Nature: Greenlanders’ unique genetics, recent evolution & the health implications

More evidence for “recent, copious, and regional” human evolution

Greenlandic Inuit in 1903.

A Danish study published in Nature explores the genetic architecture of Greenlanders. The analysis of 6,000 Greenlanders’ genomes—14% of the population!—suggests their Inuit ancestors have been largely isolated since settling the island 1,000 years ago, have undergone significant evolutionary selection due to Arctic conditions, and that identification of genetic variants specific to Greenlanders can improve screening for genetic diseases.

Nature notes:

Small, Indigenous populations—including Greenland’s—have long been a blind spot in genetics research, because most of the DNA in genetic databases comes from people of European ancestry. What little research has been done on the island suggests that living in the Arctic has profoundly altered the genetic make-up of Greenlanders, most of whom have mixed Inuit and European ancestry.

The researchers found that Greenland was initially populated by a small group of travelers, fewer than 300 people, constituting a profound founder effect. The genetics of Greenlanders thus reflect a minute original “sample” of the overall human population, rather than the general human gene pool.

Researcher Anders Koch explains that Greenlanders then underwent evolution under the unique environmental conditions of the Arctic. Greenlanders lived in isolated settlements and “developed their own traits and variants.” These variants include a gene involved in metabolizing fatty acids, which may be linked to the consumption of foods rich in omega-3 fatty acids, such as seal and whale meat.

Anders Albrechtsen, a bioinformatician at the University of Copenhagen, explains that because the Greenlandic population was so small and isolated, some recessive genes have become more prevalent. These include several linked to harmful conditions such as a type of liver disease called cholestasis familiaris groenlandica (CFG). Pregnant Greenlandic women are screened for the CFG genetic variant, which Koch notes is something which would not make sense for the overall Danish population.

The researchers found twice as many high-impact genome-wide associations to metabolic traits in Greenland compared with Europe. They infer these high-impact variants arose after the population split from Native Americans and thus are Arctic-specific. The population has had a distinct evolutionary trajectory through a combination of genetic drift and selection. European-derived polygenic scores for metabolic traits were found to be only half as accurate in Greenlanders as in Europeans, but that adding Arctic-specific variants improved overall accuracy to the same level as in Europeans.

Adapting genetic screening to a particular population’s genetics can thus greatly improve diagnosis. As Nature observes:

[The] findings have implications for diagnosing rare monogenic conditions, in which an individual’s genetic data is compared with a large and diverse reference panel of other genomes. When reference data are lacking for a population, genetic variants that are predicted to disrupt a protein’s function but which do not directly cause disease (known as non-causal loss-of-function variants) cannot be readily filtered out—possibly leading to misdiagnoses. The authors show that including whole-genome-sequencing data from Greenlandic Inuit participants in the reference panel greatly improved the filtering of non-causal loss-of-function variants.

Nature argues that including Indigenous populations in genomic reference data is justified by “the marked improvements to rare-disease diagnosis and polygenic score estimation.”

The study is very fine-grained. The researchers were able to genetically cluster Greenlanders into different regions, indicating “historically very limited migration” between parts of Greenland (perhaps not surprising given how big and barren Greenland is, about four times the size of France). This clustering “explains some of the differences in disease prevalence” among Greenlander populations.

Overall, the research provides further evidence to support the claims of writers such Henry Harpending, Gregory Cochran, and Nicholas Wade that human evolution has been “recent, copious, and regional,” and that understanding of human biodiversity is useful to tackling different populations’ health risks. As the researchers stress: “These results illustrate how including data from Greenlanders can greatly reduce inequity in genomic-based healthcare.”

The study is also an interesting example of how to ethically conduct studies with Indigenous people. Greenland exercises self-governance over education and health, and, in line with the UN Declaration on the Rights of Indigenous Peoples, protects Indigenous data sovereignty. Proposed research in Greenland must be reviewed by an ethics committee made of both professional and lay Greenland Inuit, and must involve discussions of Indigenous perspectives.

A major focus of my research is how different populations and cultures may have different conceptions of ethics which can impact genetic research, the permissibility of interventions, and ultimately their evolutionary trajectory. A recent example is a call by officials at the Africa Centres for Disease Control and Prevention (Africa CDC), urging an “Africa-centric health research ethics framework,” with features such as “more emphasis is placed on community-level autonomy rather than individual autonomy” as compared with Western/liberal ethics. Interesting stuff.

The study includes some complicated charts for readers more big-brained than myself:

Fig. 1: Genetic architecture comparisons.

Fig. 2: Consequences of genetic architecture for disease mapping.

Fig. 3: Genetic fine structure.