Here Is a Human Being

by Misha Angrist

  But mutations don’t happen only in protein coding regions. If they occur in introns (the discarded parts), they can still mess up the transcription process that gets DNA to RNA. And so I went exon by exon (BRCA1 has 24 exons; BRCA2 has 27) and intron by intron and took a look at each of the eighty-six SNPs and twenty-two indels I carried. I could ignore many out of hand because they had already been seen in other databases full of healthy people. As for the rest of the variants, the sequence and SNP databases—even BIC—often weren’t much help. The clinical significance of these changes, their frequency in the population, and even whether they were passed down in predictable Mendelian fashion—all of these facts were often unknown. It turned out to be a couple of hours of work that was somewhat reassuring—the chance I carried a “non-Ashkenazi” mutation was pretty small to begin with. But even this was not an unconditional guarantee. And frankly, even for a genome geek the whole business got to be tedious. I was ready for the dial-up age to be over.

  Thanks to Dongliang’s patience, I was finally able to download selected other subsets of data. One was a file of all of the variants in protein-coding genes that inserted or deleted bases and disrupted the proper reading of amino acids—so-called frameshift mutations. In 148 instances I carried two copies—one from each parent—of these types of mutations. In twenty-seven of those, the frameshift introduced a premature stop codon as it did in the Factor VIII example Dongliang and I had looked at; presumably premature-stop mutations would yield no protein. Francis Collins had warned me a year earlier: “You will have some breathtaking mutations.” The thinking was that if one had zero functional copies of something instead of one or two, then that might be expected to have an effect. Or not: I found that I carried two defective copies of the CASP12 gene, which is an important gene involved in inflammation. But there’s a good chance that you do, too. Most humans carry mutated versions of CASP12 and produce a truncated, nonfunctional protein. The genome often makes do with less. And perhaps it’s not just making do: nonfunctional versions of genes like CASP12 may actually be a selective advantage. This might help to explain why each of us walks around with dozens and dozens of broken genes.12

  I kept on in hand-to-hand-combat mode, going gene by gene. And time and again, the paucity of information was striking: I would find mutations in genes that coded for proteins, but the proteins’ ascribed functions would be so general and/or tentative (“may be involved in transcriptional regulation”) as to be meaningless. In some cases, the proteins didn’t even have names, let alone functions assigned to them.

  Another striking realization was that our genomes are an utter mess: chunks of DNA are not only missing, but they have often moved to different chromosomes, or flipped around. Genes we don’t need—ones that code for olfactory receptors, for example—may be completely absent. Why don’t we need them? Because we have hundreds more where those came from, for one thing. And in evolutionary terms, other than for detection of the ocasional noxious fume, we don’t necessarily need a sense of smell to survive anymore. The aroma of food can be pleasurable (pizza, popcorn, fresh-baked bread, curry) or repugnant (rotten fish, rancid Limburger cheese, your brother after he’s eaten a burrito), but these days Westerners generally don’t depend on it for hunting and gathering.

  The genome was also a source of pure banality. We all have “housekeeping genes” that are turned on all the time at the same level, doing the same boring job in nearly every cell in nearly every tissue. Like olfactory receptors, these genes are often redundant; one fewer copy would probably not be missed.

  And some genes appear to be present but not real: they are pseudo-genes. They typically have many if not all of the hallmarks of a gene: a beginning, middle, and end; a plausible sequence of amino acids; a regulatory region; binding sites for proteins. But these “genes” don’t lead to RNA and therefore they don’t lead to protein. There may be every reason to believe that the proteins encoded by them should exist, but no one has ever seen them.

  This often-maddening state of affairs triggered an analogy that kept popping into my Excel-weary brain. On a windy summer day near Harvard Square, I met Andrea Loehr, a blond German who was volunteering as a data cruncher for the PGP and who had been to the South Pole several times. She was trained as a cosmologist and explained that Antarctica affords astronomers a view that can’t be had anywhere else on earth: if one were interested in looking into space, she said, the South Pole was a great place. “It’s high, it’s dry, and the atmosphere is extremely stable.” The problem—and the reason why she decided to switch from stargazing to whole-genome sequence data analysis—is that in cosmology, getting meaningful answers can take decades. “In fact, I may not live to see them,” Andrea said. “I like the idea of a project that will have at least some return within a few years.”13

  A few months earlier Hugh Rienhoff had brought up Antarctica to me for a different reason. He had been doing some consulting for Knome and had seen a few of the company’s first customers, the ones who had shelled out $350,000 to get their complete genomes done. “What motivated them?” I wondered. “It’s curiosity,” he said. “People want to go to Antarctica. Why? They like to do it. It’s icy, it’s cold, it’s windy, it’s dangerous. People getting their genomes sequenced is that kind of thing. Though I don’t think they’re learning much they didn’t know already.”14 Or perhaps they were.

  When most people think of Henry Louis “Skip” Gates, Jr., chances are they think of his arrest for disorderly conduct in the summer of 2009, the surrounding kerfuffle, and his subsequent beer with the arresting officer and President Obama.15 They may know that he is the Alphonse Fletcher University Professor and the director of the W. E. B. Du Bois Institute for African and African American Research at Harvard University. That he is a dignified and frequently feted scholar, the winner of a MacArthur Genius Grant.16 They might also think of his African American Lives and Faces of America documentary series,17 which seem to commandeer PBS every other February (certainly more fun than pledge drives), and the famous Americans who participate in them.

  What they may not realize is that Skip Gates is hilarious and a keen student of genetics.

  As we chatted in the kitchen of his immaculate (and, in the wake of death threats, now quite secure) yellow house, a stone’s throw from Harvard’s sprawling and semistately campus, Gates made himself a high-fiber, low-fat tuna salad sandwich while I sat at the far end of the large white island in the middle of the room. Soon the doorbell rang. He looked at me.

  “If it’s the police, tell ‘em I ain’t here,” he deadpanned.18

  Gates came to see molecular genetics as a tool to uncover African American ancestry in 2000, when he connected with Rick Kittles, then a geneticist at Howard University just beginning molecular studies of African ancestry.19 But Gates’s interest really began at age nine, “the day my grandfather was buried.” The next day he began work on the Gates family tree. When Alex Haley’s Roots was broadcast in 1977, Gates was riveted. As he got older, he became a devoted Africanist, eventually visiting twenty-one countries on the continent. When Kittles explained what he was doing, “I was

  down,” said Gates. “I said, ‘You’re gonna take a little blood and tell me what tribe I’m from?’ That’s what I’m talkin’ about.” He soon donated blood.20

  Time went by and Gates called Kittles. “Hey, man. Where’s my Kunta Kinte moment?”21 In 2000 the database of genetic markers was a shadow of what it is today. And in the relatively early research phase of his studies, Kittles looked only at markers common among Africans. Consequently he could not identify a strong African link to Gates’s maternal line.22

  “I thought it was a simple test: you take some spit and a tribe lights up in Africa,” Gates recalled. “I didn’t know about private and public genetic databases. It wasn’t my field. But some of the time I’m smart enough to know what I don’t know. I realized it was time for me to pull back, not treat the subject cavalierly, study the science myself, and surround myself
with a battery of experts, some of whom disagreed with Rick.”23

  Subsequent analyses all indicated that Gates’s roots were in Europe, and the British Isles in particular. Enthralled with the science of heredity, Gates took the opportunity to school himself. He took the PGP exam and a DVD-based course in undergraduate genetics. He asked the Broad Institute’s David Altshuler, Mark Daly, and Eric Lander to mentor him.24 And George Church, too. “He had an endless series of questions and at times it seemed like it was an infinite loop,” recalled George with a smile. “Haploid this and diploid that, ‘Were genes like twenty thousand volumes in a library?’ and ten other analogies going simultaneously. He seems to have only one setting on his potentiometer, which is ecstatic. I think it’s going to be a good thing to have him involved.”25

  But involved in what exactly? How did genetic ancestry testing come to be and where is it going?

  The consensus—both from fossils and genetic variation studies—is that modern humans originated in Eastern Africa 160,000 to 200,000 years ago.26 Some of us left Africa for Eurasia, Oceania, and the Americas 60,000 to 100,000 years ago. If you look at the millions of human SNPs that have been characterized, Africa is the most genetically diverse place on the planet. All human genetic variation is a subset of what’s in Africa. As a general rule, the farther you get from Africa, the less genetic diversity you see. Genetic differences between human populations are small; however, they are undeniably real. The more markers you look at, the easier it is to distinguish an “Asian” genome from an “African” or “European” one.27 As scientists identified more markers and typed increasing numbers of individuals from different populations, the prospect of spitting in a tube and learning about one’s genetic ancestry became less of a dowsing rod and more of a bona fide science.

  Traditionally, genetic ancestry testing was based on Y-chromosome and mitochondrial DNA (mtDNA) markers. The Y chromosome is passed only from father to son. Mitochondrial DNA resides in the mitochondria, the “cellular power plants” that are thought to have evolved from bacteria. Part of this evolutionary artifact is a small circular genome that codes for just a handful of genes. It is passed only from mother to child: the spermatozoa jettison their mitochondria and therefore males do not transmit mitochondrial DNA. Y-chromosome and mtDNA markers are called lineage markers. When sperm meets egg, they do not get shuffled (recombine) the way other chromosomes do because eggs don’t have Y chromosomes and sperm don’t have mitochondria with which to pair up and exchange parts. Thus they make it easy to reconstruct maternal (mtDNA) and paternal (Y) lineages. They can provide regionally specific information: your paternal line may have roots in Native American populations, let’s say. Your maternal line may suggest a Northern European origin. The problem with these markers is they can paint a skewed picture: together mtDNA and the Y chromosome account for less than 1 percent of the human genome. And they are, by definition, linear: they follow a single line backward. But of course our family trees only get wider as we move back in time: we have four grandparents, eight great-grandparents, sixteen great-great-grandparents, and so on. At ten generations, we have 1,024 ancestors. A Y-chromosome or mtDNA test will take us directly back to only one of them.28

  More recently, with the advent of millions of SNPs scattered across the genome and better computer algorithms, genetic genealogists have availed themselves of autosomal markers, that is, DNA markers on chromosomes 1 through 22 that travel in pairs and that do get shuffled at every conception. These tests incorporate information from the full range of one’s ancestors, not just those in the direct maternal or paternal lines. They suggest, for example, that my recent genetic ancestry is 99 percent European—that is, boring.

  In 2009, 23andMe began beta testing of Relative Finder, a program that compared customers’ DNA with each other.29 When two people shared identical segments of DNA, this indicated that they shared a recent common ancestor. The length and number of these identical segments were used to predict the relationship between any two people. As I wrote this, there were fifty other 23andMe users who were predicted to be my third cousins. Did that mean we actually shared great-great-grandparents? Absolutely not. But we were the functional equivalent of third cousins: we shared the same amount of DNA as if we had the same great-great-grandparents.

  Skip Gates had similar analyses done for himself and his Faces of America participants by scientists at the Broad Institute. He was an unabashed fan of this approach. “It’s the emotional high point of the series,” he said. If you tell somebody, ‘You [and this other person] are descended from a common ancestor twenty thousand years ago,’ they’ll go, ‘Oh yeah. Wow. Big deal.’ But if you tell them they descended from a common ancestor since the time of Columbus and maybe as recently as two hundred and fifty years ago, that’s heavy, even if they don’t look alike. They share an actual human being in the recent past.”30

  Many of his colleagues (and, I should say, some of mine) in the humanities and social sciences did not share his enthusiasm for genetic ancestry testing, or even constructing family trees. In a blistering takedown in the journal PMLA, the University of Virginia’s Eric Lott wrote:

  In Bell Curve America, genetic conceptions of personhood are bound to be dangerous, and they gibe rather nicely with rollbacks of the United States’ commitments to closing racialized gaps in political and material condition.

  Nor, finally, is the reactionary conception of history entailed in familial genealogy helpful in this respect. It radically individualizes the past even as it essentializes racial inheritance, turning up people who did or didn’t work against great odds to enable their descendants a better future—and in Gates’s chosen subjects, a wealthy and famous future at that.31

  Less frothily, other folks worried that commercial genetic ancestry testing promoted the fallacious idea that “race” is rooted in our DNA.32

  Gates was, to say the least, unbowed. Yes, he worried about DNA testing being used to justify the creation of a genetic underclass. But he clearly saw it as a potential for empowerment as well. “There’s nothing that can disappoint me in any genetic or genealogical analysis of my ancestry. It provides relief, it provides answers. Identity commences as a question. Our genealogical identity and our genetic identity are subsets of one large question: Who am I? And each bit of data uncovered by your genealogy, your genetic analysis, provides another small answer to this larger conundrum. So there can be no bad or troubling news. Medically yes, these tests could be very troubling, but not in terms of ancestry. I’ve been black for fifty-nine years, and other than some radical black nationalists, nobody I’ve met minds having white ancestry. People just want to know who they were. They’d like to know the circumstances. African Americans want to find out more about their complex ancestry, not less.

  “You can’t be a Luddite. You can’t stop it. You have to try to understand it. A lot of humanists and social scientists are like this,” he said, putting hands over his ears, closing his eyes, and singing loudly. “'La la la la la la la la la la!!!’ I say to them, you people need to read a genetics book! The geneticists are not making this up. We’re in the era of the recuperation of biology. We have to become scientifically literate so that we can learn how to intelligently challenge the potential abuses. And I’m eternally grateful to Rick Kittles for introducing me to genetics and also to its dangers, perils, and limitations. I’ve learned a new field to some extent.” He paused. “I also know I don’t have APOE4.”33

  Gates and his father, Henry Louis Gates, Sr., were among the first four to be fully sequenced by Illumina’s $48,000 service.34 They were the first African Americans and the first identifiable father and son to have their complete genomes done. Gates learned that he had six hundred thousand SNPs that had never been seen before.* “Six hundred thousand,” he marveled. “I’m the Skip Chip!”35

  Gates, his father, and his brother also became PGPers, which made them outliers among African Americans. When asked by George to be among the first ten, Rick Kittles de
clined. “I think the PGP is wonderful,” he told me, “but I can’t be that ambassador or take that responsibility on behalf of other African Americans. We’re still in the enlightenment phase. This sort of information … once it’s out, it’s out. There are downstream effects I’m not sure I can control.”36 Harvard anthropologist Duana Fullwiley, who was studying the PGP, said blacks’ reticence about public genomics should not be a surprise. “The real issue is how this information might be used against African Americans. That comes from knowing the history and how certain groups really do get short shrift.” She mentioned DNA dragnets and forensic databases. She was sympathetic to Kittles. “When it is in the public realm it can be utilized in all kinds of ways.”37

  So would Skip go public? His ninety-six-year-old father had already said he would. But Gates Fils hedged. I thought maybe he was still smarting from the death threats he received and the paparazzi chasing him after his arrest. But it wasn’t that. “I have two daughters,” he said. “I have all the information about my genome, but they don’t. They would be affected by my decision. If one daughter says no, then that’s it. It’s gotta be unanimous. It can’t be undertaken cavalierly. I will probably make it public unless my daughters have strong objections. The advantage of me making mine public is that it would let people study this relationship between father and son. And particularly with the father pushing a hundred.”38

  He called me into the dining room and sat down at his computer. He called up a lavish PowerPoint series that a scientist at Knome had made for him. Colorful graphics of the two Henry Louis Gateses’ genomes came up with their photographs superimposed. And then, shockingly, his mother’s picture appeared superimposed upon her genome. Given the availability of Skip’s full DNA sequence and his father’s, it became a trivial exercise to reconstruct half of his mother’s genome (she died in 1987). “Seeing this was so moving,” he said softly. “The irony was I did it to immortalize my father, and it resurrected my mother.”39