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Recent news of James Watson’s auction of his Nobel Prize medal has unearthed a very unpleasant memory for me.

In March 2004 I attended an invitation-only genomics meeting at the famed Banbury Center at Cold Spring Harbor Laboratory. I had heard legendary stories about Banbury, and have to admit I felt honored and excited when I received the invitation. There were rumors that sometimes James Watson himself would attend meetings. The emails I received explaining the secretive policies of the Center only added to the allure. I felt that I had received an invitation to the genomics equivalent of Skull and Bones.

Although Watson did not end up attending the meeting, my high expectations were met when he did decide to drop in on dinner one evening at Robertson house. Without warning he seated himself at my table. I was in awe. The table was round with seating for six, and Honest Jim sat down right across from me. He spoke incessantly throughout dinner and we listened. Sadly though, most of the time he was spewing racist and misogynistic hate. I remember him asking rhetorically “who would want to adopt an Irish kid?” (followed by a tirade against the Irish that I later saw repeated in the news) and he made a point to disparage Rosalind Franklin referring to her derogatorily as “that woman”. No one at the table (myself included) said a word. I deeply regret that.

One of Watson’s obsessions has been to “improve” the “imperfect human” via human germline engineering. This is disturbing on many many levels. First, there is the fact that for years Watson presided over Cold Spring Harbor Laboratory which actually has a history as a center for eugenics. Then there are the numerous disparaging remarks by Watson about everyone who is not exactly like him, leaving little doubt about who he imagines the “perfect human” to be. But leaving aside creepy feelings… could he be right? Is the “perfect human” an American from Chicago of mixed Scottish/Irish ancestry? Should we look forward to a world filled with Watsons? I have recently undertaken a thought experiment along these lines that I describe below. The result of the experiment is dedicated to James Watson on the occasion of his unbirthday today.

Introduction 

SNPedia is an open database of 59,593 SNPs and their associations. A SNP entry includes fields for “magnitude” (a subjective measure of significance on a scale of 0–10) and “repute” (good or bad), and allele classifications for many diseases and medical conditions. For example, the entry for a SNP (rs1799971) that associates with alcohol cravings describes the “normal” and “bad” alleles. In addition to associating with phenotypes, SNPs can also associate with populations. For example, as seen in the Geography of Genetic Variants Browser, rs1799971 allele frequencies vary greatly among Africans, Europeans and Asians. If the genotype of an individual is known at many SNPs, it is therefore possible to guess where they are from: in the case of rs1799971 someone who is A:A is a lot more likely to be African than Japanese, and with many SNPs the probabilities can narrow the location of an individual to a very specific geographic location. This is the principle behind the application of principal component analysis (PCA) to the study of populations. Together, SNPedia and PCA therefore provide a path to determining where a “perfect human” might be from:

  1. Create a “perfect human” in silico by setting the alleles at all SNPs so that they are “good”.
  2. Add the “perfect human” to a panel of genotyped individuals from across a variety of populations and perform PCA to reveal the location and population of origin of the individual.

Results

After restricting the SNP set from SNPedia to those with green painted alleles, i.e. “good”, there are 4967 SNPs with which to construct the “perfect human” (available for download here).

A dataset of genotyped individuals can be obtain from 1000 genomes including Africans, (indigenous) Americans, East Asians and Europeans.

The PCA plot (1st and 2nd components) showing all the individuals together with the “perfect human” (in pink; see arrow) is shown below:

PCA_12

The nearest neighbor to the “perfect human” is HG00737, a female who isPuerto Rican. One might imagine that such a person already existed, maybe Yuiza, the only female Taino Cacique (chief) in Puerto Rico’s history:

Yuiza_S.Lind

Samuel Lind’s ‘Yuiza’

But as the 3rd principal component shows, reifying the “perfect human” is a misleading undertaking:

perfect_pca_13

Here the “perfect human” is revealed to be decidedly non-human. This is not surprising, and it reflects the fact that the alleles of the “perfect human” place it as significant outlier to the human population. In fact, this is even more evident in the case of the “worst human”, namely the individual that has the “bad” alleles at every SNPs. A projection of that individual onto any combination of principal components shows them to be far removed from any actual human. The best visualization appears in the projection onto the 2nd and 3rd principal components, where they appear as a clear outlier (point labeled DYS), and diametrically opposite to Africans:

worst_pca_23

The fact that the “worst human” does not project well onto any of the principal components whereas the “perfect human” does is not hard to understand from basic population genetics principles. It is an interesting exercise that I leave to the reader.

Conclusion

The fact that the “perfect human” is Puerto Rican makes a lot of sense. Since many disease SNPs are population specific, it makes sense that an individual homozygous for all “good” alleles should be admixed. And that is exactly what Puerto Ricans are. In a “women in the diaspora” study, Puerto Rican women born on the island but living in the United States were shown to be 53.3±2.8% European, 29.1±2.3% West African, and 17.6±2.4% Native American. In other words, to collect all the “good” alleles it is necessary to be admixed, but admixture itself is not sufficient for perfection. On a personal note, I was happy to see population genetic evidence supporting my admiration for the perennial championship Puerto Rico All Stars team:

As for Watson, it seems fitting that he should donate the proceeds of his auction to the Caribbean Genome Center at the University of Puerto Rico.

[Update: Dec. 7/8: Taras Oleksyk from the Department of Biology at the University of Puerto Rico Mayaguez has written an excellent post-publication peer review of this blog post and Rafael Irizarry from the Harvard School of Public Health has written a similar piece, Genéticamente, no hay tal cosa como la raza puertorriqueña in Spanish. Both are essential reading.]

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