European and other cultures of passing surnames down from a father to his sons. A woman looking for her paternal ancestry has to use DNA from a close paternal linking. The Y -DNA testing studies segments of DNA on the Y-chromosome where sequences of nucleotides repeat; these are called short tandem repeats (STRs) and are identified by a DYS number (DNAY-chromosome Segment number).

    Disadvantages of Y-chromosome analysis include the fact that loci are not completely independent and random match probabilities aren’t reliable. Testing must use haplotypes, which combine the alleles at all tested loci. Paternal images all possess the same Y-STR haplotype, so fathers, sons, brothers, paternal cousins and uncles cannot be distinguished. Y-chromosome mutations are said to be from 0.05 to 0.40 percent.

    Mitochondrial DNA (mtDNA) testing is useful in tracing a person’s maternal ancestry, as mtDNA is passed down from a mother to all of her offspring, but only the females can transmit it to the next generation. Infrequently, mutations do occur, resulting in some differences in the next generation. Then it’s necessary to compare the findings with those from other persons, to identify the time in which they shared a most recent common ancestor. (MRCA)

    Y-DNA haplotypes are clusters of results obtained by Y-DNA testing. They can be used to identify the haplotype of the progenitor of a group. Many Y-STR haplotype loci are already available, and new ones are continually being reported. Because there is a definite correlation between haplotypes and haplogroups, it is sometimes possible to predict the type of haplogroup without further testing. Otherwise, haplogroups are identified by single nucleotide polymorphisms (SNPs), which are loci on the DNA where a nucleotide has mutated to become another nucleotide. A variation of at least 1 percent is considered a SNP.

    Mitochondrial DNA testing is particularly valuable in determining haplogroups. Human mtDNA is much better defined than our DNA, consisting of 16,569 base pairs. These are located in a coding region and a control region called the D-loop, but there are some overlapping functions. Some coding regions mutate so rarely that there might have been only one mutation during the history of mankind. These are useful in defining haplogroups which can suggest African or Indian ancestry but cannot define family lineages within the haplogroups. DNA from the D-loop’s hypervarible control regions (HNR-1 or HVR-2), mutating much more frequently, is useful for genealogical studies.

    Various systems of nomenclature have evolved, which we will not attempt to document, but in general, ethnic testing has concentrated on the categories listed in Table l.

    Table 1


    Y-Chromosome and mtDNA testing

    Biogeographical ancestry

    Native American ancestry

    African ancestry

    Cohanim ancestry

    European testing

      British tribes

      European maternal clans

      Sub-European population

    Hindu testing

    Melungeon testing

    (Table modified from Wikipedia, Free Encyclopedia. For more details about one or more of the subjects, data from results is available from various dedicated websites.)

    Because of the frequency of reporting of new findings and new testing methodology, it has been difficult for genealogists to keep up with progress in DNA analysis. Some of the laboratories have created excellent websites detailing their operations. Unfortunately, much of the description is promotional, rather than an objective evaluation. Some of the DNA project administrators have done much to educate their clients about the positive and negative aspects of DNA testing.

    Those genealogists who’ve been experimenting with DNA analysis to augment their family histories are to be congratulated -- they have been pioneers in using this complicated

    new technology. They have become acutely aware of the ongoing changes which affect this new branch of genealogy. Many of them were kind enough to share their experiences with us in the Genetic Laboratory Survey conducted by NEHGS in October 2005. “Partnerships for Progress” has concentrated on the medical knowledge which becomes apparent when family ties are extended and clarified by DNA. But we also owe it to our readers to take a broad view of genetic genealogy, see what has transpired, evaluate it for newcomers, and perhaps see what might lie ahead.

    Progress has been made in adapting Y-chromosome and mitochondrial DNA analysis to the needs of the genealogist working on a family pedigree. Using Y-DNA testing to compare subjects, it was possible to develop the concept of a most recent common ancestor (MRCA). Analysis of mtDNA made it possible to recognize the mtDNA of a European woman in haplogroup H, which became known as the Cambridge Reference Sequence (CRS) Again, comparison of results enabled the recognition of the time frame in which two women shared a MRCA. Because the analyses either involved DNA which tended to mutate fairly often or DNA haplogroups which hardly ever mutated, there is an enormous interval between these two eras. Some studies have penetrated this void, usually involving elaborate tracking of ethnic groups. By pooling haplotype information, laboratories now attempt to identify ancestral Eurasian, African, East Asian, AmerIndian and other populations. As we will see, the results are sometimes confusing.

    Most human DNA is not sexually oriented like the male Y-chromosome or the female X-chromosome. The mitochondrial DNA is a relative miniscule structure which is located out in the cellular cytoplasm, rather than in the controlling cellular nucleus. It’s quite independent; some of its functions are similar to those of the surrounding cell but are achieved through different reactions. mtDNA is transmitted from a mother to all of her offspring, but only the female children can pass it on to the next generation. All of the rest of our DNA is autosomal, and it was only a matter of time before exploration began on the genealogical potentials of our other 22 chromosomes.

    Being neither paternally nor maternally linked, half of autosomal DNA is inherited from each parent. Autosomal ancestry is still in its infancy but is already being used to attempt to measure the genetic ratios of European, East Asian, African and Native American found in your autosomal DNA profile. This is done by examining the patterns of single nucleotide polymorphisms (SNPs), which are called Ancestry Informative Markers (AIMs). Elaborate patterns of population migration have already been proposed using this data.

    Unfortunately, there is no reliable uniformity of nomenclature, some of which is highly misleading, resulting in gross misinterpretation of results. The problem was well stated by Robert Charles Anderson, FASG, in a letter to The New York Times concerning their coverage of autosomal testing:

    “Today’s article on ‘Seeking Ancestry, and Privilege, in DNA Ties Uncovered by Tests’ fails to mention serious deficiencies in the tests for ethnic ancestry, deficiencies which make the results of the tests of dubious value. First, the broad ethnic categories reported do not necessarily correspond to the actual distribution of the markers. For example, the Native American markers are actually Central Asian markers and are also found in southeastern European populations. Second, most of the markers are not specific to a particular ethnic group. Thus, a given marker might have a high rate of occurrence in a European population, and thus contribute to the supposed percentage of European ancestry, but the same marker might also exist at a lower frequency inother ethnic groups. In both these instances, the test might indicate a genetic contribution from a certain ethnic group when none exists. These arguments apply equally to all the ethnic groups reported.”

    Our conclusion is that at this time, in contrast to much of the Y-chromosome and mtDNA analyses, autosomal tests cannot be considered reliable, largely because the markers are misnamed and therefore misleading. In looking into the need for quality assurance in DNA laboratory testing, I corresponded with Jacques Mobille, Senior Technical Specialist, Surveys, for the College of American Pathologists (CAP). He replied:

    “The markers used by our customers (parentage and forensic) overlap greatly with the markers used by the genealogy folks; however, I am not aware that the markers used by the genealogy folks are standardized. Therefore, it is highly likely that many laboratories use home-brew systems and/or loci not commonly used by our customers. In reading Dr. Knights’ email, I would suggest that this group of people develop standards for test/reporting -- in those standards, possibly a proficiency testing program could be developed...”

    It’s apparent that although some laboratories advertise they are accredited by the AABB Parentage testing Program, are ISO 17025 accredited, and participate in the CAP Parentage Proficiency Testing, there is no evidence that their genealogical testing is held to these standards or even done by the same personnel. There is a need to supplement parentage, histocompatibility and forensic testing surveys and staffing requirements with those dedicated to genealogical quality assurance.

    The National Geographic Society and IBM began a five-year Genographic Project in April, 2005, designed to study the migratory history of humans. With the assistance of geneticist Spencer Wells and the Waitt Family Foundation, the partnership uses laboratory and computer analysis of DNA contributed by hundreds of thousands of individuals and hopes to reveal significant information about the genetic roots of the human race. Particular attention will be paid to indigenous populations, although some resistance is expected in countries such as China and India, where exportation of genetic materials is subject to government control.

    This study will probably be the largest of its type and will no doubt provide us with considerable useful data. How it will inter-react with genealogy remains to be seen. No doubt many of the participants will be motivated to earn more about the family pedigrees, especially as so much can now be researched on the internet. And some genealogists may wish to embelish their family trees with roots showing their early origins. There is a ‘no man’s land” which separates these two entities. If the Genographic Project relies at all upon autosomal findings, hopefully it will have the foresight and the funding to create appropriate analytic standards and devise less confusing nomenclature. This would be a major contribution to the field.

    Genealogists may find “anthrogenealogy” pretty bewildering, especially when the laboratory states that the autosomal ancestry is being based upon “bio-geographical polymorphism patterns of AIMs on your autosomal DNA”. And which laboratory are you going to believe? There is some voluntary cooperation among DNA labs, but the rapidity with which new ancestral markers are discovered and used, makes any sort of uniformity and reliability a challenging task.

    How should we evalute the results of genetic testing? Table No. 2 is based upon factors recommended by the National Cancer Institute of the evaluation of genetic tests used in the diagnosis and treatment of cancer. The principles could be just as useful if applied to genetic testing in genealogy.

    Table 2

    Factors to Consider (National Cancer Institute)

    Analytic Validity
    Technical accuracy and reliability: includes methodology, laboratory techniques, special handling. specific mutations may mean sequencing tests are affected by methodology, the percentage of genes tested and the nature aberrations present.

    Clinical Validity
    Predictability of outcome in an individual. Environmental and personal behavior may also affect results. Linkage studies and family history may play significant roles.

    Clinical Utility
    How much use are results in modifying the course or outcome of a disclosed condition?
    Are other screening tests indicated?
    Will the quality of life be affected?
    Is this test really worth the cost?

    Of course the National Cancer Institute’s concerns deal with life and death situations, but these evaluations demonstrate factors which could alter DNA results in any study. Another possibility which we haven’t even seen mentioned in the laboratory promotions, is the chance that similar mutations could have occurred in multiple individuals located in widely separated parts of the world. The fact that a mutation was able to take place in a particular DNA locus in one person, also implies that the same locus in other persons might be capable or even susceptible to a similar mutation. Also, while a number of persons might have experienced this mutation, their offspring might have reverted to “normal” in subsequent generation.

    At this time, when we are likely to encounter newly recognized patterns and ancestry markers used by but a few laboratories, we need to find out just how much data exists to verify the conclusions proposed by the reporting laboratories. Are the results statistically significant?

    Was the testing done by the lab which received the sample, or was it referred to another facility? What were the qualifications of the personnel conducting the testing? Are other tests now indicated to establish more specific relationships?

    Many responders to our NEHGS 2005 DNA Laboratory Survey told us of the need for independent expert advisors to assist genealogists both in explaining the objectives of proposed DNA studies and in interpreting complex and confusing results. There is definitely a need for an entity which represents the consumers as well as the providers of genomic testing results. The field is changing rapidly and the labs are to be commended for their progress in making new data available and explaining technology to their clients. But it’s time to establish more uniformity and quality assurance so that results can be accepted with better understanding and confidence. Laboratories should be encouraged to find new means for DNA research, but these approaches need to be independently evaluated so that users can make intelligent selections of tests most appropriate to the needs of their research.

    We have a unique opportunity. We are the first generation capable of combining medical information gleaned from our relatives and ancestors with the exciting new science of molecular genomics to benefit from a torrent of new information that is pouring forth from DNA-based research and testing. Admittedly, glowing predictions of medical break-throughs which accompanied the completion of the Human DNA Project have failed to materialize; even now, we are just beginning to understand the complicated causes and mechanisms of the few diseases which have received the most attention from researchers. But it’s still important to learn our family’s medical history and to preserve DNA from our senior citizens (or those who are recently deceased) so that future generations can benefit from the stored-up genetic data that will be available for the much more efficient and informative analyses. The decision is ours -- we can act now and be among the first to benefit from this new technology or we can just watch others move ahead.

    In our previous chapters we’ve tried to give you a glimpse of what’s in store for us in the medical world. To maximize our harvest of knowledge, the other key factor is the family history. It’s role is so vital that it inspired Dr. Alan E. Buttmaher, Dr. Francis S. Collins and Dr. Richard H. Carmona to co-author an article entitled, “The Family History -- More Important than Ever”. This article was primarily directed at family physicians and internists, but it should be “must” reading for genealogists, too, as they already have expertise in acquiring family facts. A good family history can serve as the cornerstone for individual disease prevention. Combining your knowledge of a family’s medical history and inheritance pattern of common diseases with the physician’s medical expertise and benefits resulting from bioinformatics and designer drugs, can help predict such conditions as cardiovascular disease, colorectal cancer, breast and ovarian cancer, type 2 diabetes and asthma, just to name a few. The entire family can become aware of risk factors which may currently exist or threaten future generation.

    The suggested history form is known as “My Family Health Portrait” and is available free from Pueblo, CO 81009 or can be ordered by phone at 1-888-8 PUEBLO (1-888-878-3256) Monday through Friday, 8 A.M. to 8 P.M., Eastern Time.

    Participation in Family History Day isn’t the only way a family could become aware of the presence of heritable medical conditions. The ever-expanding use of DNA studies is creating enormous families that we never even realized existed 10 years ago. Yourname may be different, but your DNA says you’re a cousin -- a blood relative. So even though your DNA laboratory assures you they have no intention of discovering heritable diseases, with families this size, even recessively-inherited medical states can be recognized. Every time I mention this, I hear from genealogists who accuse me of discouraging others from cooperating in DNA-based research projects. But some very disturbing possibilities can arise when a serious heritable disease is discovered. Allparticipants should be aware that this might occur, in spite of your laboratory’s meaningless reassurances, and an administrator should have an approved plan for coping with the situation.

    Cynthia A. James and Associates at Johns Hopkins recently published the following article in Genetics in Medicine:

    “How does the mode of inheritance of a genetic condition influence families? A study of guilt, blame, stigma, and understanding of inheritance and reproductive risks in families with X-linked and autosomal recessive diseases.” This was a study of 112 members of 51 families. Findings included a better understanding of the disease, but plenty of guilt, blame and serious concerns about the reproductive risks. These individuals had agreed to participate in one of the first organized studies of such a situation. What if a similar scenario became apparent in a large DNA-linked family? There’d be some very tough decisions for the administrator!

    The DNA approach to genealogy has racked up remarkable successes, in spite of the fact that the laboratory scene is very disorganized and unregulated. The better laboratories have made impressive efforts to educate their clients about their technology and how to use it, but there is a need for better standardization, quality assurance, and protection for the genealogists using their services. Valuable guidelines have been developed pertaining to Y-chromosome and mtDNA analysis, but recent attempts to interpret autsomal findings have been badly flawed and confusing. This is partly due to the use of inaccurate nomenclature.

    Internet genealogy and genomic genealogy arrived on the scene almost simultaneously. Traditional genealogical organizations have had to make large investments of time and money in order to provide the computer services demanded by today’s genealogists and to compete with commercial sources providing internet access to vast quantities of genealogical data. As a result, the success of DNA-based research and its growing numbers of advocates did not receive an appropriate amount of attention. Although many established genealogists have used these tools to overcome “brick-wall” genealogical problems, we suspect that many new genealogists, whose research is primarily computer-based, have received little help with DNA problems from their genealogical societies and depend, instead, upon websites and promotional material from the DNA labs for their educational material.

    Genealogists who experimented with DNA as a supplement to traditional genealogical research were generally patient and supportive of this new technology, and many succeeded in solving long-standing problems. Most do not have extensive training in genetics, and although they may understand mechanisms of dominent or recessive inheritance, they are unfamiliar with the technology and the mechanics involved in DNA analysis. By the time they have learned about a technical procedure, it is being replaced by two new ones. Many have expressed the need for convenient sources of independent consultation, especially to assist in launching and interpreting DNA projects. They also need protection from a highly competitive, essentially unregulated marketplace offering DNA laboratory services.

    DNA studies have already become established and recognized in the art of genealogy. Their role will increase enormously as more people appreciate their potential value and service becomes more reliable, predictable and less expensive.


    U.S. Surgeon General’s Family History Initiative

    Guttmacher AE, Collins FS, Carmona RH: The Family History -- More Important than Ever.
    N Engl J Med Nov 25 2004; 351: 2333-2336

    Scheuner MT et al.: Family history: a comprehensive gentic risk assessment method for the chronic conditions of adulthood. Am J Med Genet 1997; 71: 31-34

    Williams RR et al.: Usefulness of cardiovascular family history data for population-based preventive medicine and medical research. Am J Cardiol 2001; 87: 129-135

    Harrison TA et al.: Family history of diabetes as a potential public health tool. Am J Prev Med 2003; 24: 152-159

    Acheson LS et al.: Family history-taking in community family practice: implications for genetic screening.

    Genet Med 2000; 2: 180-185

    James CA, Hadley DW, Holzman NA & Winkelstein JA: How does the mode of inheritance of a genetic condition influence families? A study of guilt, blame, stigma, and understanding of inheritance and reproductive risks in families with X-linked and autosomal recessive diseases.

    Genet Med 2006; 8/4: 234-242
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