Genomes Shed Light on Human Evolution, Leading Scientists to Search for More Subtle Clues

Ethnically diverse people are donating DNA to science, and the wealth of genomic data emerging from the project already is shedding light on human evolution.

A decade ago it was a big deal to spell out the entire DNA sequence of a single human being. That event marked the success of the initial Human Genome Project. Now hundreds of human genomes have been decoded. Scientists who study human evolution are using the new data to make discoveries about how Homo Sapiens may have adapted to an ever-changing, ever-challenging environment.

New traits become established in human populations because they confer a survival and reproductive advantage. In Darwinian terms they are “positively selected.” Individuals who lacked the genetic variant responsible for an important trait often did not survive long enough to leave progeny.

Mutations in general may be harmful or of no consequence, but some mutations make for a better-adapted organism. Over time these new and advantageous genetic variants can usurp those that dominated previously.

1000 Genomes Project Provides Impetus

But a new analysis of genetic data from nearly 200 humans whose DNA has been sequenced as part of the 1000 Genomes Project challenges conventional thinking among those who study evolution. The study, published in the Feb. 18 issue of Science by UCSF computational biologist Ryan Hernandez, PhD, and colleagues, questions whether the assumed mode of human adaptation, called “selective sweeps,” has actually played a dominant role.

Scientists came up with the selective sweep model more than three decades ago. The model proposes that a new, advantageously mutated gene quickly spreads throughout a population in which the change appears -- becoming a “fixed” feature of that population. The speed of the transition, reflecting the strength of the selective adaptation, would eclipse the rate at which any inconsequential mutation might become fixed in the population by chance.

Not so selectively, the model swept population geneticists who study evolution. The selective sweep quickly became favored as a way to describe how advantageous traits – or “phenotypes,” as scientists say -- become fixed in a population or species.

Natural Selection – Different Ways to Get To the Way We Are

Hernandez, equipped with the new data and the latest computational techniques, searched the entire human genome for the genetic footprints of selective sweeps.

While there are some previously well-known examples of traits arising and quickly becoming common due to selective sweeps – the ability to digest milk during adulthood, for instance – this mode of adaptation actually appears to be somewhat rare, he found.

While adaptation is fairly common, modes other than selective sweeps may guide the route to dominance for newly arising traits within a population or species, Hernandez and co-authors of the Science study conclude.

One possibility is that multiple, less conspicuous DNA changes may be acting in concert to drive evolution. Patterns of changes in the relative abundances of several linked genetic variants operating together may drive an adaptation to become the norm within a population, Hernandez says. Scientists now will be paying more attention to different modes of natural selection.

“There are many ways in which humans can adapt to novel environments and novel food sources that aren’t characterized by this situation where you have a single mutation driving the entire phenotypic effect,” Hernandez says.

Hernandez says his findings are comparable to what many disease researchers are discovering in scouring the human genome for gene variants that are implicated in common diseases. Many risk genes have been identified in recent years, but individually each appears to account for only a small increase in risk.

Genetic Footprint for Selective Sweeps Is Unconvincing

Great swaths of DNA tend to be inherited together on the same chromosome. But like a shuffled deck of cards, DNA on each matched pair of chromosomes is spliced and recombined across the pair as part of a process leading to the formation of sperm and egg cells.

Some regions of the chromosome recombine more often than others, but in general, statistical chance dictates that two pieces of DNA sequence that are close together on a chromosome are less likely to be separated during one of these recombination events compared to DNA sequences that are far apart on the chromosome. Over many generations it becomes less and less likely that DNA sequences that were neighbors on a chromosome of a long-ago ancestor will still be linked together in a living descendent.

However, selective sweeps would be expected to cause an advantageous mutation to become fixed in a population so quickly that surrounding DNA sequences would be dragged into the gene pool in ever greater proportion as well -- sweeping out much of the genetic diversity in this neighborhood of the genome within the affected population. Hernandez says evidence for such a selective sweep should remain in human genomic data for about 10,000 generations, roughly 250,000 years.

Diversity Troughs

These “diversity troughs,” as scientists call them, are real. In this study Hernandez found that the average dip in diversity around human-specific mutations was about 30 percent compared to background levels. However, he also discovered that the diversity trough was just as large around DNA changes that were not expected to be driven by selective sweeps.

A change in a single nucleotide letter within a gene’s DNA often changes the encoded protein. But the genetic code is somewhat redundant. In some cases a single-letter change within a three-letter “codon’ of DNA within a gene can specify the same amino acid within the encoded protein. Changes in DNA sequence within a gene that do not change the encoded protein should not be a driving force for evolution. Yet Hernandez found that these inconsequential changes were just as likely to be surrounded by neighboring DNA that had a low level of diversity across the population studied.

Hernandez concludes that the diversity troughs do not constitute evidence for positive selection via selective sweeps. However, it is plausible that the troughs may be a signature of negative selection – a process whereby disadvantageous genetic variants are driven out of the gene pool. In any case there is more work to be done, Hernandez says, and resources such as those provided through the 1000 Genomes Project make it possible to explore new ideas about human evolution.

Hernandez, an assistant professor with the Department of Bioengineering and Therapeutic Sciences of UCSF, led the study with Molly Przeworski, PhD, a professor with the Departments of Human Genetics and Ecology and Evolution at the University of Chicago. The two were joined in analyzing data from the 1000 Genomes Project by additional scientists from the University of Chicago, from Hebrew University, in Israel, and from the University of Oxford, in England.