French Canadians: The unexplained genetic diversity

Interior of a magasin général (source: photographiquement Frank). Wherever there was less competition from British or American merchants, it was easier for French Canadians to go into business. These same regions also have unusually high rates of neurological disorders, including Tay-Sachs. Coincidence?

French Canadians have a unique demographic history. From a founding population of some 10,000 settlers who came in the 17th and 18th centuries, they today number over ten million in Canada alone. This rapid growth shows what humans can do when war is absent, land plentiful, and government reasonably good.

Over those past three centuries, French Canadians have diverged from their cousins in France, not only culturally and politically but genetically as well. This is the finding of a recent study:

[…] in less than 20 generations of genetic isolation from the French population, the genetic pool of French-Canadians shows reduced levels of diversity, higher homozygosity, and an excess of rare variants with low variant sharing with Europeans. Furthermore, the French-Canadian population contains a larger proportion of putatively damaging functional variants, which could partially explain the increased incidence of genetic disease in the province. (Casals et al., 2013)

The authors try to explain this genetic divergence in terms of two causes: (1) a genetic bottleneck that allowed in only a small sample of France’s gene pool; and (2) relaxation of natural selection due to better living conditions, with a consequent accumulation of new genetic variants, i.e., people survived and reproduced who otherwise wouldn’t have back in Europe.

Clearly, there was a bottleneck. This is obvious from historical records and also from the degree of genetic homogeneity:

Compared to French individuals, French-Canadians have lower levels of heterozygosity (on average 19.2% and 11.5% of the variants per individual are heterozygous in French and French-Canadians, respectively) and have lower average nucleotide pairwise diversity. (Casals et al., 2013)

Despite this relative homogeneity, rare genetic variants are more frequent in French Canadians than in French people from France: 

The French-Canadian population also exhibits an excess of low frequency variants in comparison to the French population, and the proportion of variants with MAF [minor allele frequency] less than 5% is significantly higher in the French-Canadian population (p less than 0.01). The excess is not a consequence of different sample sizes; if we resample the same number of individuals from each population and include only sites where all individuals pass identical quality filters, we observe a similar excess of rare variants in the French-Canadian population compared to the French population. (Casals et al., 2013)

Why would French Canadians be less diverse for common alleles but more diverse for rare ones? The authors suggest relaxation of selection. As new mutations appeared in this new population, there was less selection than in France to weed out the bad ones.

Even so, the frequency of minor alleles seems to be higher than can be explained by relaxation of selection alone: “the shift observed in the empirical data, which shows an increase of 9.8% of variants with MAF less than 5% in the French-Canadian population compared to the French population when using the same sample sizes […], is larger than that generated by simulations” (Casals et al., 2013). The authors suggest that current theoretical models might underestimate the effects of relaxed selection, particularly under conditions of rapid population growth. Or perhaps this unexplained genetic diversity has some other cause. 

That other cause might be selection pressures that developed in some French Canadian subgroups and not in others. The authors themselves seem to raise this possibility when they go on to state that “the French-Canadian population is genetically stratified into subpopulations with differentiated demographic histories” (Casals et al., 2013).

Demographically and historically, there was a difference between frontier regions, where land was more available, and settled regions, where it was less so. Moreau et al. (2011) have shown that settlers on the wave front of colonization enjoyed a reproductive advantage over other French Canadians and thus contributed more to the current gene pool. Such settlers also seem to have been selected for higher fertility, according to a study of one French Canadian community. Between 1800 and 1940, the community of Île aux Coudres saw its mean age of first reproduction (AFR) fall by four years, not through a lowering of the mean age of marriage (which remained stable) but through a shortening of the mean interval between marriage and first birth. The study’s authors rule out better nutrition as a possible explanation, since infantile and juvenile survival rates should have likewise improved, yet they failed to do so during this period (Milot et al., 2011). 

There was also a demographic and historical difference between regions where French Canadians co-existed with American or British settlers and regions where they formed almost the entire population. In the first type of region, English-speakers dominated occupations that required business skills, i.e., numeracy, literacy, merchandising, bookkeeping, etc. In the second type of region, which covered most of eastern Quebec, these mercantile niches were much more open to any suitable French Canadian.

It is also in the second type of region that we see unusually high rates of neurological disorders. Of the top ten disorders in eastern Quebec, six are primarily neurological and two secondarily so. By comparison, only three of the top ten genetic disorders in the United Kingdom are primarily or secondarily neurological (Frost, 2012). These eastern French Canadian disorders also include two forms of Tay-Sachs: one on the south shore of the St. Lawrence and another on the north shore. In the town of Rimouski, the heterozygote frequency of Tay-Sachs is 7.6%, versus 4.2% among Ashkenazi Jews and 0.3% among French Canadians in Montreal (De Braekeleer et al., 1992). Relaxation of selection alone cannot account for this high incidence, nor can it explain the emergence of two different forms of Tay-Sachs within the same geographic area.

Instead of relaxation of selection, these eastern Quebec disorders may attest to intense selection for individuals who could exploit mercantile niches that were less available to French Canadians elsewhere. These niches were much more numerous than might seem from the relatively few people who identified themselves as ‘merchants’ to census takers. There was in fact a much larger number of ‘farmers’ who nonetheless had mercantile sidelines of one sort or another (note #1 and Frost, 2012). In eastern Quebec, the payoff for going into business, and the requisite mental skills, was so lucrative that it may have favored alleles, like Tay-Sachs, that seem to improve mental processing in the heterozygous state while being deleterious in the homozygous state (Cochran et al., 2006).

This last point bears repeating. What is harmful in the homozygote may still be adaptive in the far more numerous heterozygotes. A high prevalence of genetic disorders might just mean that a very strong selection pressure was acting for a very short time … and that there was nothing better to work with. Natural selection does its best with whatever genetic variants are available. Eventually, through random mutation, there will appear more suitable variants that provide the same benefits with fewer adverse effects, and these genetic solutions will replace the ‘rough-and-ready’ ones that had initially been favored. 

Conclusion

French Canadians are genetically unique for several reasons. First, they descend from a small founder group. Second, they had high rates of population growth over a period of some three centuries. Third, they adapted to a very different environment and a very different set of selection pressures. In France, their ancestors lived almost under steady state conditions: land scarcity, small family size, late marriage for men and women alike, rigid class distinctions, and limited geographic mobility. In Quebec, those limitations were weaker if not absent altogether. Because land was much more plentiful, the opportunities were accordingly greater for marrying younger and having larger families. This freer and less limiting environment foiled attempts to transplant feudalism to Quebec even during the French Regime, with the result that the term paysan never caught on. People called themselves habitants. Finally, in comparison to other French Canadians within the same region, business-minded individuals had more chances for economic betterment in those areas, like eastern Quebec, where competition from American or British merchants was relatively weak.

Note

1. Gustave Papillon, the founder of one of Quebec’s leading cement plants, started off as a poultry producer and probably identified himself as such to census takers. Yet he also had two sidelines: installing elevators and escalators; and reselling pharmaceutical products to local drugstores. His decision to start up a cement plant grew out of this pre-existing entrepreneurial mindset (Gadbois and Papillon, 2013).

References 

Casals, F., A. Hodgkinson, J. Hussin, Y. Idaghdour, V. Bruat, T. de Maillard, J-C. Grenier, E. Gbeha, F.F. Hamdan, S. Girard, J-F. Spinella, M. Larivière, V. Saillour, J. Healy, I. Fernandez, D. Sinnett, J.L. Michaud, G.A. Rouleau, E. Haddad, F. Le Deist, and P. Awadalla. (2013). Whole-exome sequencing reveals a rapid change in the frequency of rare functional variants in a founding population of humans. PLoS Genet 9(9): e1003815. doi:10.1371/journal.pgen.1003815

http://www.plosgenetics.org/article/info%3Adoi%2F10.1371%2Fjournal.pgen.1003815 

Cochran, G., J. Hardy, and H. Harpending. (2006). Natural history of Ashkenazi intelligence, Journal of Biosocial Science, 38, 659-693.

http://web.mit.edu/fustflum/documents/papers/kim-beder.pdf 

De Braekeleer, M., P. Hechtman, E. Andermann, and F. Kaplan. (1992). The French Canadian Tay-Sachs disease deletion mutation: Identification of probable founders, Human Genetics, 89, 83-87.

http://link.springer.com/article/10.1007/BF00207048#page-1

Frost, P. (2012). Tay-Sachs and French Canadians: A case of gene-culture co-evolution? Advances in Anthropology, 2 (3), 132-138. http://www.scirp.org/journal/PaperInformation.aspx?paperID=21701

Gadbois, M-E. and L. Papillon. (2013). Gustave Papillon. Building Ciment Québec, Ciment Québec.

Milot, E., F.M. Mayer, D.H. Nussey, M. Boisvert, F. Pelletier, and D. Réale. (2011). Evidence for evolution in response to natural selection in a contemporary human population, Proceedings of the National Academy of Sciences (USA), 108, 17040–17045.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3193187/pdf/pnas.201104210.pdf

Moreau, C., C. Bherer, H. Vezina, M. Jomphe, D. Labuda, and L. Excoffier. (2011). Deep human genealogies reveal a selective advantage to be on an expanding wave front, Science, 334, 1148–1150.

http://www.sciencemag.org/content/334/6059/1148.short