The field of study called population genetics has played a critical role in the development of modern biology, helping unite Mendelian genetics and Darwinian evolution into one coherent framework. In most genetics classes, though, it typically gets plowed through in a simplified form in a single lecture. I suspect this is because it involves a lot of math, and most biologists like being in the field precisely because it's generally possible to avoid all but the simplest math.

Nevertheless, population genetics has some critical insights to offer in the area of modern genomics, as evidenced by a paper that appeared in this week's edition of Science. Some population geneticists have looked into the results of the search for mutations in genome data. Their conclusion: the human population explosion has led to the appearance of many new, rare mutations in the human population, and it's throwing all the math off, which has some serious implications for medical research.

At the simplest level, population genetics can help us predict how often a mutation should be present in a specific population. Feed its equations things like the population size, how harmful or beneficial the mutation is, the typical mutation rate, and so forth, and it will spit out a nice prediction of what the final frequency of the mutation should be. It nicely demonstrates why even harmful mutations stick around at low levels in a population, even as evolution is doing its best to get rid of them.

The reason the math gets complicated is that the equations describe a population at equilibrium, and most populations aren't. Once you start adjusting for things like genetic drift, population bottlenecks, and migration, the equations all become a lot messier.

Most human populations exhibit just about all of these complications, but the authors focused on one aspect in particular: its rather unusual growth pattern. Over the past 400 generations of humans, it's estimated that the total population has expanded by something on the order of 1,000 fold. Not only that, but the growth has been uneven. The spread of urban centers starting about 3,000 years ago interrupted a period of relatively stable growth, and things like better nutrition, public sanitation, and vaccines have set off a period of even more rapid growth in the last 1,000 years.

Significant population growth is enough to throw a simple population genetics model off. If you have the sort of lopsided growth humans have seen and you adjust for it using a linear pattern of growth, the results will go off pretty badly. To show just how badly, the authors calculated some expected frequencies based on three different models for a European population: no growth, steady growth with bottlenecks, and the same bottlenecks, but with recent exponential growth. For a large population sample, the simple models can be off by as much as 500 percent.

The model they've developed has some pretty significant implications both for current genomic research and for medicine. As far as research goes, the conclusion is pretty simple: even though we have more human genetic samples than ever before, most studies still haven't been able to survey a large enough population to see the influence of the rapidly expanding human population. That's beginning to change, so it's important that the researchers who are doing this work use the appropriate math, or they're going to have a hard time interpreting what they see.

For medicine, the population growth means that there will be a huge abundance of mutations that have arisen in the past few generations, since population genetics won't have time to lose any via genetic drift, or get rid of them through selective pressure. Many of these mutations will be unique, limited to an original founder and their descendants.

For neutral mutations, which don't confer any harm or benefit, a modified population genetics model should work well. But that will fail for harmful mutations, since it assumes these will have been selected against. In reality, most of them will be so new that this won't have had any chance to happen. "Deleterious mutations would likely exhibit an even larger percentage of novel rare variants," the authors note. And that has consequences for our search for factors involved in complex genetic disorders like autism: "The medical implications of an excess of rare genetic variation and increased individual mutational load are of particular interest in light of the limited success of genome-wide association studies at explaining the genetic basis of complex human diseases."

In other words, our search for the causes of complex genetic diseases is going to be complicated by the fact that most of the mutations that cause them will be unique within the population.

With time, we'll have much more genetic data, and these issues will sort themselves out. But for now, it seems that we may be stuck trying to paint a picture of a dynamic human population based on a partial, static snapshot. Viewed that way, it's not much of a surprise that the completion of the human genome hasn't led to an overnight revolution in our understanding of disease.

Science, 2012. DOI: 10.1126/science.1217283 (About DOIs).