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.
SOME
SIMILAR PROBLEMS: A LOOK AT CODIS
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.
GENEALOGICAL
DNA TESTING
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.
GENEALOGICAL TESTING METHODS
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)
DNA HAPLOTYPES AND HAPLOGROUPS
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
OBJECTIVES OF ETHNIC RESEARCH
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.
WE SALUTE
THE PIONEERS IN THIS FIELD
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.
AUTOSOMAL ANALYSIS
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 GENOGRAPHIC PROJECT
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.
QUALITY
ASSURANCE OR CAVEAT EMPTOR?
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
EVALUATION OF GENETIC TESTS
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.
MEDICAL
POSSIBILITIES
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.
EFFECT
OF KNOWN HERITABLE DISEASE ON FAMILIES
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!
SUMMARY
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.
REFERENCES
U.S.
Surgeon General’s Family History Initiative
http://www.hhs.gov/familyhistory/
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