Using Population Descriptors in Genetics and Genomics Research: A New Framework for an Evolving Field (2023)

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B Glossary Admixture: An individual is described as admixed when they have lines of ancestry that trace back to multiple distant geographic origins on a recent timescale: as an example, individuals of Central and South America whose ancestry 600 years ago traces to individuals mostly living in western Europe, west Africa and Central/South America (Winkler et al., 2010). A difficulty with the concept is the often-implicit timescale being considered. All humans are admixed, but not everyone is recently admixed: for some, ancestry lines will trace back to geographically distant ancestors within a few generations, whereas for others, the same process occurs on much longer timescales. A further challenge is the framing of admixture as the blending of “source populations,” which may erroneously imply the exis- tence of homogeneous populations in the past. Ancestral recombination graph: For a set of individuals, the graph depicting the genetic ancestry lines (or paths) that trace back to their common genetic ancestors at every position in the genome (Hudson, 1990). Ancestry: a person’s origin or descent, lineage, “roots,” or heritage, includ- ing kinship (U.S. Census, 2021). Commonly associated with genealogical ancestry—that is, the collection of ancestors for an individual as found in a family tree, including parents, grandparents, great-grandparents, and so on (Mathieson and Scally, 2020). Examples of ancestry group labels include clan names or patronyms, but geographic, ethnicity, or racial labels are often used to denote groups whose members are presumed to share com- 177 PREPUBLICATION COPY—Uncorrected Proofs 

178 POPULATION DESCRIPTORS IN GENETICS AND GENOMICS RESEARCH mon ancestry. See also Genealogical ancestors, Genetic ancestors, Genetic ancestry, Genetic ancestry group, and Genetic similarity. Ancient DNA: DNA extracted from individuals who died anywhere from tens to many thousands of years ago (ISOGG, 2020). Studies using ancient DNA often integrate genetic data with archeological and historical data to make inferences about modern population origins. Continental groupings: labels based on the continent of origin of an indi- vidual. These groupings do not account for the substantial genetic, envi- ronmental, and geographic diversity within continents (Lewis et al., 2022). For example, in the United States, both someone from Japan and someone from India are often labeled as Asian. Culture: the dimension of human life including behavior, objects, and ideas that appear to express, or to stand for, something else. These include values, norms, beliefs, symbols, and symbolically meaningful practices like food- ways or religious worship (Griswold, 2013). Environment: the complex of physical, social, cultural, chemical, and biotic factors that act upon a person (Merriam-Webster, n.d.). Environment can also refer to a person’s exposure to chemicals and toxins, biological expo- sures, diet, behavioral patterns, life events, or even to more macroenviron- mental exposures such as neighborhood air pollution and violence (Glass and McAtee, 2006; Ottman, 1996). Epidemiology: the study of the distribution and determinants of risk fac- tors of disease, how these factors determine the incidence and prevalence of disease in human populations, and the application of this research to control health problems (Aschengrau and Seage, 2020). Epigenetics: the science that studies alterations in gene function through chromatin modifications and chemical changes to an individual’s DNA that do not involve alterations of the underlying nucleotide sequence (Cazaly et al., 2019; Hurle, 2022). Ethnicity: a sociopolitically constructed system for classifying human beings according to claims of shared heritage often based on perceived cultural similarities (e.g., language, religion, beliefs); the system varies globally. In the United States, ethnic group labels often derive from the country of ori- gin for voluntary immigrants (e.g., Italian Americans, Korean Americans). Outside the United States, ethnicity can denote groups that are considered PREPUBLICATION COPY—Uncorrected Proofs 

APPENDIX B 179 indigenous to a given territory, therefore, globally, ethnicity is not limited to a product of migration. Evolution: change in allele frequencies or heritable traits over successive generations, which arises from the interplay of mutation, recombination, migration, genetic drift, and natural selection (Emlen and Zimmer, 2020). Genealogical ancestors: the set of biological ancestors in an individual’s family tree or pedigree, including parents, grandparents, great-grandpar- ents, etc. Not all of an individual’s genealogical ancestors are their genetic ancestors, that is have contributed DNA to that focus individual (Mathie- son and Scally, 2020); in fact, most did not (Coop, 2017). See also Ancestry, Genetic ancestry, Genetic ancestry group, and Genetic similarity. Genetics: the science of heredity, specifically the mechanisms by which traits or characteristics (phenotypes) are transmitted from one generation to the next as well as how genes influence phenotypes (King et al., 2014). Genetic ancestors: the subset of genealogical ancestors who transmitted DNA to a focal individual (Donnelly, 1983). Genetic ancestry: the paths through an individual’s family tree by which they have inherited DNA from specific ancestors (Mathieson and Scally, 2020). Genetic ancestry can be thought of in terms of lines extending up- wards in a family tree from an individual through their genetic ancestors (see Figure 2-1). Shared genetic ancestry arises from having genetic ances- tors in common (that is, overlapping lines of ancestry). For a set of individu- als, a fundamental representation of genetic ancestry is a structure called an ancestral recombination graph (Mathieson and Scally, 2020). In practice, shared genetic ancestry is typically inferred by some measure(s) of genetic similarity. See also Ancestral recombination graph, Ancestry, Genealogical ancestors, Genetic ancestors, Genetic ancestry, and Genetic similarity. Genetic ancestry group: a set of individuals who share more similar genetic ancestries. In practice a genetic ancestry group is constituted based on some measure(s) of genetic similarity (Coop, 2022; Mathieson and Scally, 2020). Once a set is designated as a genetic ancestry group, its members are often assigned a geographic, ethnic, or other nongenetic label that is common among its members. See also Ancestry, Genealogical ancestry, Genetic an- cestors, Genetic ancestry, and Genetic similarity. Genetic epidemiology: the study of the role of genes and environmental factors, and their interactions, as risk factors in the occurrence of disease and traits in populations (Duggal et al., 2019; Seyerle and Avery, 2013). PREPUBLICATION COPY—Uncorrected Proofs 

180 POPULATION DESCRIPTORS IN GENETICS AND GENOMICS RESEARCH Genetic similarity: quantitative measure of the genetic resemblance between individuals that reflects the extent of shared genetic ancestry (e.g., the mean number of genotype differences between individuals) (Mathieson and Scally, 2020). See also Ancestry, Genealogical ancestry, Genetic ancestors, Genetic ancestry, and Genetic ancestry group. Genome: the totality of an individual’s DNA in all chromosomes, includ- ing the mitochondria, comprising all genes, their regulatory machinery, and genomic architectural elements (Green, 2022a). Genome-wide association study (GWAS): a method to associate variation in trait values (e.g., disease risk or height) with specific genetic variants in the genome (Hutter, 2022). Only a subset of associated variants is expected to be causal for the trait, as many genetic variants will only be associated owing to their correlation with the causal variants (e.g., due to linkage disequilibrium) (Hirschhorn and Daly, 2005). Genomics: the science and technologies of studying the structure and func- tion of the entire genome (Green, 2022b). Group label: name given to a population that describes or classifies it ac- cording to the dimension along which it was identified. An example is French as the label for a group identified by its members’ possession of French nationality, where nationality is the population descriptor. See also Population descriptor. Hierarchical thinking: a process of ranking people or things in regard to status; in the context of this study, this thinking assumes that one group of people is superior to another. Human genetics: the science of genes, chromosomes, and the information they encode in human heredity. Identity-by-descent: segments of the genome inherited by two or more people from the same relatively recent ancestor are referred to as identical- by-descent; such segments are often identified based on their high genetic similarity (or “identity-by-state”) (Thompson, 2013). Indigeneity: a population classification or descriptor that, like ethnicity, carries connotations of descent-based cultural traditions. Indigeneity is distinguished from other population descriptors, however, by its emphasis on the continuity of geographic location over time. Indigenous people are the aboriginal inhabitants of a land in contrast to later migrant or colonizer PREPUBLICATION COPY—Uncorrected Proofs 

APPENDIX B 181 populations; there are many histories of colonization resulting in disloca- tion of Indigenous peoples from their lands and interruption of traditional lifestyles and culture (Mudd-Martin et al., 2021). Labeling scheme: a framework for assigning labels to human participants in a study. Natural selection: the process whereby some individuals, better adapted to their surroundings, are more likely to survive and leave descendants. If a trait under selection is heritable, natural selection can lead to change in trait values over generations through changes in causal allele frequencies (Emlen and Zimmer, 2020). Phenotype: an observable trait of an individual, which arises from genetic and environmental effects and often their interaction (NHGRI, 2022; Shri- ner, 2013). Polygenic score (PGS): a score (also called polygenic risk score or polygenic index) for an individual based on a set of variants associated with a trait (Manolio, 2022). In practice, this is done by summing the alleles the person carries at these causal factors, weighted by the effect sizes on the trait (esti- mated in a prior GWAS) (Sirugo et al., 2019). A PGS provides a predictor of the deviation from a mean value in a given study population. The hope is to use PGS to identify individuals at risk for specific diseases or to disentangle genetic and environmental effects on a trait (Kullo et al., 2022). Population: a group of humans that is identified by a selected dimension or characteristic (or set of dimensions or characteristics) for the purposes of analysis; this definition does not assume that all the group’s members are identical or homogenous. For example, college students in the United States represent an identifiable population. In statistics, the concept of a population is foundational and represents a set of individuals or objects with shared identifying characteristics that is studied indirectly through observations of random samples. In population genetic theory, the concept of a population is often defined as a group with a common gene pool from which individuals choose mates with whom they reproduce (King et al., 2014), often assumed not to experience immigration or emigration (e.g., in some models, a population is characterized by a set of allele frequencies). In population genetic analysis, the concept is much like the definition in statistics. Population descriptor: a concept or classification scheme that categorizes people into groups (or “populations”) according to a perceived character- PREPUBLICATION COPY—Uncorrected Proofs 

182 POPULATION DESCRIPTORS IN GENETICS AND GENOMICS RESEARCH istic or dimension of interest. A few examples include race, ethnicity, and geographic location, although this is a non-exhaustive list. The salience of a given population descriptor may vary from place to place, so descriptors (and/or their associated group labels) that are used in the United States may not be widespread in other countries. See also Group label and Labeling scheme. Race: a sociopolitically constructed system for classifying and ranking hu- man beings according to subjective beliefs about shared ancestry based on perceived innate biological similarities; the system varies globally. Race is founded on the belief that there are naturally and innately distinct groups that can be identified. This perspective has been used to justify the unequal distribution of resources from land and labor to power and status. In short, race is the product of racism rather than the other way around. As a so- cial construct or a social invention with political, economic, and historical context (ASA, 2003; Morning, 2005), race is both an idea and a way of organizing society that varies over time and from place to place. Taxonomy: a system of classification. The explicit or implicit schema used to define categories and labels for a set of individuals (or populations) constitute a taxonomy. Typological thinking: a way of classifying individuals in terms of set types to which they belong while disregarding variation among individuals within the type; often reinforces longstanding prejudice about characteristics of groups (Lewens, 2009). REFERENCES ASA (American Sociological Association). 2003. The importance of collecting data and doing social scientific research on race. Washington D.C.: American Sociological Association. Aschengrau, A., and G. R. Seage III. 2020. Essentials of epidemiology in public health. 4th ed. Burlington, MA: Jones & Bartlett Learning. Cazaly, E., J. Saad, W. Wang, C. Heckman, M. Ollikainen, and J. Tang. 2019. Making sense of the epigenome using data integration approaches. Frontiers in Pharmacology 10. Coop, G. 2017. Our vast, shared family tree. https://gcbias.org/2017/11/20/our-vast-shared- family-tree/ (accessed November 7, 2022). Coop, G. 2022. Genetic similarity and genetic ancestry groups. arXiv pre-print. Donnelly, K. P. 1983. The probability that related individuals share some section of genome identical by descent. Theoretical Population Biology 23(1):34-63. Duggal, P., C. Ladd-Acosta, D. Ray, and T. H. Beaty. 2019. The evolving field of genetic epidemiology: From familial aggregation to genomic sequencing. American Journal of Epidemiology 188(12):2069-2077. Emlen, D. J., and C. Zimmer. 2020. Evolution: Making sense of life. Third ed. New York, NY: Macmillian Learning. PREPUBLICATION COPY—Uncorrected Proofs 

APPENDIX B 183 Glass, T. A., and M. J. McAtee. 2006. Behavioral science at the crossroads in public health: Extending horizons, envisioning the future. Social Science & Medicine 62(7):1650-1671. Green, E. 2022a. Genome. https://www.genome.gov/genetics-glossary/Genome (accessed No- vember 11, 2022). Green, E. 2022b. Genomics. https://www.genome.gov/genetics-glossary/genomics (accessed November 11, 2022). Griswold, W. 2013. Cultures and societies in a changing world. 4th ed.: Thousand Oaks, CA: SAGE. Hirschhorn, J. N., and M. J. Daly. 2005. Genome-wide association studies for common diseases and complex traits. Nature Reviews Genetics 6(2):95-108. Hudson, R. R. 1990. Gene genealogies and the coalescent process. Oxford Surveys in Evolu- tionary Biology 7(1):44. Hurle, B. 2022. Epigenetics. https://www.genome.gov/genetics-glossary/Epigenetics (accessed October 19, 2022). Hutter, C. M. 2022. Genome-wide association studies (GWAS). https://www.genome.gov/ genetics-glossary/Genome-Wide-Association-Studies?id=91 (accessed October 19, 2022). ISOGG (International Society of Genetic Genealogy). 2020. Ancient DNA https://isogg.org/ wiki/Ancient_DNA (accessed November 11, 2022). King, R. C., P. K. Mulligan, and W. D. Stansfield. 2014. A dictionary of genetics. 8th ed.: Oxford University Press Kullo, I. J., C. M. Lewis, M. Inouye, A. R. Martin, S. Ripatti, and N. Chatterjee. 2022. Poly- genic scores in biomedical research. Nature Reviews Genetics 23(9):524-532. Lewens, T. 2009. What is wrong with typological thinking? Philosophy of Science 76(3): 355-371. Lewis, A. C. F., S. J. Molina, P. S. Appelbaum, B. Dauda, A. Di Rienzo, A. Fuentes, S. M. Ful- lerton, N. A. Garrison, N. Ghosh, E. M. Hammonds, D. S. Jones, E. E. Kenny, P. Kraft, S. S. Lee, M. Mauro, J. Novembre, A. Panofsky, M. Sohail, B. M. Neale, and D. S. Allen. 2022. Getting genetic ancestry right for science and society. Science 376(6590):250-252. Manolio, T. 2022. Polygenic risk score (PRS). https://www.genome.gov/genetics-glossary/ Polygenic-Risk-Score (accessed November 11, 2022). Mathieson, I., and A. Scally. 2020. What is ancestry? PLoS Genetics 16(3):e1008624. Merriam-Webster. n.d. Environment. In Merriam-Webster.com dictionary. https://www.mer- riam-webster.com/dictionary/environment (accessed December 7, 2022). Morning, A. 2005. Keyword: Race. Contexts 4(4):44-46. Mudd-Martin, G., A. L. Cirino, V. Barcelona, K. Fox, M. Hudson, Y. V. Sun, J. Y. Taylor, and V. A. Cameron. 2021. Considerations for cardiovascular genetic and genomic research with marginalized racial and ethnic groups and Indigenous peoples: A scientific statement from the American Heart Association. Circulation: Genomic and Precision Medicine 14(4):e000084. NHGRI (National Human Genome Research Institute). 2022. Evolution. https://www.genome. gov/genetics-glossary/Evolution (accessed December 6, 2022). Ottman, R. 1996. Gene–environment interaction: Definitions and study designs. Preventive Medicine 25(6):764-770. Seyerle, A. A., and C. L. Avery. 2013. Genetic epidemiology: The potential benefits and chal- lenges of using genetic information to improve human health. North Carolina Medical Journal 74(6):505-508. Shriner, D. 2013. Overview of admixture mapping. Current Protocols in Human Genetics 94:1-23. Sirugo, G., S. M. Williams, and S. A. Tishkoff. 2019. The missing diversity in human genetic studies. Cell 177(1):26-31. Thompson, E. A. 2013. Identity by descent: Variation in meiosis, across genomes, and in populations. Genetics 194(2):301-326. PREPUBLICATION COPY—Uncorrected Proofs 

184 POPULATION DESCRIPTORS IN GENETICS AND GENOMICS RESEARCH U.S. Census. 2021. About ancestry. https://www.census.gov/topics/population/ancestry/about. html#:~:text=Ancestry%20refers%20to%20a%20person’s,arrival%20in%20the%20 United%20States (accessed November 11, 2022). Winkler, C. A., G. W. Nelson, and M. W. Smith. 2010. Admixture mapping comes of age. An- nual Review of Genomics and Human Genetics 11(1):65-89. PREPUBLICATION COPY—Uncorrected Proofs