An initial draft of the human genome sequence was first described in 2000, and was the culmination of over a decade of work at a cost of roughly three billion US dollars. In a little over a decade, sequencing technology has advanced so dramatically that a human genome can be sequenced in less than a week for $5,000, numbers that will surely be outdated by the time this is published. Accordingly, DNA sequencing has proceeded at a frenetic pace over the past several years, allowing unprecedented insights into the amount and patterns of genetic variation that exists among individuals. To be clear, genetic variation simply means that the spelling of DNA sequences varies between individuals. These spelling errors, or mutations, arise when mistakes are made during the copying of DNA. Each of us carries roughly 3 million mutations in our genome. Although many, perhaps most, are inconsequential, a subset influences our susceptibility to disease and adverse drug responses, physical characteristics, and personality.
A powerful window into the past
Beyond the influence of genetic variation on disease, it also provides a powerful window into our past, revealing stories about where humanity first arose, our ancestors struggle to survive as they inhabited new lands, and encounters with archaic humans such as Neanderthals. One of the most exciting new stories to emerge over the last year, made possible by the revolutionary advances in DNA sequencing technology, is that our DNA bears the scars of recent and explosive growth in population size. What is often overlooked in a time in which over seven billion people inhabit the earth is that for much of our history humans existed in relatively small numbers, perhaps barely enough to fill a football stadium. What happened that allowed humans to increase in size so dramatically and what are the consequences for human health and evolution?
The most important factor in our transition from thousands, to millions, to billions of people was the development of agriculture approximately 12,000 years ago, and subsequent technological and cultural innovations. Although most of the mutations in our DNA are inherited from our parents, each of us carries on the order of ~100 new mutations. As our population size started to rapidly increase following the advent of agriculture, so to did the number of newly arisen mutations that were pumped into the population. However, because these mutations are so rare, perhaps only existing in a handful of individuals, very large sample sizes are necessary to study them.
We recently sequenced the protein-coding regions of 6,515 individuals and were able to rigorously study the characteristics of rare variation. The results were staggering. We found that approximately 75% of all protein-coding mutations arose in the last 5,000 to 10,000 years, perfectly coinciding with the great expansion of human population size. In other words, the amount of genetic variation present in contemporary populations is considerably different than what existed even as recently as a few thousand years ago. To paraphrase Bob Dylan, the genetic constitution of our species is a-changin.’
New natural selection
The influx of these recently arisen and very rare mutations into our gene pool raises a number of fascinating issues. Most pragmatically, explosive population growth and the mutations that ensued may play an important role in shaping patterns and prevalence of human disease, an area of active investigation. Theory predicts that recently arisen mutations should be enriched for deleterious variants, as evolution has not had sufficient time to purge them from the population. Indeed, we estimate that 86% of all deleterious protein-coding mutations arose in the last 5,000 to 10,000 years. I am generally skeptical of the idea that natural selection no longer acts on humans, as it presumes that we understand far too much about the intricate and potentially subtle agents of selective change. Nonetheless, it is undeniable that advances in science and medicine have influenced the efficiency of selection to cull at least some deleterious mutations, which may allow such variants to persist in the population and rise in frequency. Perhaps in the future, selection will act less on mutations that govern overt disease traits, and focus its power on more nebulously defined behavioral and social characteristics, increasingly shaped by the complex and rapidly changing ways technology is influencing our culture. Although the future trajectory of human evolution is intrinsically unpredictable, what is clear is that with each generation humanity incurs billions of new mutations, providing an enormous cache of variability for selection to act upon.
In short, our past has been prologue, and our recent history has dramatically shaped the spectrum of genetic variability that exists today. As sequencing data continues to accumulate, particularly from the world’s diverse populations, we should anticipate new tales of human history to emerge from our DNA.