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How Did Natural Selection Shape Human Genes?

UPSIDE-DOWN MITO-MAPLE:Courtesy of Douglas C. WallaceResearchers constructed a phylogenetic tree based upon human mitochondrial DNA (mtDNA) variation. A branch bifurcates whenever they found an additional polymorphism. At the top of the inverted tree is mitochondrial "Eve"; the illustration shows two mtDNA sub-branches, or lineages, found in Europe and the Middle East. The J1- and J2-branch polymorphisms in the cytochrome b gene might have spread because they were climatically advantageous. (Rep

By | May 10, 2004

<p>UPSIDE-DOWN MITO-MAPLE:</p>

Courtesy of Douglas C. Wallace

Researchers constructed a phylogenetic tree based upon human mitochondrial DNA (mtDNA) variation. A branch bifurcates whenever they found an additional polymorphism. At the top of the inverted tree is mitochondrial "Eve"; the illustration shows two mtDNA sub-branches, or lineages, found in Europe and the Middle East. The J1- and J2-branch polymorphisms in the cytochrome b gene might have spread because they were climatically advantageous. (Reprinted from E. Ruiz-Pesini, et al., Science, 303:223–6, 2004.)

Many selective forces must have influenced human evolution, but the only one that all population geneticists seem to agree upon is malaria. Time and again, studies have identified certain DNA polymorphisms – most famously, the β-globin variant underlying red-cell sickling – that helped people resist this mosquito-borne disease. The reproductive success of such individuals spread these polymorphisms throughout regions where malaria is endemic.

Geneticists have been much more reluctant, in contrast, to conclude that other selective forces favored or disfavored particular polymorphisms. That attitude is changing, however, as technological advances allow the rapid sequencing and analysis of genomes. Researchers are increasingly seeking evidence of natural selection, as they question whether many newfound variants are as "neutral" as a theory dominant during the past 20 years would suppose.

Promoted by the late Motoo Kimura, the neutral theory of molecular evolution holds that most polymorphisms confer no fitness advantage or disadvantage, and spread or disappear randomly. "The problem is that we've now saturated the neutralist hypothesis," contends Douglas C. Wallace, a professor of molecular medicine at the University of California, Irvine. "There are more things going on than that, and we have to go back to Darwinian selection."

In a new paper, Wallace and colleagues at UC-Irvine attribute some polymorphisms in human mitochondrial DNA (mtDNA) to climatic adaptation.1 Other recent research suggests how selective forces might have affected autosomal genes2 and casts doubt on the neutrality of Y-chromosome variation. Besides illuminating evolution, these studies have a potential clinical benefit: Knowledge of DNA variants' evolutionary fitness might provide clues to developing better gene-based diagnostics and therapies.

TIGHT AND LOOSE COUPLING

In the decades after the human mitochondrial genome was sequenced in 1981, molecular anthropologists used mtDNA polymorphisms to chart ancestral human migrations.3 During this Herculean effort, Wallace remembers noticing "these striking geographic constraints" that confined some mtDNA variants to Africa, others to temperate zones in Europe and Asia, and still others to the Arctic and the Americas.

This pattern might have existed because the variants were present in the few founders of each continental population. But the UC-Irvine researchers doubted that explanation and decided to investigate alternative hypotheses. In their recent study,1 they analyzed the coding regions of 1,125 mitochondrial genomes to construct a detailed phylogenetic tree. Mitochondria are maternally inherited, so a primordial "Eve" topped the tree; further down, mutations defined each branch bifurcation. "One of the things that leaped out at us," says Wallace, "was that every time a new lineage – what we call a group of haplotypes, or haplogroup – appears in a climatic zone, it is founded by one or more substitutions in highly conserved amino acids."

To determine which substitutions might affect function, the group calculated the amino-acid conservation of 22 pathogenic mtDNA mutations. "That gave us a kind of ruler of how conserved an amino acid would have to be before it would cause a clinical change," Wallace recalls. Applying this "ruler" to the mitochondrial tree, his team deduced that 26% of the amino-acid substitutions, by virtue of their conservation levels, were probably functionally important. Several mtDNA mutations encoding such substitutions were prevalent in colder climates.

Judging from crystallographic models of the mitochondrion, Wallace hypothesizes that these mutations and associated amino-acid changes affect the coupling efficiency of oxidative phosphorylation, the process that transmutes a proton gradient along the electron-transport chain into ATP production. Tropical people, he explains, have a high coupling efficiency so that the process does not generate excessive heat and cause thermal exhaustion. "But if you live in the Arctic, what's going to kill you is -60°C in the winter," Wallace continues. "So you want uncoupled mitochondria to generate a lot of endogenous heat, and you're going to compensate for the lower ATP efficiency by eating a higher-calorie diet."

Wallace asserts that trouble can ensue when humans relocate from the climatic zone inhabited by their ancestors. Thus, when people from the tropics move north and eat calorie-rich foods, their tightly coupled mitochondria might transform excess calories into high levels of oxygen radicals. These, in turn, contribute to aging and degenerative disorders.

Wallace notes that, consistent with this idea, many chronic health problems, such as hypertension, diabetes, obesity, and cardiovascular disease, afflict African-Americans more than European-Americans. He says he wants to find out "whether these mitochondrial variants, in fact, account for some of this intergroup variation." Ultimately, he and other scientists hope to develop clinical strategies to sop up excess oxygen radicals, including mitochondria-targeted drugs that mimic the enzyme superoxide dismutase.

RESPECT, WITH RESERVATIONS

Other mitochondria experts profess respect for Wallace's data but don't yet buy his hypothesis. "It's really a lovely story, and I personally hope it's right," remarks Lawrence I. Grossman, a professor of molecular medicine and genetics at Wayne State University School of Medicine in Detroit. But Grossman, who investigates how mitochondrial cytochrome C oxidase evolved in anthropoid primates, asks: "Is [Wallace's theory] true at the biochemical level? And are the population data really hard?"

Neil Howell, vice president of research at MitoKor, a San Diego-based firm developing mitochondria-targeted drugs, faults the theory's reliance on a fixed prehistoric environment. He notes that climate has changed and fluctuated. Howell also questions whether the theory oversimplifies the complex relationship between mitochondrial function and body heat. Other organelles, other biological processes, and many genes are likely involved in heat generation. But Howell agrees with the Wallace paper's basic premise. Megasequencing data, he insists, show that "selection has really been a pretty potent force during the evolution of mitochondrial DNA."

As a proposition about history, Wallace's hypothesis ultimately cannot be proved. Nevertheless, biochemists might verify certain of its predictions by isolating and testing mitochondria that bear putative coupling and uncoupling polymorphisms, says Michael D. Brown, an associate genetics and pediatrics professor at Mercer University School of Medicine in Macon, Ga. Obtaining mitochondria bearing various mtDNA haplotypes, he asserts, is "extremely easy, simple, and quick"; the biochemistry conversely is "labor-intensive and expensive." Nevertheless, Brown expects Wallace's paper to impel such research because confirmation of its hypothesis "would be one of the more significant finds in human biology in the last 10 to 20 years."

In general, mtDNA is trickier to manipulate than nuclear DNA. With mitochondria, "you can't just simply pop a gene in and overexpress it or knock one out," Brown remarks. Instead, he recommends using cybrids to distinguish between the functional effects of mtDNA and nuclear DNA, which encodes the vast majority of proteins in mitochondria. This three-decade-old technique essentially involves inserting mitochondria into cells engineered to lack mtDNA. To ascertain, for example, whether an African or Lapp mtDNA variant, rather than nuclear DNA, affects coupling, mitochondria from Africans and Lapps could be placed separately into cells with identical nuclei.

J. William Ballard, a biological sciences professor at the University of Iowa, envisions other tests of Wallace's hypothesis. Ballard studies the fruit fly Drosophila simulans, a melanogaster sibling with the added benefit, for geneticists, of much greater mtDNA diversity. "We've been working for about 18 months now, looking at differences in oxidative phosphorylation potential between the different mitotypes [mtDNA haplotypes] in these flies," Ballard says. He cites two potentially useful techniques: injecting mtDNA variants into embryos; and introgression, a strategy of mating flies with disparate mitotypes.

Moreover, the brief life cycles of flies can highlight facets of evolution that are harder to track in longer-lived organisms. Ballard and postdoc Avis C. James recently discerned specific fitness differences between D. simulans mitotypes and related such dissimilarities to the flies' geographic distributions. Ballard also conducts "population cage" studies in which flies with various mitotypes compete for survival in a food-containing box.

FERTILITY AND DISEASE

<p>TURNING UP THE HEAT:</p>

Courtesy of Eduardo Ruiz-Pesini

The human mitochondrion harbors a 16,569-basepair genome. Researchers hypothesize that polymorphisms in the ATP6 (red), cytb (blue), ND2, and ND4 (green) genes aided populations' climatic adaptation because of where the genes' protein products fit into the mitochondrion's electron-transport chain. According to this theory, certain polymorphisms lead to heat generation that is useful in colder climates, and inappropriate variants can trigger overproduction of destructive reactive oxygen species (ROS).

Population geneticists regard the newly sequenced human Y chromosome (YC) as a kind of mtDNA mirror image whose paternal inheritance is useful for tracing lineages back to a primordial "Adam."3 But no work comparable to Wallace's has yet shown how natural selection might have shaped the YC. "My understanding of the literature is that there is not one Y chromosome that's better in one environment than another," comments Peter A. Underhill, a senior research scientist in Stanford University's genetics department.

All YC polymorphisms, however, are not neutral, says David C. Page, a biology professor at the Massachusetts Institute of Technology. "The field of molecular evolution has a sort of standard statistical definition of positive selection," he elaborates. "The genes of the Y chromosome have not met that standard. But in other ways, they scream out positive selection," especially YC genes such as DAZ that originated on autosomes. Page explains that the YC, because it largely foregoes recombination, would have been an inherently inhospitable destination for autosomal genes. Referring to their appearance on the YC, he adds, "It's very hard to say that this just happened by chance."

Page claims that he, MIT colleague Steve Rozen, and others recently discovered the first common YC variant with functional consequences; it increases the risk for spermatogenic failure.4 As for positive selection, no published study has apparently reported a polymorphism that enhances men's fertility. Yet Page is intrigued by "whether there is an optimal gene dosage on the Y chromosome," where many genes are present in multiple copies.

Oddly enough, one clue to fertility-enhancing variants might come from the sequencing of the chimpanzee's YC, among Page's current projects. "It turns out that chimps actually have far greater sperm production than do humans," he notes. "It relates in part to the difference in chimps' mating behavior. ... We're curious to see whether any of that shows up in the sequence, organization, and gene content of the chimp Y chromosome."

Unlike the YC, the autosomes have been fertile ground for speculation about what Michael Bamshad, an associate professor of pediatrics and human genetics at the University of Utah, calls "signatures of natural selection." Researchers have hypothesized why selection might have favored certain variants in a dozen or so genes.2 Bamshad, for example, has examined people's ability or inability to taste phenylthiocarbamide. PTC-tasting ancestors might have avoided eating poisonous substances, whereas nontasting ancestors might have been more willing to partake of bitter foods with anticancer properties.

"To date, most of the genes where we've looked for signatures of natural selection have first been found to play an important role in a disease," Bamshad says. "Now we're trying to see if we can do the reverse." After identifying variants that were subject to selection, he investigates whether they contribute to certain diseases. The analytical challenge, he adds, is to disentangle selection from population history, whose confounding factors include nonrandom mating and growth in a group's size.

Kenneth K. Kidd, a genetics professor at Yale University School of Medicine, remains skeptical about most claims of natural selection underlying human genetic variation. He studies polymorphisms in genes encoding alcohol-metabolizing enzymes. (One variant accounts for the flushing reaction of some East Asians when they drink alcoholic beverages.) "We see a pattern," Kidd reports. "We've got an idea of what might have caused it. But actually getting the proof is not that easy."

Kidd, who has scrutinized many genetic loci, says he often notices differences between populations. To believe that natural selection played a role, he says, "I really want for there to be a very good story. Even if it's a just-so story, it has to be a pretty good one and [have] a little more evidence than exists for a lot of these genes."

Douglas Steinberg dougste@attglobal.net is a freelance writer in New York.

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