Just over 20 years ago, the first study using mitochondrial DNA (mtDNA) to trace prehistoric human migrations was published. In this seminal study, scientists managed to determine that all humans alive today can trace their maternal ancestry back to one woman who lived about 200,000 years ago in Africa. The findings were revolutionary, and the idea that we could use genetics as a new tool to examine human prehistory was staggering.

One of the main reasons mtDNA was originally used was that it is passed down relatively intact, from mother to children, without recombining with any other bit of the human genome. And even more importantly, there was a small section of the mtDNA that did not code for any genes and was thus unaffected by natural selection. Any changes in this bit of mtDNA over time had to be caused by random mutations, which were believed to occur at a regular, clock-like rate. By counting and analyzing the mutations distinguishing any two individuals – or any two groups of people – scientists reasoned they could discover when their most recent maternal ancestor lived.

But there were a few problems with this idea. First, the small section of mtDNA scientists were analyzing, known as the Hyper-Variable Region (HVR), represents only about 2.5% of the entire mitochondrial genome. Some scientists argued that analyzing the genome in full would yield more accurate information about our past. Second, the idea that the mutations in our mtDNA accumulate like clockwork has been questioned continually. Just last year, 23andMe scientists reported that the mtDNA mutation rate may have been accelerating since the end of the Last Ice Age about 15,000 years ago, when human populations around the world began to grow and diversify at much faster rates. It soon seemed that many of the time estimates scientists had been calculating for years had been less accurate than previously thought.

So geneticists at the University of Leeds took decided to create a new method of calculation based on the best possible evidence. In the June 12 issue of the American Journal of Human Genetics, the team led by Pablo Soares and Martin Richards describes how they developed a way to estimate the maternal ancestry of the world’s people that is more accurate and precise.

The revised method used by these geneticists centered around the idea of natural selection. Up to now natural selection had not played a major role in calculating time estimates, mainly because scientists only used the HVR to make these calculations, which was thought to be immune from natural selection. Natural selection, an evolutionary force first described by Charles Darwin, gradually removes harmful genetic mutations and does appear to act on much of the mitochondrial genome. Failing to account for this evolutuionary force, according to Soares, has led to inaccurate and imprecise time estimates. “What we’ve done is work out a formula that corrects this effect,” says Soares. Using this newly developed mathematical formula, “we can [now] date any migration for which we have the available data.”

After developing this formula, Soares and his colleagues set about to test current theories on prehistoric human migrations patterns by comparing previous time estimates to those calculated using their new and improved formula. The results have already cleared up some problems with the previous estimates. Using their formula to calculate the time when humans first made their away across the Bering Strait to the Americas, they came up with a date of about 15,000 years, a full 2,000 years later than previous estimates. This new estimate can put to rest a longstanding discrepancy between genetic data and the archaeological record.

According to Richards, “We can settle the debate regarding mankind’s expansion through the Americas. Researchers have been estimating dates from mtDNA that are too old for the archaeological evidence, but our calculations confirm the date to be some 15,000 years ago, around the time of the first unequivocal archaeological remains.”

The 23andMe Maternal Line feature already puts that event at 15,000 years ago, because our scientists rely on both archaeological and genetic evidence when estimating the dates of past events.

Soares and colleagues found similar differences when recalculating the time estimates of other important prehistoric migration events, like the peopling of Polynesia just a few thousand years ago and the earliest migration of modern humans out of Africa nearly 70,000 years ago. But if anything, these corrections bolster the use of mtDNA in dating prehistoric events. Contrary to what some scientists have long feared, this study reveals that the principle underlying the technique was always sound; it was the specific method scientists used to analyze mtDNA that required a bit of fine-tuning.

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How can geneticists tell when a genetic difference between two human populations is an accident and when it’s the result of natural selection?

As our species moved out of Africa and spread out across the globe, there were a lot of chances for random DNA mutations to occur.  Many of these were neutral – they didn’t help or hurt a person’s chances for survival or reproduction – and whether they stuck around in a population’s gene pool was just a matter of luck. But some of these mutations actually helped people deal with the environmental changes and challenges they were facing.  These advantageous mutations tended to build up in frequency over the generations as they enhanced the reproductive success of the people who inherited them.

In some cases, there’s a satisfyingly simple story that demonstrates how a random mutation led to an advantage.  The version of the lactase gene that confers lactose tolerance, for example, is much more common in people of European ancestry than those with African or Asian ancestry.  This fits with the fact that about 8,000 years ago some of the world’s first dairy farmers emerged in – you guessed it – Europe.  For these people, the ability to digest milk would clearly have been a boon.

But some genetic differences between populations haven’t been so straightforward to explain. For example, one version of a variation in the p53 gene is found at higher levels in people with European ancestry than in those with African ancestry.  Is this just a matter of chance, or was there a reason this version of the gene increased in frequency as people moved north?

The best guess scientists have had so far is that the genetic difference has something to do with latitude and, by extension, exposure to UV radiation from the sun.  It’s certainly a plausible explanation.  The p53 gene helps protect cells from cancer, and UV radiation is known to be mutagenic.  But almost any difference between European and African populations would correlate with latitude, so that doesn’t prove anything.

In a study published online last week in the American Journal of Human Genetics, a group of researchers analyzed this p53 variation in Asian populations that are closely related genetically (at least compared to European vs. African populations), but nonetheless live at very different latitudes.  Their results were somewhat surprising.  The p53 variation does vary with latitude, but it’s not correlated with UV radiation level.  Instead, it’s how cold it gets in the winter that seems to matter.

Researchers analyzed rs1042522 in 4,029 people from 67 populations located throughout eastern Asia, from 11° south of the equator (Indonesia) to 65° north (northern China). They found that the C version of this SNP is more common at higher latitudes, as was expected based on the work in European and African populations.

The amount of UV radiation a locale receives, however, showed no correlation with the frequency of the C version of the SNP.  Instead, it was chillier winter temperatures that seemed to translate into more people in the population having the C version of rs1042522.

But why would the C version of rs1042522 be advantageous in colder climates?  Like so many genetic adaptations, it may all come down to making babies.

Using previous research about p53 as their guide, the authors of the study tested the ability of different forms of the p53 gene – containing either a C or a G at rs1042522 – to activate LIF, a gene important for embryo implantation in the womb, at different temperatures.

The results of these experiments indicate that the C version of the p53 gene is better at activating LIF in the cold.  This suggests that as populations moved into colder climates, those people with the C version of rs1042522 might have had an easier time conceiving (and therefore would have left behind more offspring, who in turn would pass the C version of the SNP on to their children).

But can a colder climate really bring down conception rates?  The parents of “blizzard babies” might disagree, but the authors point out that in cattle at least, cold temperatures have been shown to have an effect.

Bonus:
The researchers also looked at rs2279744, a variation in the MDM2 gene that (like rs1042522 in p53) is found at different frequencies in different populations.  The MDM2 variation did not vary with latitude or temperature, but did correlate with UV radiation levels.  Populations with higher UV radiation exposures had higher frequencies of the G version of rs2279744.

The MDM2 gene encodes a protein that reduces cellular levels of the p53 tumor suppressor protein. The G version of rs2279744 leads to higher levels of MDM2 protein, and thus lowers levels of p53.  The researchers speculate that as people moved out of Africa and into Asia, the lower levels of DNA-damaging UV light meant they could afford to have less p53 in their cells.  Because lower p53 levels are better for embryonic development, the scientists think nature would have favored the G version of rs2279744.

Bonus Bonus:
Do p53 and MDM2 sound familiar?  Last week the Spittoon covered recent reports linking rs1042522 to colorectal cancer survival in African Americans and rs2279744 in MDM2 to melanoma risk in young women.

Map of rs1042522 frequencies is from the HGDP Selection Browser.

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Before efforts to sequence the human genome began, scientists thought they’d find about 100,000 protein coding genes in the three billion bases pairs of DNA that are found in almost every cell. But much to everyone’s surprise, the true number turned out to be much lower. It’s now thought that the human genome contains only about 20,000 protein-coding genes, representing less than 2% of the contents of the genome.

Much of the remaining 98% of the genome remains a mystery. Some chunks of this DNA are referred to as “ultraconserved elements” because they have remained practically unchanged through hundreds of millions of years of evolution in many species.

It is a basic principle of biology that if something goes unchanged for that long, it ought to be good for something. Yet the function of ultraconserved elements is completely unknown. In fact, laboratory studies in mice have shown that the animals do just fine when some of the ultraconserved elements are deleted.

To find out if ultraconserved elements really are dispensable, Cory McLean and Gill Bejerano of Stanford University analyzed ultraconserved elements and non-conserved DNA sequences in five mammalian genomes.

Their results, published online today in Genome Research, show that regions of DNA that are identical or very similar between humans, macaques, and dogs are about 300 times less likely to be missing in rats and mice than regions that are not as closely conserved between the primate and dog species.

It’s not that ultraconserved regions are somehow protected from change. The researchers suggest that in the wild, mutations in these elements put affected animals at a disadvantage, causing the changes to be swept away over time by natural selection. But in the lab there isn’t a whole lot of natural selection — in an environment where mice are treated to filtered air, an absence of predators, and all the food and water they could ever want, any loss of fitness due to lost ultraconserved elements doesn’t seem to have any observable consequences.

McLean and Bejerano also found that DNA sequences that can be traced farther back in evolutionary time are more likely to be conserved in diverse species today.

“The longer the sequence has been in us, the less likely it is to be lost. It’s almost like the bricks in the foundation of a building, which hold up the rest of the structure,” said Bejerano in a statement.

Detailed new genome sequences from a variety of mammals will allow Bejerano’s research team to further analyze ultraconserved elements and perhaps ultimately understand what it is they are doing in the genome.

“Evolution is a lot of fun,” said Bejerano. “You answer one question, and five others pop up. But one of the most rewarding things to me is the fact that we’re developing a growing appreciation for how much these regions actually matter.”

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