February 14, 2020 Lynn B. Jorde, PhD1; Michael J. Bamshad, MD2
Author
Affiliations Article Information JAMA. Published online February 14, 2020. doi:10.1001/jama.2020.0517
Genetic ancestry testing, in which genetic
data are used to estimate the geographic origins of a person’s recent
ancestors, has grown rapidly in popularity. A recent estimate indicates that
more than 26 million people worldwide have undergone genetic ancestry testing
by direct-to-consumer (DTC) companies.1 These tests provide information
about an individual’s ancestral roots, and they can help to connect people with
their relatives, sometimes as distantly related as fourth or fifth cousins.
Such information can be particularly useful when a person does not know their
genealogical ancestry (eg, many adoptees and the descendants of forced
migrants). Increasingly and not without controversy, genetic ancestry testing
is being used beyond its original purpose, for example, to help identify or
exclude criminal suspects.2 In the clinical setting, persons
may share their ancestry test results with their clinician with the expectation
that the results will inform health care decisions.
How It Works
Genetic ancestry testing involves the comparison
of a large number of DNA variants measured in an individual with the
frequencies of these variants in reference populations sampled from across the
world. The geographic region in which an individual variant has its highest
frequency is assumed to be the most likely location of an ancestor who
transmitted the variant to the person being tested. Ancestry testing is
traditionally done for mitochondrial DNA (transmitted only by females and
reflecting the origin of 1 maternal ancestor) and for Y chromosome DNA
(transmitted only from father to son and reflecting the origin of 1 paternal
ancestor). A more comprehensive assessment of ancestry can be conducted by
assaying a half million or more autosomal variants (single-nucleotide variants [SNVs];
formerly single-nucleotide polymorphisms [SNPs]), which are inherited from both
parents. Most commonly, these SNVs are assayed using a DNA microarray, but DNA sequence data can also be
used. For autosomal testing, it is common to portray the most likely geographic
origin of a group of SNVs located within a chromosome segment (eg, ancestry
painting) (Figure).3 By counting the percentage of
SNVs originating from each geographic region, the percentage of an individual’s
ancestry derived from each region can be estimated.
Figure.
Estimates of Ancestry Composition
Breakdown of estimated percentages of ancestry
from different worldwide populations ranked from highest to lowest and from
continental to regional levels for one of the authors. Illustration adapted
from results reported by 23andMe.
Ancestry can be designated very broadly (eg,
western Asian, southern European) or as finely as by regions within individual
countries. In the latter case, accuracy is likely to decrease, and some DTC
companies allow the user correspondingly to adjust the degree of speculation in
ancestral estimation. In all cases, accuracy is strongly affected by the choice
of reference populations and the selection and number of SNVs, all of which
vary among ancestry testing companies. Consequently, it is not unusual for different
companies to report somewhat different ancestral profiles for the same DNA
sample.4 Furthermore, many human
populations have migrated considerably during their history5; therefore, modern-day samples
represent a static and potentially inaccurate portrayal of a region’s
inhabitants in the past. Even the term ancestry is subject to
a variety of interpretations and can be based on geographic, historical,
cultural, or religious definitions.6 For these reasons, there is
considerable room for error or ambiguity in inferring and interpreting a
person’s genetic ancestry. Nonetheless, some studies have shown concordance
between self-reported and genetically estimated ancestry.7
Important Clinical Care Considerations
Knowledge of a person’s ancestry can be
important because the frequencies of genetic risk variants sometimes vary with
ancestry, although most such risk variants are not assayed directly by ancestry
tests. However, some DTC ancestry testing companies provide health reports in
which they directly test a limited number of DNA variants associated with
conditions such as breast cancer and Alzheimer disease or less common genetic
conditions such as cystic fibrosis, polycystic kidney disease, and various
inborn errors of metabolism (the latter enabling identification of carrier
status).
In most genetic research studies of health and
disease, ancestry information has replaced the use of racial categories.
Because of its increased accuracy in comparison with self-reported ancestry,
genetically estimated ancestry can improve statistical power to detect genetic
risk factors for common diseases in genome-wide association studies.8 Often such risk factors vary by
ancestry, and the cumulative disease risk aggregated across multiple DNA
variants (ie, the polygenic risk score) appears to be highly sensitive to
differences in ancestry.9 Accordingly, if the clinical
utility of polygenic risk scores is eventually established, ancestry
information could be important for accurate interpretation of risk. Moreover,
because the great majority of genetic studies have been done in populations of
European ancestry, the pathogenicity of rare variants is more difficult to
assess in persons of predominantly non-European ancestry. Ancestry information
can thus help to avoid misinterpretation of genetic tests.
Ancestry testing also can yield unanticipated
results such as lack of expected ancestry or the presence of unexpected
ancestry. Discordance between pairs of siblings or between father and child can
reveal nonpaternity, which is estimated to occur in approximately 1% to 2% of
births in Western populations.10 Large identical regions of DNA
on both chromosomes in a tested individual can identify parental consanguinity.
These results could have significant psychosocial impacts.
Value
Ancestry information has interpretive value in
both clinical and research settings, and provides more accurate and
personalized information about a patient’s genetic heritage than do broad
categories like race or ethnicity. For example, in a self-identified African
American patient with recurrent respiratory infections, ancestry testing could
reveal that both copies of the CFTR gene are likely to have a
European origin, increasing the relative likelihood of a diagnosis of cystic
fibrosis. Although DTC ancestry testing does not predict an individual’s future
health, it is relatively inexpensive (approximately $100) and widely available.
If DTC delivery of health-related genetic test results gains acceptance, it is
likely that ancestry testing companies will add more variants of medical
relevance to their platforms, and clinicians will be expected to understand and
explain these results.
Evidence Base
The authors are aware of no clinical care
guidelines regarding ancestry testing. In a clinical setting, ancestry
information can be helpful for selecting the most appropriate genetic test (eg,
for rare genetic conditions), interpreting genetic test results, and assessing
risk for common diseases. However, associations between ancestry and disease
are indirect, and measurement of ancestry is subject to error. Ancestry testing
is unlikely to become part of routine clinical care of any major medical
specialty, particularly if risk variants can be tested directly, as is expected
with advances in precision medicine.
Bottom Line
Genetic ancestry testing can provide insights
on the geographic origins of an individual’s ancestors, as well as some
information that can aid in assessment of risk for some heritable conditions.
The accuracy of testing is limited by the migrations and mixing of populations
over time. Unexpected findings regarding ancestral origins and family
relationships can have psychosocial consequences.
Section Editor: W. Gregory Feero, MD, PhD, Associate
Editor, JAMA.
Article Information
Corresponding Author: Lynn B. Jorde, PhD, Department of Human
Genetics, University of Utah School of Medicine, Salt Lake City, UT 84112 (lbj@genetics.utah.edu).
Published Online: February 14, 2020. doi:10.1001/jama.2020.0517
Conflict of Interest Disclosures: None reported.
References
1. Regalado A. More than
26 million people have taken an at-home ancestry test. MIT Technology Review;
2019. https://www.technologyreview.com/s/612880/more-than-26-million-people-have-taken-an-at-home-ancestry-test/.
Accessed February 12, 2020.
2. Phillips C. Forensic genetic
analysis of bio-geographical ancestry. Forensic Sci Int Genet.
2015;18:49-65. doi:10.1016/j.fsigen.2015.05.012PubMedGoogle ScholarCrossref
3. Callaway E. Ancestry testing
goes for pinpoint accuracy. Nature. 2012;486(7401):17. doi:10.1038/486017aPubMedGoogle ScholarCrossref
4. Huml AM, Sullivan C, Figueroa
M, Scott K, Sehgal AR. Consistency of
direct-to-consumer genetic testing results among identical twins. Am
J Med. 2019;133(1):143-146.e2. doi:10.1016/j.amjmed.2019.04.052PubMedGoogle ScholarCrossref
5. Hellenthal G, Busby GBJ, Band
G, et al. A genetic atlas of human admixture history. Science.
2014;343(6172):747-751. doi:10.1126/science.1243518PubMedGoogle ScholarCrossref
6. Royal CD, Novembre J, Fullerton
SM, et al. Inferring genetic ancestry: opportunities,
challenges, and implications. Am J Hum Genet.
2010;86(5):661-673. doi:10.1016/j.ajhg.2010.03.011PubMedGoogle ScholarCrossref
7. Banda Y, Kvale MN, Hoffmann
TJ, et al. Characterizing race/ethnicity and genetic ancestry
for 100 000 subjects in the Genetic Epidemiology Research on Adult Health and
Aging (GERA) cohort. Genetics. 2015;200(4):1285-1295. doi:10.1534/genetics.115.178616PubMedGoogle ScholarCrossref
8. Guo X, Rotter JI.
Genome-wide association studies. JAMA.
2019;322(17):1705-1706. doi:10.1001/jama.2019.16479
ArticlePubMedGoogle ScholarCrossref
ArticlePubMedGoogle ScholarCrossref
9. Sugrue LP, Desikan RS.
What are polygenic scores and why are they important? JAMA.
2019;321(18):1820-1821. doi:10.1001/jama.2019.3893
ArticlePubMedGoogle ScholarCrossref
ArticlePubMedGoogle ScholarCrossref
10. Larmuseau MHD, Matthijs K,
Wenseleers T. Cuckolded fathers rare in human populations. Trends
Ecol Evol. 2016;31(5):327-329. doi:10.1016/j.tree.2016.03.004PubMedGoogle ScholarCrossref
No comments:
Post a Comment