New evidence casts doubt on the theory that sabre-toothed cats, mammoths and other big North American mammals were driven to extinction by human hunting.
The human hunting theory has been left out in the cold
Genetic analysis of bison remains shows their populations started to crash around 37,000 years ago - long before humans arrived in the New World.
Researchers claim that climate change and other factors are more likely culprits in the extinction.
An international team has published its findings in Science magazine.
Until as recently as 20,000 years ago, North America had a range of large mammals to rival the wildlife of present-day Africa.
The continent was home to woolly mammoth and mastodon, horses, camels, giant ground sloths and bear-sized beavers, as well as sabre-tooths.
By about 10,000 years ago, most of these animals were gone. Some 70 North American species disappeared - three-quarters of them large mammals.
This so-called "megafaunal extinction" has been blamed by some on human hunters who appear in North America around 12,000 years ago.
But the latest research seriously questions this hypothesis. Scientists extracted mitochondrial DNA from 442 bison remains found in the US, including Alaska; and in Canada, Siberia and China.
Mitochondrial DNA comes from the cell's "power houses" and is inherited through the maternal line only.
Some of the best-preserved material used in the study was unearthed from beneath the Alaskan permafrost by gold miners, some of whom even kept the remains refrigerated until the scientists came to claim them.
Scientists stand a much better chance of extracting useful DNA sequences from such frozen remains.
From this ancient genetic material, Alan Cooper at the University of Oxford, UK, and colleagues were able to reconstruct a genetic history of bison over a period of around 150,000 years.
Co-author Dr Beth Shapiro, also at Oxford, told the BBC News website: "When people try to reconstruct processes that happened in the past, they devise models based on the genetics of modern populations and extrapolate backwards in time.
The DNA came from over 400 remains, recent and ancient
"But because we have ancient DNA from the specimens, we can actually look at slices of time and see what the genetic diversity of that population was."
Using mathematical analysis, the researchers were able to extract information about bison population size through time.
During the late Pleistocene and Holocene Epochs, bison roamed across a territory called Beringia, an ice-free refuge that stretched from eastern Siberia to the north-west of Canada.
Until around 37,000 years ago, there was a large, diverse population living in Beringia. But after this date, the population's genetic diversity began to decline dramatically.
The fall in numbers coincides with a warm period in which the steppe tundra that bison like was covered by forests. These forests may have acted as a barrier to bison dispersal and would have provided few sources of food.
This warm period was followed by cold, arid conditions.
America was once home to giant ground sloths
"Some component of these ecological changes may have been sufficient to stress bison populations across Beringia," the researchers write in their research paper.
But John Alroy, a palaeobiologist at the University of California, Santa Barbara, told Science: "I think the interpretation is overblown and not supported by the data."
He points out that, in other areas, bison have managed to shrug off dramatic shifts in climate.
The results show that modern bison are distinct from ancient Beringian bison. They are descended from bison that spread southward through an ice-free corridor from Beringia perhaps as early as 100,000 years ago.