Essays on Science and SocietyGenome-Sequencing Anniversary

What Does a “Normal” Human Genome Look Like?

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Science  18 Feb 2011:
Vol. 331, Issue 6019, pp. 872
DOI: 10.1126/science.1203236

During the past 10 years, we have had our first glimpse of why individuals differ so much from one another. This is not the right place to revisit the nature-nurture wars or to reflect on the extent to which our impression of high phenotypic variability in humans is a narcissistic illusion. For the moment, let us just acknowledge the obvious: In any small group of people, we see a lot of variation in traits we care about—and not just those that affect health. Geneticists shy away from studying these traits—and for good reason. They prefer not to revisit a subject whose premature investigation accounted for the worst moments of their young science. Nonetheless, questions about the genetic basis of variability among generally healthy humans will not go away. Public fascination alone will keep it alive, as will the realization that genetics is unlikely to revolutionize medicine until we develop a better understanding of normal phenotypic variation. So, what have our first glimpses of variation in the genomes of generally healthy people taught us? First, balancing selection, the evolutionary process that favors genetic diversification rather than the fixation of a single “best” variant, appears to play a minor role outside the immune system. Local adaptation, which accounts for variation in traits such as pigmentation, dietary specialization, and susceptibility to particular pathogens is also a second-tier player. What is on the top tier? Increasingly, the answer appears to be mutations that are “deleterious” by biochemical or standard evolutionary criteria. These mutations, as has long been appreciated, overwhelmingly make up the most abundant form of nonneutral variation in all genomes. A model for human genetic individuality is emerging in which there actually is a “wild-type” human genome—one in which most genes exist in an evolutionarily optimized form. There just are no “wild-type” humans: We each fall short of this Platonic ideal in our own distinctive ways.

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